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(Journal of Leukocyte Biology. 2001;70:478-490.)
© 2001 by Society for Leukocyte Biology

Microenvironmental influence on macrophage regulation of angiogenesis in wounds and malignant tumors

M. Crowther*, N. J. Brown{dagger}, E. T. Bishop{ddagger} and C. E. Lewis*

* Tumor Targeting Group, Section of Oncology & Pathology, Division of Genomic Medicine, and
{dagger} Microcirculation Unit, Surgical & Anaesthetic Sciences, Division of Clinical Sciences, University of Sheffield Medical School, Sheffield S10 2RX, and
{ddagger} Medisys PLC, Cell Pathology Unit, University of Aberdeen, Aberdeen AB24 5UA, United Kingdom

Correspondence: Professor Claire Lewis, Tumor Targeting Group, Section of Oncology & Pathology, Division of Genomic Medicine, University of Sheffield Medical School, Beech Hill Road, Sheffield S10, United Kingdom. E-mail: claire.lewis{at}sheffield.ac.uk


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ABSTRACT
 
Angiogenesis is the development of blood vessels from an existing vasculature. This process is fundamental to both physiological wound healing and the growth of malignant tumors, as it restores or creates a blood supply to growing tissue. In both cases, the release of angiogenic molecules by macrophages recruited to the wound or tumor site is central to the formation of these neovessels. Reduced vascular perfusion in tissues generates tissue ischemia and a marked reduction in local levels of oxygen (hypoxia) and glucose. Cells adapt by switching to anaerobic metabolic pathways, with a concomitant increase in lactate production and reduction in extracellular pH. In tumors, these microenvironmental "stress" factors stimulate tumor cells to secrete a wide array of proangiogenic cytokines and enzymes, promoting the re-establishment of a local vascular supply. Here we review the evidence that these stress factors, in particular hypoxia and high lactate levels, stimulate macrophages to perform similar proangiogenic functions in both tumors and wounds. The resolution of wounds results in restoration of tissue integrity and perfusion, and macrophage presence is reduced to preinjury levels. However, in tumors a high number of macrophages persists and might contribute to the ongoing growth, neovascularization, and metastasis of malignant cells.

Key Words: wound healing • VEGF • hypoxia


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INTRODUCTION
 
Angiogenesis is the development of new blood vessels from an existing vascular bed [1 ]. This process involves the migration, proliferation, and differentiation of vascular endothelial cells, resulting in tubule formation [2 ]. Vessel maturation is then completed by apoptosis of endothelial cells, secretion of a basement membrane, recruitment of accessory cells, and deposition of extracellular matrix (ECM). Together, these provide morphological and phenotypic stabilization of the neovessels [3 , 4 ]. The primary function of angiogenesis is to provide a blood supply to reverse tissue ischemia (poor vascular perfusion) and the resultant hypoxia (low oxygen), nutrient deprivation, and accumulation of metabolic waste products [5 ]. Angiogenesis differs from vasculogenesis, the formation of blood vessels from mesodermal angioblasts in the developing embryo [6 ]. Angiogenesis occurs during embryonic morphogenesis [7 ] but not usually in healthy adult tissue, with the exceptions of cycling ovaries and the endometrium [8 ] and wound healing [9 ]. The presence of excessive angiogenesis is usually associated with such pathological conditions as diabetic retinopathy [10 ], rheumatoid arthritis [11 ], psoriasis [12 ], and malignant tumors [13 ].

In wound healing, angiogenesis serves to restore vascular perfusion to damaged tissues [9 ] and to facilitate the ingress of inflammatory leukocytes such as neutrophils and macrophages, which are integral to the healing process. In pathological states, angiogenesis is often central to disease progression. Indeed, diabetic retinopathy, rheumatoid arthritis, and psoriasis have been described as "angiogenesis-dependent" diseases [14 ]. The generation of neovessels in diabetic retinopathy represents an undesirable but predictable physiological reaction to the presence of retinal ischemia. However, angiogenesis in psoriatic skin or the inflamed synovium of rheumatoid arthritis is more difficult to explain. Certainly, hypoxia is present in both diseases [15 ], partly due to the metabolic activity of the increased inflammatory cell exudate in such affected areas. This causes the levels of oxygen, glucose, and other cellular nutrients to decrease, inducing compensatory angiogenesis. The pathobiology of these two diseases, including the role of multiple factors in the promotion of angiogenesis, is reviewed in detail elsewhere [11 , 16 , 17 ].

Perhaps the most widely studied angiogenesis-dependent disease is the growth of malignant tumors. A developing tumor reaches a threshold size of around 1–2mm3, beyond which exchange of oxygen, nutrients, and waste products with surrounding tissues by diffusion is insufficient to maintain cellular viability [18 ]. This results in the development of a central area which is hypoxic and hypoglycemic, and where cell death is extensive. To grow further, the tumor needs to stimulate the formation of its own vasculature to overcome the detrimental effects of these cellular stresses [19 ].

This is controlled mainly by factors released from local cells in the tissue microenvironment, which activate the various endothelial cell functions required for angiogenesis. For example, vascular endothelial growth factor (VEGF) was first characterized as a potent endothelial cell-specific mitogen [20 ]. However, it is now known to be one of a family of related molecules, all of which promote neovessel formation during both vasculogenesis and angiogenesis [21 ] and act as survival factors for endothelium [22 ]. Other important angiogenic agents include basic fibroblast growth factor (bFGF), tumor necrosis factor (TNF) {alpha}, thymidine phosphorylase, and interleukin (IL) 4. It is important to recognize, however, that angiogenesis is more than a simple response to growth factors. Rather, it results from an intricate and complex local balance of pro- and antiangiogenic agents [23 ], whose expression might vary between neighboring microenvironments. Important examples of naturally occurring angiogenesis inhibitors include angiostatin [24 ], thrombospondin (TSP)-1, endostatin [25 ], and fibrinogen E fragment [26 ].

Other factors involved in the regulation of angiogenesis include components of the ECM, which acts as a mechanical regulator of cell phenotype. For example, endothelial cells might adopt a proliferative or differentiating phenotype according to the specific components present in neighboring ECM [27 ]. Agents that modify the ECM, such as proteases, might influence angiogenesis by altering these cell-matrix interactions. The release of matrix metalloproteases (MMPs) and plasmin by local macrophages might have profound effects on the formation of new vasculature as the ECM and hence cell-matrix interactions are modified. Moreover, both proangiogenic and antiangiogenic factors have been shown to be sequestered within the intact ECM, and proteolytic modification of this matrix might release such factors into the pericellular space. bFGF, VEGF, and transforming growth factor (TGF) ß are examples of cytokines stored in this way [28 ], as they bind to heparan sulfate proteoglycans. Modification of the ECM also yields fragments of constituent proteins, which have potent effects on the angiogenic process. The most clearly defined example of this phenomenon is the proteolytic release of the angiogenesis inhibitor endostatin, a proteolytic fragment of collagen XVIII [25 ]. Other factors that indirectly influence angiogenesis include granulocyte-macrophage colony-stimulating factor, a product of many tumors and a potent chemoattractant for macrophages [29 , 30 ]. Similarly, IL-8 is released by macrophages under hypoxic conditions and attracts monocytes and other leukocytes to sites of inflammation [31 ].

The vast number of factors now known to be capable of regulating angiogenesis illustrates the complexity of the cytokine and enzyme milieu involved in maintaining a quiescent vasculature in normal tissues. Manipulation of the angiogenic process shows promise in the development of novel strategies for the treatment of disease [32 ]. For example, promotion of angiogenesis might be used to clinical advantage to restore tissue oxygenation in diseased tissues such as the ischemic limbs of diabetic patients and the ischemic myocardium [33 ].


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RELEASE OF ANGIOGENIC STIMULI BY MACROPHAGES
 
Recent evidence suggests that macrophages play an important role in the regulation of angiogenesis in both normal and diseased tissues [34 ] (Table 1 ). These cells are derived from blood monocytes that enter tissues by adherence to vascular endothelium via the interaction of ligands such as lymphocyte function-associated molecule (LFA)-1 on monocytes and intercellular adhesion molecule 1 (ICAM-1) on endothelial cells [35 ]. E- and P-selectin are up-regulated on endothelial cells in tumors and healing wounds by the local production of the cytokines IL-1ß, TNF-{alpha}, and interferon (IFN) {gamma} [36 37 38 39 ]. After extravasation, monocytes undergo differentiation into macrophages and remain resident in tissues for 30–90 days before dying or emigrating to local lymph nodes [40 ].


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  		Table 1. Comparison of the Expression of Angiogenic Factors by Macrophages in Wounds and Malignant Tumors: The Current State of Play

Macrophages express various phenotypes depending on the balance of local, tissue-specific signals. For example, resident tissue macrophages such as alveolar macrophages (lung), Küppfer cells (liver), Langerhans cells (skin), and dendritic cells (lymph nodes) not only perform phagocytosis and antigen processing/presentation but also release a tissue-specific combination of 1 or more of the 150 proteins in their secretory repertoire [40 , 41 ]. Further specialization and activation of macrophages is also prompted by local stimuli produced during pathological processes such as the presence of cytokines, adhesion molecule binding, or interaction with foreign/infectious agents. Recently, Paulnock et al. demonstrated differential gene expression during IFN-{gamma}-dependent and -independent activation of macrophages [42 ], illustrating the potential for a diversity of macrophage phenotypes. It is hardly surprising, therefore, that macrophages are capable of releasing a wide range of molecules, including cytokines, complement components, reactive oxygen species, proteases, inhibitors, and growth factors, depending on their activation status. When stimulated, macrophages secrete an array of angiogenic cytokines and growth factors [43 ], along with an array of proteolytic enzymes [44 ], illustrated in a recent paper by Moldovan et al. [45 ] which suggested that macrophages might play a role in myocardial revascularization by "digging" channels that become invested with endothelial cells to form capillaries. When the net release of proangiogenic factors outweighs the local production of angiogenesis inhibitors, the angiogenic pathway is stimulated.

Activated macrophages have been shown to accumulate during angiogenesis in the corpus luteum of the postovulatory ovary and the endometrial lining of the womb [8 , 46 ]. They are also recruited to wounds (and other sites of tissue damage), primarily to phagocytose/destroy infectious agents and fragments of ECM, and to revascularize the area. Macrophages are also found in large numbers in malignant human and murine tumors, where they are often termed tumor-associated macrophages (TAMs). Recent studies have shown TAMs to be an important source of angiogenic factors [47 ] (Table 1) . This could explain, in part, why elevated levels of TAMs have been found to correlate with increased tumor angiogenesis in breast cancer [48 ]. Further evidence of a significant role for TAMs in tumor angiogenesis has been provided by studies on endometrial carcinoma [48 ], pulmonary adenocarcinoma [49 ], and malignant melanoma [50 ].

In this review we compare the proangiogenic functions performed by macrophages in two well-characterized, angiogenesis-dependent tissues: healing wounds and malignant tumors. We also review recent evidence for the role of hypoxia and other microenvironmental "stress" factors present in poorly vascularized areas of tissues, such as low pH, low glucose levels, and high lactate levels, in the regulation of macrophage function.


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MACROPHAGES IN WOUND ANGIOGENESIS
 
Although a large body of literature exists on the cellular events occurring in wound healing, most data have been based on animal models or on cells from human wound fluid rather than on monitoring of the development of human wound tissue per se. From these studies, wound healing has been described as a complex process involving three main phases: inflammation, proliferation, and remodelling [9 ]. Much of the research carried out on healing wounds has studied cutaneous damage, so the following summary outlines this repair process. However, it is equally relevant to tissues in which a similar fibrotic response occurs.

The initial, inflammatory phase of murine cutaneous wounds involves initiation of clotting and the complement cascade, and degranulation of platelets, which mediates the influx of leukocytes and the formation of a provisional fibrin matrix. Neutrophil influx peaks at 1–2 days postwounding [51 ], followed by macrophage infiltration, which peaks between 2 and 4 days. During this time, macrophages are attracted to wounds by gradients of cellular and ECM debris emanating from the wound and by neutrophil-derived chemotactic signals [52 ]. Working together, neutrophils and macrophages remove debris by phagocytosis and secrete chemotactic factors to attract fibroblasts, lymphocytes, and endothelial cells into the wound. These cell types are the major cellular constituents of mature wounds, peaking at ~7 days, and participate in the synthesis of new matrix and development of blood vessels during the proliferation phase of epithelial cell expansion, reinstating tissue architecture and restoring perfusion. Finally, the remodelling phase involves regression of neovessels and proteolytic modification of collagen matrix to improve mechanical strength and adhesion.

By day 2, macrophages are the predominant leukocyte in the wound space, and they persist through to the remodelling phase. They appear to perform a number of important functions in wounds. Leibovich and Ross [53 ] have demonstrated that depletion of tissue macrophages and circulating monocytes in a guinea pig model of injury results in reductions in both wound debridement and the ability of the wound to recruit fibroblasts and promote fibrosis. Wound angiogenesis was not addressed in this study, although it has recently been demonstrated that macrophages in aged mice produce significantly less VEGF than those in young mice, which results in reduced angiogenesis and slower wound repair, thereby indicating an important role for macrophages in mediating angiogenesis in wound healing. In contrast, depletion of neutrophils has no discernible effect on the process of tissue repair, although the lack of a rapid phagocytic response to contaminating bacteria might result in persistence of infection at the wound site [54 ].

Some of the earliest studies demonstrating the angiogenic activity of wound macrophages examined cells isolated from wound fluid [55 , 56 ]. Injection of these macrophages into rat corneas induces neovessel formation. Furthermore, culture supernatants from thioglycollate-induced guinea pig peritoneal macrophages have been found to be proangiogenic in a similar corneal model of angiogenesis [57 ]. Table 1 summarizes the evidence for expression of VEGF and other angiogenesis-modulating factors by wound macrophages.

Various studies have shown that wound macrophages, but not unstimulated monocytes or macrophages, are capable of inducing angiogenesis [58 ]. For example, corneal angiogenesis is accelerated only when autologous wound macrophages are used [59 ]. Similarly, adding macrophages isolated from a 3-week-old wound to a rabbit ear chamber model of wounding produces significant acceleration of angiogenesis [55 ]. These studies suggest that activation of macrophages by wound-specific microenvironmental factors is essential for their proangiogenic activity in such tissues.

The extremely low oxygen tensions (hypoxia) in areas of wounds appear to be one such wound signal (Fig. 1 ). Hypoxia occurs in early wounds due to lack of perfusion caused by damage to the vasculature and the intense metabolic activity of cells infiltrating the wound. However, it is apparent that hypoxia is not the initial driving force behind macrophage infiltration of wound tissue, since wounds have been shown to be normoxic immediately after injury [60 ]. Measurement of oxygen tensions in wound tissue has revealed both the temporal pattern of hypoxia and the extent of oxygen deprivation. Oxygen levels decrease over the first and second days postinjury, and oxygen tensions as low as 20–30 mm Hg on the first day, which steadily decreased to reach a minimum of 5–7 mm Hg by days 5–7 postinjury, have been reported in a rodent wound chamber model [61 ]. In extended studies using subcutaneous sponge-induced granulation tissue in rats, tissue oxygen tension has been shown to decrease from 28 to 22 mm Hg between days 7 and 14 postinjury [62 ]. These studies suggest a temporal pattern of hypoxia in wounds, with infiltration of the damaged tissue by macrophages and development of granulation tissue and neovessels occurring as oxygen tensions progressively fall.



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  		Figure 1. Comparison of the oxygen levels [pO2 (mmHg)] in (A) an experimental rat wound and (B) a human breast carcinoma. The left panel shows the rapid drop in mean (±SE) pO2 measurements (down to 5–10 mmHg) in wounds that occurs immediately after wounding, followed by a gradual increase in oxygen levels as revascularization ensues and the wound heals. The right panel illustrates pooled pO2 measurements taken at various sites in a number of normal and malignant human breast tissues. A greater proportion of these recorded extremely low oxygen tensions (i.e., pO2 0–20 mmHg) in malignant than normal tissues. [Adapted (with permission) from ref. 61 and 140.]

Initiation of wound angiogenesis and subsequent tissue reoxygenation are hallmark features of successful wound healing. In a study on colonic anastomosis in rabbits, a persistent tissue pO2 of <20 mm Hg at 10 days postsurgery was associated with a high rate of vascular leakage and poor wound healing, whereas successful operations recorded pO2 levels gradually increasing to that in normal tissues, >55 mm Hg [63 ]. In a similar study on rabbit aortic anastomosis, oxygen tension in the aortic media decreased to 17 mm Hg at day 2 postoperation, continued to fall until day 14, and then increased to reach normoxic levels, associated with complete tissue repair, 6 weeks after injury [64 ]. Haroon et al. have proposed that the normoxia observed immediately postwounding occurs due to diffusion of ambient oxygen through the disrupted epithelial barrier into the wound site; this continues until it is prevented by the formation of a thrombus and provisional fibrin matrix [60 ], after which the disrupted vasculature and cellular demand for oxygen result in increasing hypoxia.

Exposure of cells in wounds to hypoxia is essential for promoting angiogenesis in wound healing. Support for this hypothesis has been provided by studies in which wound angiogenesis is markedly reduced when the oxygen tension gradient from the center to the periphery of the wound is abolished [65 ]. Although there is now clear evidence for hypoxic regulation of the proangiogenic activity of macrophages in vitro (Table 2 ), there have been no studies investigating whether hypoxia is required for macrophage-mediated angiogenesis in wounds. A recent histological study investigating the expression of the transcription factor hypoxia-inducible factor (HIF) 1 in mouse dermal wound tissue has revealed that HIF-1 is expressed in reepithelializing keratinocytes but not in wound macrophages, even though the latter appear to produce abundant VEGF [66 ]. This is consistent either with macrophages producing such angiogenic factors in the absence of hypoxia or with VEGF being secreted in response to hypoxia via a HIF-1-independent pathway of gene induction. However, studies in our laboratories have demonstrated expression of HIF-1 by macrophages in human dermal scar tissue (Fig. 2 ), suggesting a role for hypoxia-regulated control of gene expression in wound healing. The roles of HIF-1 and other transcription factors in mediating the effects of hypoxia on the expression of various genes in macrophages are discussed below.


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  		Table 2. Effects of Hypoxia on the Production of Proangiogenic and Antiangiogenic Factors by Macrophages



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  		Figure 2. Photomicrographs illustrating the expression of HIF-1 by macrophages in a human dermal wound, 2 weeks postinjury (A, B) and an ovarian carcinoma (C, D). Macrophages (A, C) are highlighted in red and were stained using a monoclonal anti-human CD68 coupled to an alkaline phosphatase/Fast Red staining method, and HIF-1 (B, D) is highlighted in brown and was stained using a monoclonal anti-human HIF-1{alpha} coupled to a peroxidase/DAB staining method. Scale bars, 50 µm.

Once new collagen matrix has been deposited in the wound space and formation of a fibrotic scar has begun, the cellularity of the wound is reduced. Little evidence for the induction of this process exists, but the reduced demands on oxygen supply might lead to regression of the neovessels by endothelial cell apoptosis. It has been suggested that macrophages might switch to secreting antiangiogenic factors at this time, although there is no documented evidence for this phenomenon. However, it is known that macrophages are capable of producing TSP [67 ] and ELR- CXC chemokines such as platelet factor-4 [68 ] in response to IFNs. These chemokines, which are associated with the inhibition of angiogenesis, have been correlated with diminished endothelial cell proliferation in wounds [68 , 69 ]. This reduction in angiogenic activity in resolving wounds might suggest that promotion of neovessel formation by wound macrophages depends on the presence of such ischemia-linked factors as hypoxia, which is reduced as vascular perfusion/normoxia is restored.

Other microenvironmental stress factors are also present in wounds. These include high lactate concentrations and low pH, which could affect the phenotype and secretory profile of macrophages and other wound cells (Table 3 ). These conditions arise through reduced perfusion, resulting in a switch to anaerobic metabolism in the ischemic tissue and the subsequent accumulation of lactate, with associated tissue acidosis. Lactate has been shown to increase the release of proangiogenic factors by the murine macrophage cell line RAW264.7 [70 ]. The stimulatory activity of medium conditioned by these cells was blocked by the addition of a neutralizing anti-VEGF antibody, suggesting that it was due to lactate-induced VEGF released by these cells. Indeed, lactate has recently been shown to increase VEGF production and expression in human primary macrophages [71 ].


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  		Table 3. Comparison of the Levels of pH, Glucose, and Lactate in Normal Tissue, Wounds, and Tumors

The influence of pH on macrophage secretion is less well documented. Jensen et al. have shown that a wound-equivalent pH of 6.2 has no effect on the angiogenic activity of primary human macrophages [72 ]. Interestingly, Mraz et al. have reported that tissue acidosis is important for recruitment of macrophages to the wound site [73 ]. These data are specific to macrophages and cannot be repeated using human endothelial cells or fibroblasts. Glucose deprivation, which occurs in wounds due to reduced perfusion (ischemia), has been demonstrated to decrease the expression of TNF-{alpha} in hypoxic human cultured macrophages, whereas hypoxia alone increases expression [29 ]. Interestingly, Hunt et al. have speculated that the microenvironmental physiology of a wound might be important in the control of collagen production by wound fibroblasts [74 ].

In summary, it is apparent that while stress factors in general might influence the release of angiogenic factors from wound macrophages, only hypoxia has been directly linked to the control of VEGF production. No evidence is available for the role of lactate, hypoglycemia, or pH in this process. However, it should be noted that hypoglycemia has been shown to influence VEGF expression in other cell types. For example, Stein et al. have demonstrated the stabilizing effect of hypoglycemia on the VEGF transcript in glioma cells [75 ] and have also shown coregulation of VEGF with other ischemia-induced genes such as the glucose transporter, GLUT-1. Furthermore, D’Arcangelo et al. have shown that acidosis increases expression of both VEGF and bFGF in endothelial cells and inhibits their apoptotic death [76 ]. Interestingly, a study on a range of breast carcinoma cell lines has demonstrated that VEGF expression responds differently to hypoxia and hypoglycemia, suggesting cell- or tissue-specific regulation of VEGF [77 ], and could in part explain why such regulation is not apparent in macrophages. It should again be stressed that much of the work performed on wound macrophages has used animal (i.e., nonhuman) models and that further research is needed to unambiguously define the effects of hypoxia and other stress factors on macrophage involvement in human wound angiogenesis. Recently, an in vitro model of angiogenesis has been described which accurately reflects many of the steps in the angiogenic pathway in vivo and could be used in this type of investigation [78 ].


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MACROPHAGES AND TUMOR ANGIOGENESIS
 
TAMs are recruited mainly from the circulating monocyte pool [79 , 80 ] rather than being co-opted from resident tissue macrophages [81 ]. There is great heterogeneity in the number of macrophages in individual tumors of a given type, and they can represent up to 80% of the total cell mass of tumors such as breast carcinoma [reviewed by us in reference 47]. Originally, it was thought that the main function of TAMs was to exert direct cytotoxic effects on tumor cells, phagocytose apoptotic/necrotic cell debris, and present tumor-associated antigens (when present) to T cells. However, several have recently suggested that these cells can also promote tumor growth and metastasis [82 ]. Indeed, we have shown that TAMs are an important source of epidermal growth factor, a potent tumor cell mitogen, in breast carcinomas [83 ] and that, in specific regions of human tumors, angiogenesis might be stimulated by up-regulation of a range of angiogenic factors [34 , 84 ]. Indeed, as early as 1984, Polverini and Leibovich [85 ] showed that TAMs isolated from rodent tumors are capable of stimulating endothelial cell proliferation in vitro and inducing corneal angiogenesis in a syngeneic rodent model.

TAMs are now known to be an important source of proangiogenic factors such as VEGF [86 ], TNF-{alpha} [87 ], IL-8 [88 ], and bFGF [89 ]. VEGF and bFGF stimulate endothelial cell proliferation and migration [90 ], in addition to differentiation in vitro [91 ]. Angiogenesis is also facilitated by TAM-derived proteases released in tumors. These include MMPs 1, 2, 3, 9, and 12, and urokinase plasminogen activator, its receptor [47 , 92 ], and plasmin. These enzymes release various proangiogenic molecules bound to heparan sulfates in proteoglycans, as well as fragments of fibrin and collagen [93 ]. Their combined action results in the degradation of the basement membrane and other ECM components, destabilizing the local vasculature and permitting the migration and proliferation of endothelial cells. This proteolytic activity also contributes to the migration and extravasation of tumor cells during the metastatic process [94 ].

TAMs produce IL-8, a CXC chemokine, which, like VEGF, binds to heparin in the ECM and has been shown to stimulate the proliferation and migration of endothelial cells in vitro [95 ] and angiogenesis in rat corneas in vivo [96 ]. Interestingly TAM-derived cytokines can act indirectly on angiogenesis by stimulating TAM activity in an autocrine manner. For example, VEGF and TNF-{alpha} released by TAMs stimulate the release of tissue-type plasminogen activator and urokinase plasminogen activator [97 , 98 ].

Recruitment of new blood vessels is a two-stage process in malignant tumors. The first stage involves tumor cell expression of an angiogenic phenotype, the so-called "angiogenic switch" [99 ]. This is caused by activation of various oncogenes and/or mutation of tumor suppressor genes in tumor cells, which collectively triggers the activation of a range of proangiogenic genes [99 ]. The second phase involves coupling the first phase of tumor cell-regulated angiogenesis to the costimulatory effects of various microenvironmental stress factors present in tumors (Table 3) . Several have shown hypoxia to be a potent stimulus for the release of angiogenic factors by tumor cells in vitro and in vivo [100 , 101 ]. The presence of hypoxic areas is a typical feature of malignant human tumors; for example, in breast carcinomas, polarographic microelectrodes have been used to measure multiple areas within each tumor, demonstrating a mean pO2 of <25 mm Hg, compared to a mean pO2 of 65 mm Hg in surrounding normal breast tissue. Moreover, neovessels in tumors often malfunction due to structural and functional abnormalities [102 ]. Tumor vessels are often immature, exhibiting tortuosity, blind ends, and increased permeability, resulting in spatial heterogeneity of blood supply both between and within individual tumors [103 ].

TAMs are also attracted into and/or immobilized in avascular [104 ] and necrotic hypoxic [105 ] areas of vascularized human tumors both by specific factors produced by hypoxic tumor cells and by the direct immobilizing effect of hypoxia on macrophages [106 ]. Moreover, higher numbers of TAMs are seen to extravasate from the bloodstream into tumors containing high levels of necrosis than into those with low or no necrosis [105 ]. This is an important phenomenon, as evidence has recently emerged to show that TAMs are stimulated by hypoxia in such sites to co-operate with tumor cells to promote revascularization [84 ]. The level of hypoxia present in ischemic areas of tumors stimulates the release of VEGF from human macrophages in vitro [107 ]. Moreover, TAMs up-regulate VEGF in avascular and necrotic areas of breast carcinomas [84 , 108 ]. However, the increased production of VEGF might also be due, in part, to the presence of other "stress factors" generated in areas of poor vascular supply. Figure 2 shows the expression of HIF-1 by macrophages in specific areas of human breast carcinoma.

Glucose consumption, like oxygen consumption, generally overwhelms supply due to the high metabolic activity of tumor cells and compromised delivery [109 ] (Table 3) . The corresponding accumulation of metabolic waste products, mainly lactic acid as originally described by Warburg [110 ], results in tissue acidosis, particularly in larger, rapidly growing tumors [111 ]. An interesting aspect of tumor pH is that the extracellular pH of tumors is often lower than that of normal tissue (~7.0 compared to ~7.5), whereas intracellular pH is often greater (~7.4 compared to 7.0) [112 ]. This reversal of the normal pH gradient leads to greater invasiveness of tumor cells in vitro, associated with enhanced proteolysis, for example, by increased MMP activation [113 ] and cell surface localization of the serine protease cathepsin B [114 ]. Although this might not affect macrophages directly, studies have shown that low extracellular pH affects the ability of macrophages to maintain their intracellular pH and hence impairs function [115 ]. Thus, various TAM functions might be reduced rather than augmented in the acidic microenvironment of a tumor. As described above, exposure to the low pH levels found in wound tissues has no effect on the angiogenic activity of macrophages [72 ], suggesting that this function of TAMs might not be altered by acidosis in tumors.

The effects of lactate on TAMs have not been studied directly, but inference from the preceding section might suggest that the release of angiogenic factors might be enhanced under high lactate conditions, which could contribute to tumor angiogenesis. Lactate has recently been shown to correlate with increasing metastatic activity and worsened prognosis in human head and neck cancers and cervical carcinoma [116 ]. These findings have not been associated with alteration of TAM function or angiogenesis, but they do illustrate that elevated microenvironmental lactate levels might influence tumor behavior.

In addition to their direct effects, hypoxia and/or other stress factors might also exert an indirect effect on the proangiogenic activity of TAMs. The release of cytokines/factors might be modulated, and they, in turn, recruit/stimulate TAMs in ischemic areas. For instance, tumor cells are known to produce large amounts of VEGF [34 ], which is a potent chemoattractant for macrophages [117 ] and is controlled by oxygen tension [118 ]. bFGF, another hypoxia-regulated cytokine, is also produced by tumor cells [34 ] and macrophages in vitro [119 ] and is strongly associated with angiogenesis in neoplasms [120 ]. It is also possible that activation of TAMs during extravasation across the tumor endothelium into the tumor [121 ], and/or during exposure to cytokines/signals within the tumor milieu, might modulate TAM susceptibility to stress factors.


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COMPARISON OF MACROPHAGE FUNCTION IN WOUNDS AND TUMORS
 
Macrophages present in wounds and tumors appear to play similar roles with regard to angiogenic function, with a remarkable similarity in the range of proangiogenic factors (cytokines and enzymes) produced in these two conditions. Indeed, Whalen [122 ] has postulated that TAMs "recognize" tumors as persistent, nonhealing wounds. He has suggested that tumor growth is analogous to wound repair, both of which involve the formation of new tissue and angiogenesis in response to local signals. We now know that at least two microenvironmental stress factors, hypoxia and lactate, common to both tissues, have the potential to evoke proangiogenic functions such as the release of VEGF by macrophages. So far, there is no evidence showing that other microenvironmental "stress factors" present in hypoxic areas of both tissues, i.e., reduced extracellular pH and reduced glucose levels, modulate these activities. However, further studies are now required to investigate their possible roles in this phenomenon.

Circumstantial evidence suggests that one difference between wounds and tumors might be the relative contribution of macrophages to the regulation of angiogenesis. In tumors, macrophages are only one source of angiogenic factors, the majority of which are derived from the tumor cell population and surrounding stroma (although this could vary with the angiogenic potential of the tumor cell population). We have recently demonstrated that on the rare occasions when tumor cells do not produce VEGF in breast carcinomas, TAMs represent the sole source of this important cytokine. By contrast, macrophages recruited to wounds appear to be the principal source of angiogenic factors, as well as mediating the influx of smooth muscle cells and fibroblasts. However, direct comparisons of the contributions of macrophages to angiogenesis are made almost impossible by the extreme complexity of these pathologies.

Another difference between the activities of macrophages in wound healing and tumors is their relative persistence at the target site. In wounds, macrophages remain present until debridement of debris is complete and perfusion and normoxia are restored. The repaired tissue then becomes less cellular, and fibrosis dominates. It is unclear how macrophages are removed from the wound site. They might undergo apoptosis or necrosis, enter the local vasculature, or migrate to a new site. By contrast, the heterogenous, dynamic nature of the vascular network in tumors produces areas of ischemia in which there are high concentrations of chemoattractive agents for TAMs. This causes TAMs to persist within tumors for several months, accumulating in these ischemic areas, where their angiogenic activity is most pronounced [84 , 104 ]. It might also reflect the presence of other, unknown tumor-specific factors which prevent the death or departure of TAMs from tumors via lymphatic vessels.

Of the various stress factors present in wounds and tumors, the effects of hypoxia on macrophage gene expression are becoming increasingly well characterized and have already been reviewed by us in depth [108 ]. The most germane of these are summarized briefly below. However, as many of these effects have been demonstrated in vitro, it remains to be seen whether any or all of these changes occur in macrophages in hypoxic areas of human wounds and tumors in vivo.


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MACROPHAGE RESPONSES TO STRESS FACTORS
 
Macrophages have the ability to adapt to unfavorable conditions such as hypoxia by altering their gene expression profile and metabolic activity. Adaptation to hypoxia initially involves a reduction in the use of aerobic pathways to generate energy and a switch to anaerobic, glycolytic mechanisms [123 ]. Hypoxia then induces the release of proinflammatory and proangiogenic factors. These effects are achieved via the enhanced transcription of individual genes and/or increased stability of associated mRNA transcripts and/or translated protein.

Some genes that are hypoxically up-regulated at the transcriptional level have been identified [124 , 125 ], but only one of these, VEGF, has been demonstrated to be controlled by oxygen tension in macrophages [118 ]. Increased transcription of VEGF is mediated by binding of the transcription factor HIF-1 to the hypoxia response element consensus sequence (5'-CTGT-3') in its promoter. HIF-1 is a heterodimer, consisting of an {alpha} and a ß subunit [126 ]. The mRNAs for these are constitutively expressed in the majority of cell types [127 ]. However, HIF-1 protein levels increase rapidly in cells exposed to hypoxia, suggesting a posttranslational mechanism of control [128 ]. Recent studies have shown that HIF-1{alpha} is rapidly degraded by a ubiquitin-proteasome pathway in normoxia [129 ]. This process is inhibited by hypoxia, which increases production, stabilization, and DNA binding of HIF-1{alpha} at oxygen concentrations of <2%, peaking at 0.5% [130 ].

HIF-1 is up-regulated in macrophages exposed to hypoxia, along with another form of HIF, HIF-2, which comprises HIF-1ß coupled to another subunit, HIF-2{alpha} (EPAS-1) [131 ]. HIF-2 has DNA binding/activation properties similar to those of HIF-1 [132 ]. Although HIF-2 has recently been identified as the major form of HIF produced by macrophages in solid tumors [133 ], we have now shown this to be incorrect, as HIF-1 is also produced by primary macrophages and macrophage cell lines in hypoxia in vitro, and in avascular areas of breast carcinomas [B. Burke, N. Tang, K. Corke, D. Tazzyman, K. Ameri, M. Wells, and C. E. Lewis, unpublished results]. A third form of the {alpha} subunit, HIF-3{alpha}, has recently been characterized [135 ], suggesting that a family of related transcription factors might exist. Up-regulation of this third form of HIF has yet to be identified in hypoxic macrophages.

Various HIF-independent oxygen-signaling mechanisms have also been described in macrophages. For example, the binding of activator protein 1, a complex of the c-fos and c-jun gene products, to its DNA motif within target gene promoters is markedly reduced when a cysteine residue within this domain is oxidized [136 ]. Similarly, expression of the transcription factor early growth response-1 is increased under hypoxic conditions in human monocytes and macrophages [137 ]. NF-{kappa}B is also known to be active in macrophages under hypoxic conditions [138 ].

Lactate is known to affect in vitro expression of angiogenic activity by macrophages [139 ]. However, the role of lactate in regulating specific angiogenic gene expression in these cells has not been studied in depth. Zabel et al. have postulated that enhanced production of NAD+ and poly(adenosine diphosphate-ribose) polymerase results in increased transcription of (unspecified) angiogenic factor genes, and Constant et al. have shown that VEGF expression is increased by this mechanism [71 ].

Recently, we have designed a novel gene therapy strategy that exploits these responses of macrophages to hypoxia to deliver therapeutic genes to hypoxic areas of tumors. This is important because these sites are notoriously unresponsive to conventional anticancer therapies. In this strategy, hypoxia-responsive elements from the promoter of oxygen-regulated genes are used to control the expression of a therapeutic gene inserted into macrophages. Once transfected, macrophages migrate into hypoxic areas of a given tumor mass and up-regulate their expression of the therapeutic gene [131 ]. We are currently using this method to target expression of novel antiangiogenic peptides [26 ] to hypoxic (i.e., the most highly angiogenic) areas of tumors.

This form of macrophage-mediated gene therapy could also be used to target high-level expression of proangiogenic factors specifically to ischemic tissues in wounds. The localized, hypoxia-induced expression of genes and chemoattractants produced by transfected macrophages could enhance granulation by enhancing fibroblast and endothelial cell infiltration into the wound. The tendency of macrophages to accumulate in hypoxic areas of atherosclerotic plaques, psoriatic skin, and the arthritic synovium [reviewed by us in ref. 108 ] has prompted the suggestion that this macrophage-based gene delivery system could also be used to deliver therapeutic genes to these tissues. Moreover, genes (and their protein products) expressed by hypoxic macrophages could represent targets for the development of new drugs for such diseases.


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CONCLUDING REMARKS
 
This review highlights similarities in the proangiogenic activities of macrophages in wounds and tumors, and indicates a common role for the microenvironmental stress factors, hypoxia and high lactate levels, in the onset and maintenance of these functions. It remains to be seen whether this phenomenon extends to other diseased tissues in which macrophages have also been seen to accumulate in areas of poor vascularity and tissue necrosis. Our rapidly increasing knowledge of macrophage responses to hypoxia in tumors might inform our understanding of wound healing and facilitate improved wound and burn management, antiscar strategies, and other facets of this important field. It has also led to the development of novel therapeutic approaches for cancer, which could have utility in other human diseases.


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ACKNOWLEDGEMENTS
 
We gratefully acknowledge the support of the UK Department of Trade & Industry (a Teaching Company grant), Medisys PLC, and the Breast Cancer Campaign.

Received April 1, 2001; revised June 12, 2001; accepted June 14, 2001.


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REFERENCES
 
    1
  1. Folkman, J., Shing, Y. (1992) Angiogenesis J. Biol. Chem. 267,10931-10934[Free Full Text]
    2. 2
  2. Risau, W. (1997) Mechanisms of angiogenesis Nature 386,671-674[Medline]
    3. 3
  3. Carmeliet, P. (2000) Mechanisms of angiogenesis and arteriogenesis Nat. Med. 6,389-395[Medline]
    4. 4
  4. Benjamin, L. E., Hemo, I., Keshet, E. (1998) A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF Development 125,1591-1598[Abstract]
    5. 5
  5. Rogers, P. A., Lederman, F., Taylor, N. (1998) Endometrial microvascular growth in normal and dysfunctional states Hum. Reprod. Update 4,503-508[Abstract/Free Full Text]
    6. 6
  6. Risau, W., Flamme, I. (1995) Vasculogenesis Annu. Rev. Cell Dev. Biol. 11,73-79[Medline]
    7. 7
  7. Risau, W. (1991) Embryonic angiogenesis factors Pharmacol. Ther. 51,371-376[Medline]
    8. 8
  8. Smith, S. K. (1998) Angiogenesis, vascular endothelial growth factor and the endometrium Hum. Reprod. Update 4,509-519[Abstract/Free Full Text]
    9. 9
  9. Wong, M. E., Hollinger, J. O., Pinero, G. J. (1996) Integrated processes responsible for soft tissue healing Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 82,475-492[Medline]
    10. 10
  10. Engerman, R. L. (1989) Pathogenesis of diabetic retinopathy Diabetes 38,1203-1206[Abstract]
    11. 11
  11. Szekanecz, Z., Szegedi, G., Koch, A. E. (1998) Angiogenesis in rheumatoid arthritis: pathogenic and clinical significance J. Invest. Med. 46,27-41[Medline]
    12. 12
  12. Creamer, J. D., Barker, J. N. (1995) Vascular proliferation and angiogenic factors in psoriasis Clin. Exp. Dermatol. 20,6-9[Medline]
    13. 13
  13. Folkman, J. (1992) The role of angiogenesis in tumor growth Semin. Cancer Biol. 3,65-71[Medline]
    14. 14
  14. Folkman, J. (1986) How is blood vessel growth regulated in normal and neoplastic tissue? G. H. A. Clowes Memorial Award Lecture Cancer Res. 46,467-473[Free Full Text]
    15. 15
  15. Claffey, K. P., Robinson, G. S. (1996) Regulation of VEGF/VPF expression in tumor cells: consequences for tumor growth and metastasis Cancer Metastasis Rev 15,165-176[Medline]
    16. 16
  16. Koch, A. E. (1998) Angiogenesis: implications for rheumatoid arthritis Arthritis Rheum 41,951-962[Medline]
    17. 17
  17. Walsh, D. A. (1999) Angiogenesis and arthritis Rheumatology (Oxford) 38,103-112[Free Full Text]
    18. 18
  18. Folkman, J. (1971) Tumor angiogenesis: therapeutic implications N. Engl. J. Med. 285,1182-1186
    19. 19
  19. Richard, D. E., Berra, E., Pouyssegur, J. (1999) Angiogenesis: how a tumor adapts to hypoxia Biochem. Biophys. Res. Commun. 266,718-722[Medline]
    20. 20
  20. Senger, D. R., Galli, S. J., Dvorak, A. M., Perruzzi, C. A., Harvey, V. S., Dvorak, H. F. (1983) Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid Science 219,983-985[Abstract/Free Full Text]
    21. 21
  21. Achen, M. G., Stacker, S. A. (1998) The vascular endothelial growth factor family; proteins which guide the development of the vasculature Int. J. Exp. Pathol. 79,255-265[Medline]
    22. 22
  22. Gerber, H. P., Hillan, K. J., Ryan, A. M., Kowalski, J., Keller, G. A., Rangell, L., Wright, B. D., Radtke, F., Aguet, M., Ferrara, N. (1999) VEGF is required for growth and survival in neonatal mice Development 126,1149-1159[Abstract]
    23. 23
  23. Folkman, J. (1997) Angiogenesis and angiogenesis inhibition: an overview EXS 79,1-8[Medline]
    24. 24
  24. O’Reilly, M. S., Holmgren, L., Shing, Y., Chen, C., Rosenthal, R. A., Moses, M., Lane, W. S., Cao, Y., Sage, E. H., Folkman, J. (1994) Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma Cell 79,315-328[Medline]
    25. 25
  25. O’Reilly, M. S., Boehm, T., Shing, Y., Fukai, N., Vasios, G., Lane, W. S., Flynn, E., Birkhead, J. R., Olsen, B. R., Folkman, J. (1997) Endostatin: an endogenous inhibitor of angiogenesis and tumor growth Cell 88,277-285[Medline]
    26. 26
  26. Bootle-Wilbraham, C. A., Tazzyman, S., Marshall, J. M., Lewis, C. E. (2000) Fibrinogen E-fragment inhibits the migration and tubule formation of human dermal microvascular endothelial cells in vitro Cancer Res 60,4719-4724[Abstract/Free Full Text]
    27. 27
  27. Ingber, D. E. (1992) Extracellular matrix as a solid-state regulator in angiogenesis: identification of new targets for anti-cancer therapy Semin. Cancer Biol. 3,57-63[Medline]
    28. 28
  28. Cardon-Cardo, C., Vlodavsky, I., Haimovitz-Friedman, A., Hicklin, D., Fuks, Z. (1990) Expression of basic fibroblast growth factor in normal human tissues Lab. Invest. 63,832-840[Medline]
    29. 29
  29. Guida, E., Stewart, A. (1998) Influence of hypoxia and glucose deprivation on tumour necrosis factor-alpha and granulocyte-macrophage colony-stimulating factor expression in human cultured monocytes Cell Physiol. Biochem. 8,75-88[Medline]
    30. 30
  30. Bottazzi, B., Ghezzi, P., Taraboletti, G., Salmona, M., Colombo, N., Bonazzi, C., Mangioni, C., Mantovani, A. (1985) Tumor-derived chemotactic factor(s) from human ovarian carcinoma: evidence for a role in the regulation of macrophage content of neoplastic tissues Int. J. Cancer 36,167-173[Medline]
    31. 31
  31. Metinko, A. P., Kunkel, S. L., Standiford, T. J., Strieter, R. M. (1992) Anoxia-hyperoxia induces monocyte-derived interleukin-8 J. Clin. Invest. 90,791-798
    32. 32
  32. Thompson, W. D., Li, W. W., Maragoudakis, M. (2000) The clinical manipulation of angiogenesis: pathology, side-effects, surprises, and opportunities with novel human therapies J. Pathol. 190,330-337[Medline]
    33. 33
  33. Henry, T. D. (1999) Therapeutic angiogenesis BMJ 318,1536-1539[Free Full Text]
    34. 34
  34. Leek, R. D., Harris, A. L., Lewis, C. E. (1994) Cytokine networks in solid human tumors: regulation of angiogenesis J. Leukoc. Biol. 56,423-435[Abstract]
    35. 35
  35. Koshikawa, N., Takenaga, K., Tagawa, M., Sakiyama, S. (2000) Therapeutic efficacy of the suicide gene driven by the promoter of vascular endothelial growth factor gene against hypoxic tumor cells Cancer Res 60,2936-2941[Abstract/Free Full Text]
    36. 36
  36. Ray, K. P., Farrow, S., Daly, M., Talabot, F., Searle, N. (1997) Induction of the E-selectin promoter by interleukin 1 and tumour necrosis factor alpha, and inhibition by glucocorticoids Biochem. J. 328 (Pt. 2),707-715
    37. 37
  37. Fox, S. B., Turner, G. D., Gatter, K. C., Harris, A. L. (1995) The increased expression of adhesion molecules ICAM-3, E- and P-selectins on breast cancer endothelium J. Pathol. 177,369-376[Medline]
    38. 38
  38. Sterner-Kock, A., Braun, R. K., Schrenzel, M. D., Hyde, D. M. (1996) Recombinant tumour necrosis factor-alpha and platelet-activating factor synergistically increase intercellular adhesion molecule-1 and E-selectin-dependent neutrophil adherence to endothelium in vitro Immunology 87,454-460[Medline]
    39. 39
  39. Ioculano, M., Altavilla, D., Squadrito, F., Canale, P., Squadrito, G., Saitta, A., Campo, G. M., Caputi, A. P. (1995) Tumour necrosis factor mediates E-selectin production and leukocyte accumulation in myocardial ischaemia-reperfusion injury Pharmacol. Res. 31,281-288[Medline]
    40. 40
  40. Auger, M. J., Roos, J. A. (1992) The biology of the macrophage Lewis, C. E. McGee, J. O. eds. The Macrophage ,3-74 Oxford University Press Oxford.
    41. 41
  41. Nathan, C. F., Murray, H. W., Cohn, Z. A. (1980) The macrophage as an effector cell N. Engl. J. Med. 303,622-626[Medline]
    42. 42
  42. Paulnock, D. M., Demick, K. P., Coller, S. P. (2000) Analysis of interferon-{gamma}-dependent and -independent pathways of macrophage activation J. Leukoc. Biol. 67,677-682[Abstract]
    43. 43
  43. Sunderkotter, C., Goebeler, M., Schulze-Osthoff, K., Bhardwaj, R., Sorg, C. (1991) Macrophage-derived angiogenesis factors Pharmacol. Ther. 51,195-216[Medline]
    44. 44
  44. Shapiro, S. D., Campbell, E. J., Senior, R. M., Welgus, H. G. (1991) Proteinases secreted by human mononuclear phagocytes J. Rheumatol. Suppl. 27,95-98[Medline]
    45. 45
  45. Moldovan, N. I., Goldschmidt-Clermont, P.J., Parker-Thornburg, J., Shapiro, S. D., Kolattukudy, P. E. (2000) Contribution of monocytes/macrophages to compensatory neovascularization: the drilling of metalloelastase-positive tunnels in ischemic myocardium Circ. Res. 87,378-384[Abstract/Free Full Text]
    46. 46
  46. Goede, V., Brogelli, L., Ziche, M., Augustin, H. G. (1999) Induction of inflammatory angiogenesis by monocyte chemoattractant protein-1 Int. J. Cancer 82,765-770[Medline]
    47. 47
  47. Lewis, C. E., Leek, R., Harris, A., McGee, J. O. (1995) Cytokine regulation of angiogenesis in breast cancer: the role of tumor-associated macrophages J. Leukoc. Biol. 57,747-751[Abstract]
    48. 48
  48. Salvesen, H. B., Akslen, L. A. (1999) Significance of tumour-associated macrophages, vascular endothelial growth factor and thrombospondin-1 expression for tumour angiogenesis and prognosis in endometrial carcinomas Int. J. Cancer 84,538-543[Medline]
    49. 49
  49. Takanami, I., Takeuchi, K., Kodaira, S. (1999) Tumor-associated macrophage infiltration in pulmonary adenocarcinoma: association with angiogenesis and poor prognosis Oncology 57,138-142[Medline]
    50. 50
  50. Torisu, H., Ono, M., Kiryu, H., Furue, M., Ohmoto, Y., Nakayama, J., Nishioka, Y., Sone, S., Kuwano, M. (2000) Macrophage infiltration correlates with tumor stage and angiogenesis in human malignant melanoma: possible involvement of TNF-{alpha} and IL-1{alpha} Int. J. Cancer 85,182-188[Medline]
    51. 51
  51. Stewart, R. J., Duley, J. A., Rosman, I., Fraser, R., Allardyce, R. A. (1981) The wound fibroblast and macrophage. I. Wound cell population changes observed in tissue culture Br. J. Surg. 68,125-128[Medline]
    52. 52
  52. Meszaros, A. J., Reichner, J. S., Albina, J. E. (1999) Macrophage phagocytosis of wound neutrophils J. Leukoc. Biol. 65,35-42[Abstract]
    53. 53
  53. Leibovich, S. J., Ross, R. (1975) The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum Am. J. Pathol. 78,71-100[Abstract]
    54. 54
  54. Simpson, D. M., Ross, R. (1972) The neutrophilic leukocyte in wound repair: a study with antineutrophil serum J. Clin. Invest. 51,2009-2023
    55. 55
  55. Thakral, K. K., Goodson, W. H., III, Hunt, T. K. (1979) Stimulation of wound blood vessel growth by wound macrophages J. Surg. Res. 26,430-436[Medline]
    56. 56
  56. Greenburg, G. B., Hunt, T. K. (1978) The proliferative response in vitro of vascular endothelial and smooth muscle cells exposed to wound fluids and macrophages J. Cell. Physiol. 97,353-360[Medline]
    57. 57
  57. Polverini, P. J., Cotran, P. S., Gimbrone, M. A., Jr, Unanue, E. R. (1977) Activated macrophages induce vascular proliferation Nature 269,804-806[Medline]
    58. 58
  58. Koch, A. E., Polverini, P. J., Leibovich, S. J. (1986) Induction of neovascularization by activated human monocytes J. Leukoc. Biol. 39,233-238[Abstract]
    59. 59
  59. Clark, R. A., Stone, R. D., Leung, D. Y., Silver, I., Hohn, D. C., Hunt, T. K. (1976) Role of macrophages in wound healing Surg. Forum 27,16-18[Medline]
    60. 60
  60. Haroon, Z. A., Raleigh, J. A., Greenberg, C. S., Dewhirst, M. W. (2000) Early wound healing exhibits cytokine surge without evidence of hypoxia Ann. Surg. 231,137-147[Medline]
    61. 61
  61. Niinikoski, J., Heughan, C., Hunt, T. K. (1971) Oxygen and carbon dioxide tensions in experimental wounds Surg. Gynecol. Obstet. 133,1003-1007[Medline]
    62. 62
  62. Kivisaari, J. (1975) Oxygen and carbon dioxide tensions in healing tissue Acta Chir. Scand. 141,693-696[Medline]
    63. 63
  63. Shandall, A., Lowndes, R., Young, H. L. (1985) Colonic anastomotic healing and oxygen tension Br. J. Surg. 72,606-609[Medline]
    64. 64
  64. Kivisaari, J., Niinikoski, J. (1975) Oxygen tensions in healing anastomosis of rabbit aorta Surgery 78,165-175
    65. 65
  65. Knighton, D. R., Hunt, T. K., Scheuenstuhl, H., Halliday, B. J., Werb, Z., Banda, M. J. (1983) Oxygen tension regulates the expression of angiogenesis factor by macrophages Science 221,1283-1285[Abstract/Free Full Text]
    66. 66
  66. Elson, D. A., Ryan, H. E., Snow, J. W., Johnson, R., Arbeit, J. M. (2000) Coordinate up-regulation of hypoxia inducible factor (HIF)-1{alpha} and HIF-1 target genes during multi-stage epidermal carcinogenesis and wound healing Cancer Res 60,6189-6195[Abstract/Free Full Text]
    67. 67
  67. Jaffe, E. A., Ruggiero, J. T., Falcone, D. J. (1985) Monocytes and macrophages synthesize and secrete thrombospondin Blood 65,79-84[Abstract/Free Full Text]
    68. 68
  68. Belperio, J. A., Keane, M. P., Arenberg, D. A., Addison, C. L., Ehlert, J. E., Burdick, M. D., Strieter, R. M. (2000) CXC chemokines in angiogenesis J. Leukoc. Biol. 68,1-8[Abstract/Free Full Text]
    69. 69
  69. Fivenson, D. P., Faria, D. T., Nickoloff, B. J., Polverini, P. J., Kunkel, S. L., Burdick, M., Strieter, R. M. (1997) Chemokine and inflammatory cytokine changes during chronic wound healing Wound Repair Regen 5,310-322
    70. 70
  70. Xiong, M., Elson, G., Legarda, D., Leibovich, S. J. (1998) Production of vascular endothelial growth factor by murine macrophages: regulation by hypoxia, lactate, and the inducible nitric oxide synthase pathway Am. J. Pathol. 153,587-598[Abstract/Free Full Text]
    71. 71
  71. Constant, J. S., Feng, J. J., Zabel, D. D., Yuan, H., Suh, D. Y., Scheuenstuhl, H., Hunt, T. K., Hussain, M. Z. (2000) Lactate elicits vascular endothelial growth factor from macrophages: a possible alternative to hypoxia Wound Repair Regen 8,353-360[Medline]
    72. 72
  72. Jensen, J. A., Hunt, T. K., Scheuenstuhl, H., Banda, M. J. (1986) Effect of lactate, pyruvate, and pH on secretion of angiogenesis and mitogenesis factors by macrophages Lab. Invest. 54,574-578[Medline]
    73. 73
  73. Mraz, J., Sedlacek, J., Berka, V., Zdansky, P. (1969) Acidosis as one of the delivering factors of alveolar macrophages during suffocation Br. J. Exp. Pathol. 50,340-342[Medline]
    74. 74
  74. Hunt, T. K., Conolly, W. B., Aronson, S. B., Goldstein, P. (1978) Anaerobic metabolism and wound healing: an hypothesis for the initiation and cessation of collagen synthesis in wounds Am. J. Surg. 135,328-332[Medline]
    75. 75
  75. Stein, I., Neeman, M., Shweiki, D., Itin, A., Keshet, E. (1995) Stabilization of vascular endothelial growth factor mRNA by hypoxia and hypoglycemia and coregulation with other ischemia-induced genes Mol. Cell. Biol. 15,5363-5368[Abstract]
    76. 76
  76. D’Arcangelo, D., Facchiano, F., Barlucchi, L. M., Melillo, G., Illi, B., Testolin, L., Gaetano, C., Capogrossi, M. C. (2000) Acidosis inhibits endothelial cell apoptosis and function and induces basic fibroblast growth factor and vascular endothelial growth factor expression Circ. Res. 86,312-318[Abstract/Free Full Text]
    77. 77
  77. Scott, P. A., Gleadle, J. M., Bicknell, R., Harris, A. L. (1998) Role of the hypoxia sensing system, acidity and reproductive hormones in the variability of vascular endothelial growth factor induction in human breast carcinoma cell lines Int. J. Cancer 75,706-712[Medline]
    78. 78
  78. Bishop, E. T., Bell, G. T., Bloor, S., Broom, I. J., Hendry, N. F. K., Wheatley, D. N. (2000) An in vitro model of angiogenesis: basic features Angiogenesis 3,335-344
    79. 79
  79. Eccles, S. A., Alexander, P. (1974) Macrophage content of tumours in relation to metastatic spread and host immune reaction Nature 250,667-669[Medline]
    80. 80
  80. Wood, G. W., Gollahon, K. A. (1977) Detection and quantitation of macrophage infiltration into primary human tumors with the use of cell-surface markers J. Natl. Cancer Inst. 59,1081-1087
    81. 81
  81. Adams, D. O., Hamilton, T. A. (1984) The cell biology of macrophage activation Annu. Rev. Immunol. 2,283-318[Medline]
    82. 82
  82. Mantovani, A. (1994) Tumor-associated macrophages in neoplastic progression: a paradigm for the in vivo function of chemokines Lab. Invest. 71,5-16[Medline]
    83. 83
  83. O’Sullivan, C., Lewis, C. E., Harris, A. L., McGee, J. O. (1993) Secretion of epidermal growth factor by macrophages associated with breast carcinoma Lancet 342,148-149[Medline]
    84. 84
  84. Lewis, J. S., Landers, R. J., Underwood, J. C., Harris, A. L., Lewis, C. E. (2000) Expression of vascular endothelial growth factor by macrophages is up-regulated in poorly vascularized areas of breast carcinomas J. Pathol. 192,150-158[Medline]
    85. 85
  85. Polverini, P. J., Leibovich, S. J. (1984) Induction of neovascularization in vivo and endothelial proliferation in vitro by tumor-associated macrophages Lab. Invest. 51,635-642[Medline]
    86. 86
  86. Leek, R. D., Hunt, N. C., Landers, R. J., Lewis, C. E., Royds, J. A., Harris, A. L. (2000) Macrophage infiltration is associated with VEGF and EGFR expression in breast cancer J. Pathol. 190,430-436[Medline]
    87. 87
  87. Pusztai, L., Clover, L. M., Cooper, K., Starkey, P. M., Lewis, C. E., McGee, J. O. (1994) Expression of tumour necrosis factor alpha and its receptors in carcinoma of the breast Br. J. Cancer 70,289-292[Medline]
    88. 88
  88. Fujimoto, J., Sakaguchi, H., Aoki, I., Tamaya, T. (2000) Clinical implications of expression of interleukin 8 related to angiogenesis in uterine cervical cancers Cancer Res 60,2632-2635[Abstract/Free Full Text]
    89. 89
  89. Stupack, D. G., Storgard, C. M., Cheresh, D. A. (1999) A role for angiogenesis in rheumatoid arthritis Braz. J. Med. Biol. Res. 32,573-581[Medline]
    90. 90
  90. Connolly, D. T., Stoddard, B. L., Harakas, N. K., Feder, J. (1987) Human fibroblast-derived growth factor is a mitogen and chemoattractant for endothelial cells Biochem. Biophys. Res. Commun. 144,705-712[Medline]
    91. 91
  91. Montesano, R., Vassalli, J. D., Baird, A., Guillemin, R., Orci, L. (1986) Basic fibroblast growth factor induces angiogenesis in vitro Proc. Natl. Acad. Sci. USA 83,7297-7301[Abstract/Free Full Text]
    92. 92
  92. Pyke, C., Graem, N., Ralfkiaer, E., Ronne, E., Hoyer-Hansen, G., Brunner, N., Dano, K. (1993) Receptor for urokinase is present in tumor-associated macrophages in ductal breast carcinoma Cancer Res 53,1911-1915[Abstract/Free Full Text]
    93. 93
  93. Thompson, W. D., Smith, E. B., Stirk, C. M., Marshall, F. I., Stout, A. J., Kocchar, A. (1992) Angiogenic activity of fibrin degradation products is located in fibrin fragment E J. Pathol. 168,47-53[Medline]
    94. 94
  94. Orr, F. W., Wang, H. H., Lafrenie, R. M., Scherbarth, S., Nance, D. M. (2000) Interactions between cancer cells and the endothelium in metastasis J. Pathol. 190,310-329[Medline]
    95. 95
  95. Koch, A. E., Polverini, P. J., Kunkel, S. L., Harlow, L. A., DiPietro, L. A., Elner, V. M., Elner, S. G., Strieter, R. M. (1992) Interleukin-8 as a macrophage-derived mediator of angiogenesis Science 258,1798-1801[Abstract/Free Full Text]
    96. 96
  96. Hu, D. E., Hori, Y., Fan, T. P. (1993) Interleukin-8 stimulates angiogenesis in rats Inflammation 17,135-143[Medline]
    97. 97
  97. Unemori, E. N., Ferrara, N., Bauer, E. A., Amento, E. P. (1992) Vascular endothelial growth factor induces interstitial collagenase expression in human endothelial cells J. Cell. Physiol. 153,557-562[Medline]
    98. 98
  98. Niedbala, M. J., Stein, M. (1991) Tumor necrosis factor induction of urokinase-type plasminogen activator in human endothelial cells Biomed. Biochim. Acta 50,427-436[Medline]
    99. 99
  99. Hanahan, D., Folkman, J. (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis Cell 86,353-364[Medline]
    100. 100
  100. Neeman, M., Abramovitch, R., Schiffenbauer, Y. S., Tempel, C. (1997) Regulation of angiogenesis by hypoxic stress: from solid tumours to the ovarian follicle Int. J. Exp. Pathol. 78,57-70[Medline]
    101. 101
  101. Damert, A., Machein, M., Breier, G., Fujita, M. Q., Hanahan, D., Risau, W., Plate, K. H. (1997) Up-regulation of vascular endothelial growth factor expression in a rat glioma is conferred by two distinct hypoxia-driven mechanisms Cancer Res 57,3860-3864[Abstract/Free Full Text]
    102. 102
  102. Vaupel, P., Schlenger, K., Knoop, C., Hockel, M. (1991) Oxygenation of human tumors: evaluation of tissue oxygen distribution in breast cancers by computerized O2 tension measurements Cancer Res 51,3316-3322[Abstract/Free Full Text]
    103. 103
  103. Vaupel, P., Kallinowski, F., Okunieff, P. (1989) Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review Cancer Res 49,6449-6465[Abstract/Free Full Text]
    104. 104
  104. Leek, R. D., Lewis, C. E., Whitehouse, R., Greenall, M., Clarke, J., Harris, A. L. (1996) Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma Cancer Res 56,4625-4629[Abstract/Free Full Text]
    105. 105
  105. Leek, R. D., Landers, R. J., Harris, A. L., Lewis, C. E. (1999) Necrosis correlates with high vascular density and focal macrophage infiltration in invasive carcinoma of the breast Br. J. Cancer 79,991-995[Medline]
    106. 106
  106. O’Sullivan, C., Lewis, C. E. (1994) Tumour-associated leucocytes: friends or foes in breast carcinoma J. Pathol. 172,229-235[Medline]
    107. 107
  107. Harmey, J. H., Dimitriadis, E., Kay, E., Redmond, H. P., Bouchier-Hayes, D. (1998) Regulation of macrophage production of vascular endothelial growth factor (VEGF) by hypoxia and transforming growth factor ß-1 Ann. Surg. Oncol. 5,271-278[Abstract]
    108. 108
  108. Lewis, J. S., Lee, J. A., Underwood, J. C., Harris, A. L., Lewis, C. E. (1999) Macrophage responses to hypoxia: relevance to disease mechanisms J. Leukoc. Biol. 66,889-900[Abstract]
    109. 109
  109. Sauer, L. A., Dauchy, R. T. (1986) In vivo lactate production and utilization by Jensen sarcoma and Morris hepatoma 7288CTC Cancer Res 46,689-693[Abstract/Free Full Text]
    110. 110
  110. Warburg, O. (1956) On the origin of cancer cells Science 123,309-314[Free Full Text]
    111. 111
  111. Kallinowski, F., Schlenger, K. H., Runkel, S., Kloes, M., Stohrer, M., Okunieff, P., Vaupel, P. (1989) Blood flow, metabolism, cellular microenvironment, and growth rate of human tumor xenografts Cancer Res 49,3759-3764[Abstract/Free Full Text]
    112. 112
  112. Tannock, I. F., Rotin, D. (1989) Acid pH in tumors and its potential for therapeutic exploitation Cancer Res 49,4373-4384[Abstract/Free Full Text]
    113. 113
  113. Martinez-Zaguilan, R., Seftor, E. A., Seftor, R. E., Chu, Y. W., Gillies, R. J., Hendrix, M. J. (1996) Acidic pH enhances the invasive behavior of human melanoma cells Clin. Exp. Metastasis 14,176-186[Medline]
    114. 114
  114. Rozhin, J., Sameni, M., Ziegler, G., Sloane, B. F. (1994) Pericellular pH affects distribution and secretion of cathepsin B in malignant cells Cancer Res 54,6517-6525[Abstract/Free Full Text]
    115. 115
  115. Swallow, C. J., Grinstein, S., Rotstein, O. D. (1992) Lipopolysaccharide impairs macrophage cytoplasmic pH regulation under conditions simulating the inflammatory microenvironment J. Leukoc. Biol. 52,395-399[Abstract]
    116. 116
  116. Walenta, S., Wetterling, M., Lehrke, M., Schwickert, G., Sundfor, K., Rofstad, E. K., Mueller-Klieser, W. (2000) High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers Cancer Res 60,916-921[Abstract/Free Full Text]
    117. 117
  117. Clauss, M., Gerlach, M., Gerlach, H., Brett, J., Wang, F., Familletti, P. C., Pan, Y. C., Olander, J. V., Connolly, D. T., Stern, D. (1990) Vascular permeability factor: a tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration J. Exp. Med. 172,1535-1545[Abstract/Free Full Text]
    118. 118
  118. Levy, A. P., Levy, N. S., Wegner, S., Goldberg, M. A. (1995) Transcriptional regulation of the rat vascular endothelial growth factor gene by hypoxia J. Biol. Chem. 270,13333-13340[Abstract/Free Full Text]
    119. 119
  119. Kuwabara, K., Ogawa, S., Matsumoto, M., Koga, S., Clauss, M., Pinsky, D. J., Lyn, P., Leavy, J., Witte, L., Joseph-Silverstein, J. (1995) Hypoxia-mediated induction of acidic/basic fibroblast growth factor and platelet-derived growth factor in mononuclear phagocytes stimulates growth of hypoxic endothelial cells Proc. Natl. Acad. Sci. USA 92,4606-4610[Abstract/Free Full Text]
    120. 120
  120. Kandel, J., Bossy-Wetzel, E., Radvanyi, F., Klagsbrun, M., Folkman, J., Hanahan, D. (1991) Neovascularization is associated with a switch to the export of bFGF in the multistep development of fibrosarcoma Cell 66,1095-1104[Medline]
    121. 121
  121. Takahashi, M., Ikeda, U., Kasahara, T., Kitagawa, S., Takahashi, Y., Shimada, K., Kano, S., Morimoto, C., Masuyama, J. (1997) Activation of human monocytes for enhanced production of interleukin 8 during transendothelial migration in vitro J. Clin. Immunol. 17,53-62[Medline]
    122. 122
  122. Whalen, G. F. (1990) Solid tumours and wounds: transformed cells misunderstood as injured tissue? Lancet 336,1489-1492[Medline]
    123. 123
  123. Butterick, C. J., Williams, D. A., Boxer, L. A., Jersild, R. A., Jr, Mantich, N., Higgins, C., Baehner, R. L. (1981) Changes in energy metabolism, structure and function in alveolar macrophages under anaerobic conditions Br. J. Haematol. 48,523-532[Medline]
    124. 124
  124. Firth, J. D., Ebert, B. L., Pugh, C. W., Ratcliffe, P. J. (1994) Oxygen-regulated control elements in the phosphoglycerate kinase 1 and lactate dehydrogenase A genes: similarities with the erythropoietin 3' enhancer Proc. Natl. Acad. Sci. USA 91,6496-6500[Abstract/Free Full Text]
    125. 125
  125. Ebert, B. L., Gleadle, J. M., O’Rourke, J. F., Bartlett, S. M., Poulton, J., Ratcliffe, P. J. (1996) Isoenzyme-specific regulation of genes involved in energy metabolism by hypoxia: similarities with the regulation of erythropoietin Biochem. J. 313,809-814
    126. 126
  126. Wang, G. L., Semenza, G. L. (1995) Purification and characterization of hypoxia-inducible factor 1 J. Biol. Chem. 270,1230-1237[Abstract/Free Full Text]
    127. 127
  127. Wang, G. L., Jiang, B. H., Rue, E. A., Semenza, G. L. (1995) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension Proc. Natl. Acad. Sci. USA 92,5510-5514[Abstract/Free Full Text]
    128. 128
  128. Wood, S. M., Gleadle, J. M., Pugh, C. W., Hankinson, O., Ratcliffe, P. J. (1996) The role of the aryl hydrocarbon receptor nuclear translocator (ARNT) in hypoxic induction of gene expression Studies in ARNT-deficient cells. J. Biol. Chem. 271,15117-15123
    129. 129
  129. Salvesen, H. B., Iversen, O. E., Akslen, L. A. (1998) Independent prognostic importance of microvessel density in endometrial carcinoma Br. J. Cancer 77,1140-1144[Medline]
    130. 130
  130. Jiang, B. H., Semenza, G. L., Bauer, C., Marti, H. H. (1996) Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension Am. J. Physiol. 271,C1172-C1180[Abstract/Free Full Text]
    131. 131
  131. Griffiths, L., Binley, K., Iqball, S., Kan, O., Maxwell, P., Ratcliffe, P., Lewis, C., Harris, A., Kingsman, S., Naylor, S. (2000) The macrophage—a novel system to deliver gene therapy to pathological hypoxia Gene Ther 7,255-262[Medline]
    132. 132
  132. Wiesener, M. S., Turley, H., Allen, W. E., Willam, C., Eckardt, K. U., Talks, K. L., Wood, S. M., Gatter, K. C., Harris, A. L., Pugh, C. W., Ratcliffe, P. J., Maxwell, P. H. (1998) Induction of endothelial PAS domain protein-1 by hypoxia: characterization and comparison with hypoxia-inducible factor-1{alpha} Blood 92,2260-2268[Abstract/Free Full Text]
    133. 133
  133. Talks, K. L., Turley, H., Gatter, K. C., Maxwell, P. H., Pugh, C. W., Ratcliffe, P. J., Harris, A. L. (2000) The expression and distribution of the hypoxia-inducible factors HIF-1{alpha} and HIF-2{alpha} in normal human tissues, cancers, and tumor-associated macrophages Am. J. Pathol. 157,411-421[Abstract/Free Full Text]
    134. 135
  134. Gu, Y. Z., Moran, S. M., Hogenesch, J. B., Wartman, L., Bradfield, C. A. (1998) Molecular characterization and chromosomal localization of a third alpha-class hypoxia inducible factor subunit, HIF3{alpha} Gene Expr 7,205-213[Medline]
    135. 136
  135. Marshall, H. E., Merchant, K., Stamler, J. S. (2000) Nitrosation and oxidation in the regulation of gene expression FASEB J 14,1889-1900[Abstract/Free Full Text]
    136. 137
  136. Yan, S. F., Lu, J., Zou, Y. S., Soh-Won, J., Cohen, D. M., Buttrick, P. M., Cooper, D. R., Steinberg, S. F., Mackman, N., Pinsky, D. J., Stern, D. M. (1999) Hypoxia-associated induction of early growth response-1 gene expression J. Biol. Chem. 274,15030-15040[Abstract/Free Full Text]
    137. 138
  137. Lo, C. J., Cryer, H. G., Fu, M., Lo, F. R. (1998) Regulation of macrophage eicosanoid generation is dependent on nuclear factor {kappa}B J. Trauma 45,19-23[Medline]
    138. 139
  138. Zabel, D. D., Feng, J. J., Scheuenstuhl, H., Hunt, T. K., Hussain, M. Z. (1996) Lactate stimulation of macrophage-derived angiogenic activity is associated with inhibition of poly(ADP-ribose) synthesis Lab. Invest. 74,644-649[Medline]
    139. 140
  139. Runkel, S., Kaven, E. (1999) In vivo distribution of oxygen partial pressures in female breast tumors Vaupel, P. Kelleher, D. eds. Hypoxia Tumour, Pathophysiology, Significance Clinical, Perspectives Therapeutic ,13-18 Wissenschaftliche Verlagsgesellschaft Stuttgart, Germany.
    140. 141
  140. Swift, M. E., Kleinman, H. K., DiPietro, L. A. (1999) Impaired wound repair and delayed angiogenesis in aged mice Lab. Invest. 79,1479-1487[Medline]
    141. 142
  141. Kvanta, A., Sarman, S., Fagerholm, P., Seregard, S., Steen, B. (2000) Expression of matrix metalloproteinase-2 (MMP-2) and vascular endothelial growth factor (VEGF) in inflammation-associated corneal neovascularization Exp. Eye Res. 70,419-428[Medline]
    142. 143
  142. Yoneda, J., Kuniyasu, H., Crispens, M. A., Price, J. E., Bucana, C. D., Fidler, I. J. (1998) Expression of angiogenesis-related genes and progression of human ovarian carcinomas in nude mice J. Natl. Cancer Inst. 90,447-454[Abstract/Free Full Text]
    143. 144
  143. Brown, L. F., Yeo, K. T., Berse, B., Yeo, T. K., Senger, D. R., Dvorak, H. F., Van de, Water, L. (1992) Expression of vascular permeability factor (vascular endothelial growth factor) by epidermal keratinocytes during wound healing J. Exp. Med. 176,1375-1379[Abstract/Free Full Text]
    144. 145
  144. Shoji, M., Hancock, W. W., Abe, K., Micko, C., Casper, K. A., Baine, R. M., Wilcox, J. N., Danave, I., Dillehay, D. L., Matthews, E., Contrino, J., Morrissey, J. H., Gordon, S., Edgington, T. S., Kudryk, B., Kreutzer, D. L., Rickles, F. R. (1998) Activation of coagulation and angiogenesis in cancer: immunohistochemical localization in situ of clotting proteins and vascular endothelial growth factor in human cancer Am. J. Pathol. 152,399-411[Abstract]
    145. 146
  145. Xu, J. W., Konttinen, Y. T., Li, T. F., Waris, V., Lassus, J., Matucci-Cerinic, M., Sorsa, T., Santavirta, T. S. (1998) Production of platelet-derived growth factor in aseptic loosening of total hip replacement Rheumatol. Int. 17,215-221[Medline]
    146. 147
  146. Vignaud, J. M., Marie, B., Klein, N., Plenat, F., Pech, M., Borrelly, J., Martinet, N., Duprez, A., Martinet, Y. (1994) The role of platelet-derived growth factor production by tumor-associated macrophages in tumor stroma formation in lung cancer Cancer Res 54,5455-5463[Abstract/Free Full Text]
    147. 148
  147. Plemons, J. M., Dill, R. E., Rees, T. D., Dyer, B. J., Ng, M. C., Iacopino, A. M. (1996) PDGF-B producing cells and PDGF-B gene expression in normal gingival and cyclosporine A-induced gingival overgrowth J. Periodontol. 67,264-270[Medline]
    148. 149
  148. Lindmark, G., Sundberg, C., Glimelius, B., Pahlman, L., Rubin, K., Gerdin, B. (1993) Stromal expression of platelet-derived growth factor beta-receptor and platelet-derived growth factor B-chain in colorectal cancer Lab. Invest. 69,682-689[Medline]
    149. 150
  149. Compton, R., Williams, D., Browder, W. (1996) The beneficial effect of enhanced macrophage function on the healing of bowel anastomoses Am. Surg. 62,14-18[Medline]
    150. 151
  150. Bourque, W. T., Gross, M., Hall, B. K. (1993) Expression of four growth factors during fracture repair Int. J. Dev. Biol. 37,573-579[Medline]
    151. 152
  151. Appleton, I., Tomlinson, A., Colville-Nash, P. R., Willoughby, D. A. (1993) Temporal and spatial immunolocalization of cytokines in murine chronic granulomatous tissue. Implications for their role in tissue development and repair processes Lab. Invest. 69,405-414[Medline]
    152. 153
  152. Kraiss, L. W., Raines, E. W., Wilcox, J. N., Seifert, R. A., Barrett, T. B., Kirkman, T. R., Hart, C. E., Bowen-Pope, D. F., Ross, R., Clowes, A. W. (1993) Regional expression of the platelet-derived growth factor and its receptors in a primate graft model of vessel wall assembly J. Clin. Invest. 92,338-348
    153. 154
  153. Rappolee, D. A., Mark, D., Banda, M. J., Werb, Z. (1988) Wound macrophages express TGF-alpha and other growth factors in vivo: analysis by mRNA phenotyping Science 241,708-712[Abstract/Free Full Text]
    154. 155
  154. Takahashi, Y., Bucana, C. D., Liu, W., Yoneda, J., Kitadai, Y., Cleary, K. R., Ellis, L. M. (1996) Platelet-derived endothelial cell growth factor in human colon cancer angiogenesis: role of infiltrating cells J. Natl. Cancer Inst. 88,1146-1151[Abstract/Free Full Text]
    155. 156
  155. Matsumura, M., Chiba, Y., Lu, C., Amaya, H., Shimomatsuya, T., Horiuchi, T., Muraoka, R., Tanigawa, N. (1998) Platelet-derived endothelial cell growth factor/thymidine phosphorylase expression correlated with tumor angiogenesis and macrophage infiltration in colorectal cancer Cancer Lett 128,55-63[Medline]
    156. 157
  156. Nagaoka, H., Iino, Y., Takei, H., Morishita, Y. (1998) Platelet-derived endothelial cell growth factor/thymidine phosphorylase expression in macrophages correlates with tumor angiogenesis and prognosis in invasive breast cancer Int. J. Oncol. 13,449-454[Medline]
    157. 158
  157. Takahashi, Y., Bucana, C. D., Akagi, Y., Liu, W., Cleary, K. R., Mai, M., Ellis, L. M. (1998) Significance of platelet-derived endothelial cell growth factor in the angiogenesis of human gastric cancer Clin. Cancer Res. 4,429-434[Abstract/Free Full Text]
    158. 159
  158. Naylor, M. S., Stamp, G. W., Foulkes, W. D., Eccles, D., Balkwill, F. R. (1993) Tumor necrosis factor and its receptors in human ovarian cancer: potential role in disease progression J. Clin. Invest. 91,2194-2206
    159. 160
  159. Fahey, T. J., III, Sherry, B., Tracey, K. J., van Deventer, S., Jones, W. G., Minei, J. P., Morgello, S., Shires, G. T., Cerami, A. (1990) Cytokine production in a model of wound healing: the appearance of MIP-1, MIP-2, cachectin/TNF and IL-1 Cytokine 2,92-99[Medline]
    160. 161
  160. Abe, H., Rodgers, K. E., Ellefson, D., diZerega, G. S. (1991) Kinetics of interleukin-1 and tumor necrosis factor secretion by rabbit macrophages recovered from the peritoneal cavity after surgery J. Invest. Surg. 4,141-151[Medline]
    161. 162
  161. Alvarez, J. A., Baird, A., Tatum, A., Daucher, J., Chorsky, R., Gonzalez, A. M., Stopa, E. G. (1992) Localization of basic fibroblast growth factor and vascular endothelial growth factor in human glial neoplasms Mod. Pathol. 5,303-307[Medline]
    162. 163
  162. Motoo, Y., Sawabu, N., Yamaguchi, Y., Terada, T., Nakanuma, Y. (1993) Sinusoidal capillarization of human hepatocellular carcinoma: possible promotion by fibroblast growth factor Oncology 50,270-274[Medline]
    163. 164
  163. Diaz, J. I., Muro-Cucho, C. A. (1996) Macrophage expression of interleukin-1 in lymphoepithelioid cell ("Lennert’s") lymphoma Leuk. Lymphoma 21,305-309[Medline]
    164. 165
  164. Parajuli, P., Singh, S. M. (1996) Alteration in IL-1 and arginase activity of tumor-associated macrophages: a role in the promotion of tumor growth Cancer Lett 107,249-256[Medline]
    165. 166
  165. Eifuku, R., Yoshimatsu, T., Yoshino, I., Takenoyama, M., Imahayashi, S., So, T., Hanagiri, T., Nomoto, K., Yasumoto, K. (2000) Heterogeneous response patterns of alveolar macrophages from patients with lung cancer by stimulation with interferon-gamma Jpn. J. Clin. Oncol. 30,295-300[Abstract/Free Full Text]
    166. 167
  166. Buttner, C., Skupin, A., Reimann, T., Rieber, E. P., Unteregger, G., Geyer, P., Frank, K. H. (1997) Local production of interleukin-4 during radiation-induced pneumonitis and pulmonary fibrosis in rats: macrophages as a prominent source of interleukin-4 Am. J. Respir. Cell Mol. Biol. 17,315-325[Abstract/Free Full Text]
    167. 168
  167. Leskovar, A., Moriarty, L. J., Turek, J. J., Schoenlein, I. A., Borgens, R. B. (2000) The macrophage in acute neural injury: changes in cell numbers over time and levels of cytokine production in mammalian central and peripheral nervous systems J. Exp. Biol. 203,1783-1795[Abstract]
    168. 169
  168. McCarter, M. D., Mack, V. E., Daly, J. M., Naama, H. A., Calvano, S. E. (1998) Trauma-induced alterations in macrophage function Surgery 123,96-101[Medline]
    169. 170
  169. Kelly, C. J., Gallagher, H., Wolf, B. A., Daly, J. M. (1994) Alterations in macrophage signal transduction pathways mediate post-traumatic changes in macrophage function J. Surg. Res. 57,221-226[Medline]
    170. 171
  170. Ogle, C. K., Guo, X., Alexander, J. W., Fukushima, R., Ogle, J. D. (1993) The activation of bone marrow macrophages 24 hours after thermal injury Arch. Surg. 128,96-100[Abstract/Free Full Text]
    171. 172
  171. Reed, M. J., Puolakkainen, P., Lane, T. F., Dickerson, D., Bornstein, P., Sage, E. H. (1993) Differential expression of SPARC and thrombospondin 1 in wound repair: immunolocalization and in situ hybridization J. Histochem. Cytochem. 41,1467-1477[Abstract]
    172. 173
  172. Pyke, C., Ralfkiaer, E., Tryggvason, K., Dano, K. (1993) Messenger RNA for two type IV collagenases is located in stromal cells in human colon cancer Am. J. Pathol. 142,359-365[Abstract]
    173. 174
  173. Ring, P., Johansson, K., Hoyhtya, M., Rubin, K., Lindmark, G. (1997) Expression of tissue inhibitor of metalloproteinases TIMP-2 in human colorectal cancer—a predictor of tumour stage Br. J. Cancer 76,805-811[Medline]
    174. 175
  174. Zeng, Z. S., Guillem, J. G. (1995) Distinct pattern of matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 mRNA expression in human colorectal cancer and liver metastases Br. J. Cancer 72,575-582[Medline]
    175. 176
  175. Heppner, K. J., Matrisian, L. M., Jensen, R. A., Rodgers, W. H. (1996) Expression of most matrix metalloproteinase family members in breast cancer represents a tumor-induced host response Am. J. Pathol. 149,273-282[Abstract]
    176. 177
  176. Schafer, B. M., Maier, K., Eickhoff, U., Todd, R. F., Kramer, M. D. (1994) Plasminogen activation in healing human wounds Am. J. Pathol. 144,1269-1280[Abstract]
    177. 178
  177. DiPietro, L. A., Nissen, N. N., Gamelli, R. L., Koch, A. E., Pyle, J. M., Polverini, P. J. (1996) Thrombospondin 1 synthesis and function in wound repair Am. J. Pathol. 148,1851-1860[Abstract]
    178. 179
  178. Fiorelli, V., Gendelman, R., Sirianni, M. C., Chang, H. K., Colombini, S., Markham, P. D., Monini, P., Sonnabend, J., Pintus, A., Gallo, R. C., Ensoli, B. (1998) Gamma-interferon produced by CD8+ T cells infiltrating Kaposi’s sarcoma induces spindle cells with angiogenic phenotype and synergy with human immunodeficiency virus-1 Tat protein: an immune response to human herpesvirus-8 infection? Blood 91,956-967[Abstract/Free Full Text]
    179. 180
  179. Ashcroft, G. S., Herrick, S. E., Tarnuzzer, R. W., Horan, M. A., Schultz, G. S., Ferguson, M. W. (1997) Human ageing impairs injury-induced in vivo expression of tissue inhibitor of matrix metalloproteinases (TIMP)-1 and -2 proteins and mRNA J. Pathol. 183,169-176[Medline]
    180. 181
  180. Saarialho-Kere, U. K. (1998) Patterns of matrix metalloproteinase and TIMP expression in chronic ulcers Arch. Dermatol. Res. 290(Suppl.),S47-S54
    181. 182
  181. Yun, J. K., McCormick, T. S., Villabona, C., Judware, R. R., Espinosa, M. B., Lapetina, E. G. (1997) Inflammatory mediators are perpetuated in macrophages resistant to apoptosis induced by hypoxia Proc. Natl. Acad. Sci. USA 94,13903-13908[Abstract/Free Full Text]
    182. 183
  182. Sampson, L. E., Chaplin, D. J. (1996) The influence of oxygen and carbon dioxide tension on the production of TNF alpha by activated macrophages Br. J. Cancer Suppl. 27,S133-S135[Medline]
    183. 184
  183. Scannell, G., Waxman, K., Kaml, G. J., Ioli, G., Gatanaga, T., Yamamoto, R., Granger, G. A. (1993) Hypoxia induces a human macrophage cell line to release tumor necrosis factor-alpha and its soluble receptors in vitro J. Surg. Res. 54,281-285[Medline]
    184. 185
  184. Hempel, S. L., Monick, M. M., Hunninghake, G. W. (1996) Effect of hypoxia on release of IL-1 and TNF by human alveolar macrophages Am. J. Respir. Cell Mol. Biol. 14,170-176[Abstract]
    185. 186
  185. West, M. A., Li, M. H., Seatter, S. C., Bubrick, M. P. (1994) Pre-exposure to hypoxia or septic stimuli differentially regulates endotoxin release of tumor necrosis factor, interleukin-6, interleukin-1, prostaglandin E2, nitric oxide, and superoxide by macrophages J. Trauma 37,82-89[Medline]
    186. 187
  186. Sjostrand, M., Holmang, A., Strindberg, L., Lonnroth, P. (2000) Estimations of muscle interstitial insulin, glucose, and lactate in type 2 diabetic subjects Am. J. Physiol. Endocrinol. Metab. 279,E1097-E1103[Abstract/Free Full Text]
    187. 188
  187. Walenta, S., Salameh, A., Lyng, H., Evensen, J. F., Mitze, M., Rofstad, E. K., Mueller-Klieser, W. (1997) Correlation of high lactate levels in head and neck tumors with incidence of metastasis Am. J. Pathol. 150,409-415[Abstract]
    188. 189
  188. Hunt, T. K., Twomey, P., Zederfeldt, B., Dunphy, J. E. (1967) Respiratory gas tensions and pH in healing wounds Am. J. Surg. 114,302-307[Medline]

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Invest. Ophthalmol. Vis. Sci., September 1, 2008; 49(9): 4195 - 4202.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
L. Wang, G.-G. Zheng, C.-H. Ma, Y.-M. Lin, H.-Y. Zhang, Y.-Y. Ma, J.-H. Chong, and K.-F. Wu
A Special Linker between Macrophage and Hematopoietic Malignant Cells: Membrane Form of Macrophage Colony-Stimulating Factor
Cancer Res., July 15, 2008; 68(14): 5639 - 5647.
[Abstract] [Full Text] [PDF]

Home page
 Integr Cancer TherHome page
C. Guruvayoorappan
Tumor Versus Tumor-Associated Macrophages: How Hot is the Link?
Integr Cancer Ther, June 1, 2008; 7(2): 90 - 95.
[Abstract] [PDF]

Home page
 FASEB J.Home page
W. Tan, T. R. Palmby, J. Gavard, P. Amornphimoltham, Y. Zheng, and J. S. Gutkind
An essential role for Rac1 in endothelial cell function and vascular development
FASEB J, June 1, 2008; 22(6): 1829 - 1838.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Pathol.Home page
C-Y Chai, W-T Chen, W-C Hung, W-Y Kang, Y-C Huang, Y-C Su, and C-H Yang
Hypoxia-inducible factor-1{alpha} expression correlates with focal macrophage infiltration, angiogenesis and unfavourable prognosis in urothelial carcinoma
J. Clin. Pathol., May 1, 2008; 61(5): 658 - 664.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
C.-C. Ho, W.-Y. Liao, C.-Y. Wang, Y.-H. Lu, H.-Y. Huang, H.-Y. Chen, W.-K. Chan, H.-W. Chen, and P.-C. Yang
TREM-1 Expression in Tumor-associated Macrophages and Clinical Outcome in Lung Cancer
Am. J. Respir. Crit. Care Med., April 1, 2008; 177(7): 763 - 770.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
N. R. Miselis, Z. J. Wu, N. Van Rooijen, and A. B. Kane
Targeting tumor-associated macrophages in an orthotopic murine model of diffuse malignant mesothelioma
Mol. Cancer Ther., April 1, 2008; 7(4): 788 - 799.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
A. G. McDonald, K. Yang, H. R. Roberts, D. M. Monroe, and M. Hoffman
Perivascular tissue factor is down-regulated following cutaneous wounding: implications for bleeding in hemophilia
Blood, February 15, 2008; 111(4): 2046 - 2048.
[Abstract] [Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
V. Tchaikovski, G. Fellbrich, and J. Waltenberger
The Molecular Basis of VEGFR-1 Signal Transduction Pathways in Primary Human Monocytes
Arterioscler. Thromb. Vasc. Biol., February 1, 2008; 28(2): 322 - 328.
[Abstract] [Full Text] [PDF]

Home page
 Hum ReprodHome page
S. Matsuzaki, M. Canis, J.-E. Bazin, C. Darcha, J.-L. Pouly, and G. Mage
Effects of supplemental perioperative oxygen on post-operative abdominal wound adhesions in a mouse laparotomy model with controlled respiratory support
Hum. Reprod., October 1, 2007; 22(10): 2702 - 2706.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
E. Y. Lin and J. W. Pollard
Tumor-Associated Macrophages Press the Angiogenic Switch in Breast Cancer
Cancer Res., June 1, 2007; 67(11): 5064 - 5066.
[Abstract] [Full Text] [PDF]

Home page
 ReproductionHome page
V L Bosquiazzo, J G Ramos, J Varayoud, M Munoz-de-Toro, and E H Luque
Mast cell degranulation in rat uterine cervix during pregnancy correlates with expression of vascular endothelial growth factor mRNA and angiogenesis
Reproduction, May 1, 2007; 133(5): 1045 - 1055.
[Abstract] [Full Text] [PDF]

Home page
 Hum ReprodHome page
N. Bourdel, S. Matsuzaki, J.-E. Bazin, J.-L. Pouly, G. Mage, and M. Canis
Peritoneal tissue-oxygen tension during a carbon dioxide pneumoperitoneum in a mouse laparoscopic model with controlled respiratory support
Hum. Reprod., April 1, 2007; 22(4): 1149 - 1155.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
S.-H. Jeon, B.-C. Chae, H.-A Kim, G.-Y. Seo, D.-W. Seo, G.-T. Chun, N.-S. Kim, S.-W. Yie, W.-H. Byeon, S.-H. Eom, et al.
Mechanisms underlying TGF-{beta}1-induced expression of VEGF and Flk-1 in mouse macrophages and their implications for angiogenesis
J. Leukoc. Biol., February 1, 2007; 81(2): 557 - 566.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
M. Puppo, M. C. Bosco, M. Federico, S. Pastorino, and L. Varesio
Hypoxia inhibits Moloney murine leukemia virus expression in activated macrophages
J. Leukoc. Biol., February 1, 2007; 81(2): 528 - 538.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
X. Li, E. Calvo, M. Cool, P. Chrobak, D. G. Kay, and P. Jolicoeur
Overexpression of Notch1 Ectodomain in Myeloid Cells Induces Vascular Malformations through a Paracrine Pathway
Am. J. Pathol., January 1, 2007; 170(1): 399 - 415.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Biol. CellHome page
M. Ramanathan, G. Pinhal-Enfield, I. Hao, and S. J. Leibovich
Synergistic Up-Regulation of Vascular Endothelial Growth Factor (VEGF) Expression in Macrophages by Adenosine A2A Receptor Agonists and Endotoxin Involves Transcriptional Regulation via the Hypoxia Response Element in the VEGF Promoter
Mol. Biol. Cell, January 1, 2007; 18(1): 14 - 23.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
W-Y. Hsieh, M-W. Chen, H-T. Ho, T-M. You, and Y-T. Lu
Identification of differentially expressed proteins in human malignant pleural effusions
Eur. Respir. J., December 1, 2006; 28(6): 1178 - 1185.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
A. E. M. Dirkx, M. G. A. oude Egbrink, J. Wagstaff, and A. W. Griffioen
Monocyte/macrophage infiltration in tumors: modulators of angiogenesis
J. Leukoc. Biol., December 1, 2006; 80(6): 1183 - 1196.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
E. Y. Lin, J.-F. Li, L. Gnatovskiy, Y. Deng, L. Zhu, D. A. Grzesik, H. Qian, X.-n. Xue, and J. W. Pollard
Macrophages Regulate the Angiogenic Switch in a Mouse Model of Breast Cancer
Cancer Res., December 1, 2006; 66(23): 11238 - 11246.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
V. D'Arcy, Z. K. Abdullaev, N. Pore, F. Docquier, V. Torrano, I. Chernukhin, M. Smart, D. Farrar, M. Metodiev, N. Fernandez, et al.
The Potential of BORIS Detected in the Leukocytes of Breast Cancer Patients as an Early Marker of Tumorigenesis.
Clin. Cancer Res., October 15, 2006; 12(20): 5978 - 5986.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
C. Lamagna, M. Aurrand-Lions, and B. A. Imhof
Dual role of macrophages in tumor growth and angiogenesis
J. Leukoc. Biol., October 1, 2006; 80(4): 705 - 713.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
J. E. Qualls, A. M. Kaplan, N. van Rooijen, and D. A. Cohen
Suppression of experimental colitis by intestinal mononuclear phagocytes
J. Leukoc. Biol., October 1, 2006; 80(4): 802 - 815.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
D. Checchin, F. Sennlaub, E. Levavasseur, M. Leduc, and S. Chemtob
Potential role of microglia in retinal blood vessel formation.
Invest. Ophthalmol. Vis. Sci., August 1, 2006; 47(8): 3595 - 3602.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
M. C. Bosco, M. Puppo, C. Santangelo, L. Anfosso, U. Pfeffer, P. Fardin, F. Battaglia, and L. Varesio
Hypoxia Modifies the Transcriptome of Primary Human Monocytes: Modulation of Novel Immune-Related Genes and Identification Of CC-Chemokine Ligand 20 as a New Hypoxia-Inducible Gene
J. Immunol., August 1, 2006; 177(3): 1941 - 1955.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
G. Cao, R. C. Savani, M. Fehrenbach, C. Lyons, L. Zhang, G. Coukos, and H. M. DeLisser
Involvement of Endothelial CD44 during in Vivo Angiogenesis
Am. J. Pathol., July 1, 2006; 169(1): 325 - 336.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
J. W. Rohrer, A. L. Barsoum, and J. H. Coggin Jr.
Identification of Oncofetal Antigen/Immature Laminin Receptor Protein Epitopes That Activate BALB/c Mouse OFA/iLRP-Specific Effector and Regulatory T Cell Clones.
J. Immunol., March 1, 2006; 176(5): 2844 - 2856.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
E. M. Wagner, I. Petrache, B. Schofield, and W. Mitzner
Pulmonary ischemia induces lung remodeling and angiogenesis
J Appl Physiol, February 1, 2006; 100(2): 587 - 593.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
M. Anghelina, P. Krishnan, L. Moldovan, and N. I. Moldovan
Monocytes/Macrophages Cooperate with Progenitor Cells during Neovascularization and Tissue Repair: Conversion of Cell Columns into Fibrovascular Bundles
Am. J. Pathol., February 1, 2006; 168(2): 529 - 541.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
M. R. Ritter, J. Reinisch, S. F. Friedlander, and M. Friedlander
Myeloid Cells in Infantile Hemangioma
Am. J. Pathol., February 1, 2006; 168(2): 621 - 628.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
J. M. Lloyd, C. M. McIver, S.-A. Stephenson, P. J. Hewett, N. Rieger, and J. E. Hardingham
Identification of Early-Stage Colorectal Cancer Patients at Risk of Relapse Post-Resection by Immunobead Reverse Transcription-PCR Analysis of Peritoneal Lavage Fluid for Malignant Cells
Clin. Cancer Res., January 15, 2006; 12(2): 417 - 423.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
M. L. Lindsey, G. P. Escobar, L. W. Dobrucki, D. K. Goshorn, S. Bouges, J. T. Mingoia, D. M. McClister Jr., H. Su, J. Gannon, C. MacGillivray, et al.
Matrix metalloproteinase-9 gene deletion facilitates angiogenesis after myocardial infarction
Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H232 - H239.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
C. Murdoch, M. Muthana, and C. E. Lewis
Hypoxia Regulates Macrophage Functions in Inflammation
J. Immunol., November 15, 2005; 175(10): 6257 - 6263.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
T. Kuroda, Y. Kitadai, S. Tanaka, X. Yang, N. Mukaida, M. Yoshihara, and K. Chayama
Monocyte Chemoattractant Protein-1 Transfection Induces Angiogenesis and Tumorigenesis of Gastric Carcinoma in Nude Mice via Macrophage Recruitment
Clin. Cancer Res., November 1, 2005; 11(21): 7629 - 7636.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
J. An and M. B. Rettig
Mechanism of von Hippel-Lindau Protein-Mediated Suppression of Nuclear Factor kappa B Activity
Mol. Cell. Biol., September 1, 2005; 25(17): 7546 - 7556.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
C. Lewis and C. Murdoch
Macrophage Responses to Hypoxia: Implications for Tumor Progression and Anti-Cancer Therapies
Am. J. Pathol., September 1, 2005; 167(3): 627 - 635.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
C. Lamagna, K. M. Hodivala-Dilke, B. A. Imhof, and M. Aurrand-Lions
Antibody against Junctional Adhesion Molecule-C Inhibits Angiogenesis and Tumor Growth
Cancer Res., July 1, 2005; 65(13): 5703 - 5710.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
Y. Liang, M. Diehn, N. Watson, A. W. Bollen, K. D. Aldape, M. K. Nicholas, K. R. Lamborn, M. S. Berger, D. Botstein, P. O. Brown, et al.
Gene expression profiling reveals molecularly and clinically distinct subtypes of glioblastoma multiforme
PNAS, April 19, 2005; 102(16): 5814 - 5819.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
P. Allavena, M. Signorelli, M. Chieppa, E. Erba, G. Bianchi, F. Marchesi, C. O. Olimpio, C. Bonardi, A. Garbi, A. Lissoni, et al.
Anti-inflammatory Properties of the Novel Antitumor Agent Yondelis (Trabectedin): Inhibition of Macrophage Differentiation and Cytokine Production
Cancer Res., April 1, 2005; 65(7): 2964 - 2971.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
C. Murdoch, A. Giannoudis, and C. E. Lewis
Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues
Blood, October 15, 2004; 104(8): 2224 - 2234.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
J.-L. Roh, M.-W. Sung, S.-W. Park, D.-S. Heo, D. W. Lee, and K. H. Kim
Celecoxib Can Prevent Tumor Growth and Distant Metastasis in Postoperative Setting
Cancer Res., May 1, 2004; 64(9): 3230 - 3235.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
M. Vermeulen, M. Giordano, A. S. Trevani, C. Sedlik, R. Gamberale, P. Fernandez-Calotti, G. Salamone, S. Raiden, J. Sanjurjo, and J. R. Geffner
Acidosis Improves Uptake of Antigens and MHC Class I-Restricted Presentation by Dendritic Cells
J. Immunol., March 1, 2004; 172(5): 3196 - 3204.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
N. Zhang, Z. Fang, P. R. Contag, A. F. Purchio, and D. B. West
Tracking angiogenesis induced by skin wounding and contact hypersensitivity using a Vegfr2-luciferase transgenic mouse
Blood, January 15, 2004; 103(2): 617 - 626.
[Abstract] [Full Text] [PDF]

Home page
 JEMHome page
T. Schioppa, B. Uranchimeg, A. Saccani, S. K. Biswas, A. Doni, A. Rapisarda, S. Bernasconi, S. Saccani, M. Nebuloni, L. Vago, et al.
Regulation of the Chemokine Receptor CXCR4 by Hypoxia
J. Exp. Med., November 3, 2003; 198(9): 1391 - 1402.
[Abstract] [Full Text] [PDF]

Home page
 ChestHome page
J. G. Edwards, D. E. B. Swinson, J. L. Jones, S. Muller, D. A. Waller, and K. J. O'Byrne
Tumor Necrosis Correlates With Angiogenesis and Is a Predictor of Poor Prognosis in Malignant Mesothelioma
Chest, November 1, 2003; 124(5): 1916 - 1923.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
B. Burke, A. Giannoudis, K. P. Corke, D. Gill, M. Wells, L. Ziegler-Heitbrock, and C. E. Lewis
Hypoxia-Induced Gene Expression in Human Macrophages: Implications for Ischemic Tissues and Hypoxia-Regulated Gene Therapy
Am. J. Pathol., October 1, 2003; 163(4): 1233 - 1243.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
C. Tsutsumi, K.-H. Sonoda, K. Egashira, H. Qiao, T. Hisatomi, S. Nakao, M. Ishibashi, I. F. Charo, T. Sakamoto, T. Murata, et al.
The critical role of ocular-infiltrating macrophages in the development of choroidal neovascularization
J. Leukoc. Biol., July 1, 2003; 74(1): 25 - 32.
[Abstract] [Full Text] [PDF]

Home page
 Exp. Biol. Med.Home page
M. Ramanathan, A. Giladi, and S. J. Leibovich
Regulation of Vascular Endothelial Growth Factor Gene Expression in Murine Macrophages by Nitric Oxide and Hypoxia
Experimental Biology and Medicine, June 1, 2003; 228(6): 697 - 705.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
J. A. Posey, T. C. Ng, B. Yang, M. B. Khazaeli, M. D. Carpenter, F. Fox, M. Needle, H. Waksal, and A. F. LoBuglio
A Phase I Study of Anti-Kinase Insert Domain-containing Receptor Antibody, IMC-1C11, in Patients with Liver Metastases from Colorectal Carcinoma
Clin. Cancer Res., April 1, 2003; 9(4): 1323 - 1332.
[Abstract] [Full Text] [PDF]

Home page
 JEMHome page
J. Mattes, M. Hulett, W. Xie, S. Hogan, M. E. Rothenberg, P. Foster, and C. Parish
Immunotherapy of Cytotoxic T Cell-resistant Tumors by T Helper 2 Cells: An Eotaxin and STAT6-dependent Process
J. Exp. Med., February 3, 2003; 197(3): 387 - 393.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
S. Yoshida, A. Yoshida, T. Ishibashi, S. G. Elner, and V. M. Elner
Role of MCP-1 and MIP-1{alpha} in retinal neovascularization during postischemic inflammation in a mouse model of retinal neovascularization
J. Leukoc. Biol., January 1, 2003; 73(1): 137 - 144.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
B. Burke, S. Sumner, N. Maitland, and C. E. Lewis
Macrophages in gene therapy: cellular delivery vehicles and in vivo targets
J. Leukoc. Biol., September 1, 2002; 72(3): 417 - 428.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
C. S. Brissette-Storkus, S. M. Reynolds, A. J. Lepisto, and R. L. Hendricks
Identification of a Novel Macrophage Population in the Normal Mouse Corneal Stroma
Invest. Ophthalmol. Vis. Sci., July 1, 2002; 43(7): 2264 - 2271.
[Abstract] [Full Text] [PDF]

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