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Published online before print July 18, 2006
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Division of Experimental Oncology, Lausanne Cancer Center, Epalinges, Switzerland, and Swiss Institute for Experimental Cancer Research (ISREC), NCCR Molecular Oncology, Epalinges, Switzerland
1 Correspondence: CePO, 155 Chemin des Boveresses, CH-1066 Epalinges, Switzerland. E-mail: curzio.ruegg{at}isrec.ch
ABSTRACT
Leukocytes are cells of defense. Their main function is to protect our body against invading microorganisms. Some leukocytes, in particular, polymorphonuclear and monocytes, accumulate at sites of infection and neutralize pathogens through innate mechanisms. The blood and lymphatic vascular system are essential partners in this defensive reaction: Activated endothelial cells promote leukocyte recruitment at inflammatory sites; new blood vessel formation, a process called angiogenesis, sustains chronic inflammation, and lymphatic vessels transport antigens and antigen-presenting cells to lymph nodes, where they stimulate naive T and B lymphocytes to elicit an antigen-specific immune response. In contrast, leukocytes and lymphocytes are far less efficient in protecting us from cancer, the "enemy from within." Worse, cancer can exploit inflammation to its advantage. The role of angiogenesis, leukocytes, and inflammation in tumor progression was discussed at the second Monte Verità Conference, Tumor Host Interaction and Angiogenesis: Basic Mechanisms and Therapeutic Perspectives, held in Ascona, Switzerland, October 1–5, 2005. (Conference chairs were K. Alitalo, M. Aguet, C. Rüegg, and I. Stamenkovic.) Eight articles reporting about topics presented at the conference are featured in this issue of the Journal of Leukocyte Biology.
Key Words: invasion • metastasis • tumor stroma • monocytes • lymphocytes
Tumorigenesis is a multistep process in which cancer cells arise from normal cells following the accumulation of mutations, leading to the activation of proto-oncogenes and the inactivation of tumor suppressor genes. The fate of a cancer cell, however, strongly depends on the generation of a "supportive" environment, the tumor stroma, and the establishment of a bidirectional cross-talk among tumor cells, tissue-resident cells (e.g., fibroblasts), and tumor-infiltrating cells [1 ]. The formation of a tumor-associated vasculature (i.e., tumor angiogenesis) has emerged as a critical step promoting local tumor progression and metastatic spreading. The relevance of tumor angiogenesis to cancer progression is best exemplified by the approval in 2004 of Avastin, an antibody neutralizing the angiogenic vascular endothelial growth factor (VEGF), as the first antiangiogenic drug for the treatment of human cancer [2 ]. Solid cancers often show typical signs of inflammation and are infiltrated by many leukocyte populations, i.e., neutrophils, eosinophils, basophils, monocytes/macrophages, dendritic cells, natural killer cells, and lymphocytes. The concept that inflammation promotes tumorigenesis is not novel. Indeed, a causal relationship between chronic inflammation and cancer formation was proposed over a century ago based on the observations that cancers often develop at sites of chronic inflammation (e.g., colorectal cancer in Crohn’s disease or esophageal cancer in chronic reflux esophagitis) [3 ]. Nelson and Ganss review and discuss some aspects of the role of inflammation in promoting or suppressing cancer growth. Although many of these leukocytes are potentially capable of killing tumor cells, experimental and clinical evidence suggests that in most cases, they actually contribute to tumor progression [4 ].
Today, some of the underlying cellular and molecular events linking inflammation and cancer have been unraveled (Fig. 1 ). Tumor-associated monocytes/macrophages are essential promoters of tumor cell migration, invasion, and metastasis [5 ]. Monocytes are attracted by cytokines and chemokines (e.g., CSF-1, GM-CSF, MCP-1), released by tumor cells or cells of the tumor microenvironment, and once within the tumor, are induced to express proangiogenic and tumor-promoting factors, including VEGF-A and -C, fibroblast growth factor-2, TNF, platelet-derived growth factor, and matrix metalloproteinase-9 (MMP-9). Lamagna et al. review the role of tumor macrophages in modulating tumor growth and angiogenesis and discuss some of the associated molecular events. TNF family members are among the best-characterized cytokines produced by activated leukocytes. Some members of this family [e.g., vascular endothelial growth inhibitor (VEGF)] can suppress angiogenesis and tumor growth and even induce tumor necrosis (hence, the name, tumor necrosis factor, given to the first member of this family), and others (e.g., a proliferation-inducing TNF ligand, APRIL) promote tumor progression [6 ]. Mhawech-Fauceglia et al. report that neutrophils present in the tumor stroma are the main source of APRIL. Leukocytes also contribute to the proteolytic modification of the extracellular matrix (ECM) by delivering proteinases, including MMPs, cathepsins, plasminogen, and urokinase. The emerging role of proteolysis in tumor progression is far more complex than the mere degradation of structural ECM components as originally assumed. Proteinases can regulate angiogenesis positively and negatively by releasing and activating matrix-immobilized angiogenic factors, processing of cytokines and cytokine receptors, and producing endogenous inhibitors of angiogenesis, such as angiostatin, endostatin, or tumstatin [7 ]. Schaffhauser et al. report a study in which they use the rat insulin promoter 1/T-antigen 2 (Rip1 Tag2) model of multistep tumorigenesis to compare the effect of endostatin produced locally within the tumor environment with that of endostatin delivered systemically and show that systemic administration was more effective than local production in inhibiting tumor growth.
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Leukocyte trafficking across the vessel wall is a complex event requiring the coordinated expression of adhesion molecule and chemokines on activated endothelial cells. Recently, a new family of cell adhesion molecules, junctional adhesion molecules (JAMs), emerged as an important regulator of leukocyte transendothelial migration [9 ]. Nourshargh et al. review the role of JAM-A and the related molecule PECAM-1/CD31 in modulating leukocyte recruitment in inflamed and ischemic tissues. The angiopoietin Tie and the ephrin Eph ligand receptor systems were discovered originally as specific modulators of angiogenesis, remodeling, and vascular homeostasis [10 ]. Recent reports indicate that these systems may also regulate cell trafficking across the endothelium, thereby revealing unsuspected connections among the regulation of vascular homeostasis, angiogenesis, and leukocyte trafficking. Pfaff et al. reviewed these recent findings.
Tumor cells exploit mechanisms that occur physiologically during inflammation to invade and metastasize, in particular, the chemokine system (e.g., IL-8, stromal cell-derived factor-1/CXCL12) [11 ] and existing draining lymphatics [12 ]. Tobler and Detmar review recent advances about the understanding of the mechanisms promoting tumor cell spread to lymph nodes and beyond.
If inflammation promotes cancer, could anti-inflammatory drugs suppress cancer? Experimental and clinical evidence indeed suggests so. A good example is cyclooxygenase-2 expression and prostaglandin production within the tumor environment, which stimulate tumor growth and angiogenesis. Nonsteroidal anti-inflammatory drugs reduce the risk of developing cancer significantly, in particular, of the gastrointestinal tract [13 ], and may also induce tumor regression [14 ]. In conclusion, although it is becoming increasingly clear that leukocytes, inflammation, and angiogenesis build up a fatal attraction in cancer, anti-inflammatory drugs may emerge in the future as useful drugs to treat cancer [15 ].
Received June 12, 2006; accepted June 14, 2006.
REFERENCES
This article has been cited by other articles:
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  P. Sinha, C. Okoro, D. Foell, H. H. Freeze, S. Ostrand-Rosenberg, and G. Srikrishna Proinflammatory S100 Proteins Regulate the Accumulation of Myeloid-Derived Suppressor Cells J. Immunol., October 1, 2008; 181(7): 4666 - 4675. [Abstract] [Full Text] [PDF]
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