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Originally published online as doi:10.1189/jlb.1105655 on June 22, 2006

Published online before print June 22, 2006
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(Journal of Leukocyte Biology. 2006;80:697-704.)
© 2006 by Society for Leukocyte Biology

The source of APRIL up-regulation in human solid tumor lesions

P. Mhawech-Fauceglia*, G. Kaya{dagger}, G. Sauter{ddagger}, T. McKee§, O. Donze, J. Schwaller|| and B. Huard#,1

* Department of Pathology and Laboratory Medicine, Roswell Park Cancer Institute, Buffalo, New York;
{dagger} Department of Dermatology, Geneva University Hospital, Geneva, Switzerland;
{ddagger} Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
§ Department of Pathology, Geneva University Medical Center, Geneva, Switzerland;
Apotech Corp., Epalinges, Switzerland;
|| Department of Research, Basel University Hospital, Basel, Switzerland; and
# Louis Jeantet Laboratory, Departments of Dermatology and Pathology-Immunlogy, Geneva University Medical Center, Geneva, Switzerland

1 Correspondence: Louis Jeantet Laboratory, University Medical Center, rue Michel Servet 1, 1211 Geneva 4, Switzerland. E-mail: bertrand.huard{at}medecine.unige.ch

ABSTRACT

Abundant mRNA expression for a proliferation-inducing ligand (APRIL) from tumor necrosis factor (TNF) family is observed in many solid tumors. Here, we analyzed in situ the cellular source of APRIL in human solid tumors with anti-APRIL antibodies. In most cases, neutrophils present in the tumor stroma constituted the main source of APRIL. In cutaneous lesions such as melanoma or basal cell carcinoma, tumor-adjacent keratinocytes also produced APRIL. APRIL production by tumor cells themselves was a rare event, only observed in urothelial bladder cancer and squamous cell carcinoma. Detailed analysis revealed that APRIL dissociated from producing cells, and secreted APRIL was retained in the tumor lesions. A direct binding onto tumor cells via heparan sulfate proteoglycans (HSPG) was observed in in vitro experiments and confirmed in situ. Taken together, our analysis indicates a potential role for HSPG/APRIL interactions in the development of solid tumors.

Key Words: cancer • neutrophils • inflammation • TNF • proteoglycan

INTRODUCTION

In the TNF superfamily, a proliferation-inducing ligand (APRIL), also known as TALL-2 and TNFSF13, is closely related to the B-cell activation factor from the TNF family (BAFF), also known as BLys, TALL-1, THANK, zTNF4, and RNFSF13B. These two TNF ligands share the receptors B cell maturation antigen (BCMA) and transmembrane activator, calcium modulator, and cyclophilin ligand interactor (TACI) [1 ]. Recently, APRIL binding to the heparan sulfate side-chains of proteoglycans (HSPG) was demonstrated [2 , 3 ]. In contrast, BAFF does not bind HSPG. In animal models, APRIL and BAFF show a tumor-promoting activity, as their overexpression induces development of B cell neoplasia [4 , 5 ]. This activity is consistent with the B cell survival role described for APRIL and BAFF [6 ]. However, the differences in receptor binding described above suggest nonredundant, physiological functions for APRIL and BAFF.

APRIL tumor-promoting activity is not restricted to B cell lymphomas. Indeed, APRIL was also shown to provide a proliferative/survival signal to solid tumor cells. Although modestly detectable in vitro [7 , 8 ], this activity has been observed significantly in vivo by overexpressing APRIL in tumor cells [7 ] or by blocking endogenous APRIL [9 ]. In vitro, APRIL mRNA expression is observed in solid tumor cell lines [7 , 8 , 10 ] and in hematopoietic cells from the myeloid lineage [11 12 13 14 ]. This indicates that the cellular source of APRIL in tumor lesions could be tumor cells themselves or infiltrating hematopoietic cells. Here, we analyzed in situ APRIL protein expression in human solid tumors. We found that APRIL is produced mainly by tumor-infiltrating neutrophils and by normal epithelial cells adjacent to cutaneous tumors, such as melanoma and basal cell carcinoma (BCC). Notably, secreted APRIL-rich regions are constituted around tumor cells. The role of APRIL in the context of solid tumor is discussed.

MATERIALS AND METHODS

Cells and reagents
Hela cervix carcinoma cells, HT-29 adenocarcinoma and Kim-1 hepatocellular carcinoma, were purchased from American Type Culture Collection (Manassas, VA). The melanoma cell lines Me-190, -245, -67.8, and -300 and Mewo were kindly provided by Dr. Donata Rimoldi (ISREC, Epalinges, Switzerland). All cell lines were grown in Dulbecco’s modified Eagle’s medium supplemented with 10% fetal calf serum. DNA plasmids encoding for soluble APRIL and human embryonic kidney-293T cell transfection have been described elsewhere [2 ]. Heparin (Liquemin, 5000 i.u./ml) was from Roche Pharmaceuticals (Nutley, NJ). The anti-APRIL [Clone Aprily-1, -2, mouse immunoglobulin G1 (IgG1)] against the extracellular portion (88–233) of APRIL and the rabbit polyclonal ED against the APRIL peptide amino acids (aa) 67–79 (Stalk-1 hereafter) were obtained from Alexis Biochemicals (Lausen, Switzerland). An antiserum against the extracellular portion (aa 88–233) of APRIL was made in rabbit and used as detection reagent in enzyme-linked immunosorbent assay (ELISA). MegaAPRIL, consisting of extracellular APRIL (88–233), fused to ACRP30 (16–108), its control headless ACRP30, hereafter called acrpAPRIL and acrp, respectively, were also from Alexis Biochemicals. Anti-CD15 (Clone C3D-1, IgM), anti-elastase (Clone NP57, IgG1), and pan-keratin (rabbit polyclonal) were from Dakocytomation (Glostrup, Denmark). Rabbit polyclonal anti-syndecan-1 was from Santa Cruz Biotechnology Inc. (CA).

Flow cytometry
For antibody staining, cells were washed in phosphate-buffered saline (PBS) and incubated for 30 min at 4°C with primary antibodies. Cells were washed once in PBS and incubated with secondary Alexa 488-conjugated goat antimouse serum (Molecular Probes, Eugene, OR) for an additional 30 min at 4°C. Cells were washed once in PBS before analysis using a FACScan and CellQuest software (Becton Dickinson Biosciences, Franklin Lakes, NJ). Ligand staining was performed in a similar way, except that an anti-Flag antibody at 5 µg/ml (IgG1, Clone M2, Sigma-Aldrich, St. Louis, MO) was used as a secondary reagent, and staining was revealed with phycoerythrin (PE)-conjugated goat anti-mouse IgG1 (Jackson Immunoresearch Laboratories, West Grove, PA). For total staining, cells were fixed/permeabilized with PBS, 1% formaldehyde, and staining was performed in the presence of 1% saponin as described previously [15 ].

ELISA
Microplates were coated overnight at 4°C with 1 µg/ml BCMA-Ig (Alexis Biochemicals). Plates were blocked in PBS, 0.05% NaN3, 1% bovine serum albumin, 5% sucrose. Cell supernatants were prediluted 1/2 in PBS, 0.05% Tween 20. Standard was acrp-APRIL. Detection was performed with a rabbit polyclonal anti-human APRIL (1 µg/ml), followed by horseradish peroxidase (HRP)-conjugated goat anti-rabbit IgG serum (Jackson Immunoresearch Laboratories). Tetramethylbenzidine (Sigma-Aldrich) was used as substrate for HRP. Two washes with PBS, 0.05% Tween 20, were performed between each step.

Immunohistochemistry
Multitumor tissue microarrays were constructed using surgical specimens as described previously [16 ]. Briefly, after carefully choosing a morphologically representative region on paraffin-embedded blocks (donor blocks), a core tissue biopsy of 0.6 mm was punched and transferred to a second paraffin-embedded block (receiver block). After deparaffinization, sections were incubated for 10 min in methanol plus 0.6% hydrogen peroxide at room temperature, followed by washing with PBS solution. Slides were boiled in 0.01 M citrate buffer, pH 6.0, for 3 min. Incubation with antibodies was carried out for 1 h at room temperature. For immunoperoxidase staining, secondary reagents were goat Ig anti-rabbit or anti-mouse IgG conjugated to biotin (Jackson Immunoresearch Laboratories), followed by streptABComplex/HRP (Dakocytomation) and 3-amino-9-ethylcarbazole substrate (Sigma-Aldrich). For two-color immunofluorescence stainings, isotype-specific goat anti-mouse sera conjugated to PE (Jackson Immunoresearch Laboratories) and goat Ig anti-rabbit IgG conjugated to Alexa-488 (Molecular Probes) were used. Images were visualized under light or fluorescent microscopy with Axiophot 1, captured with an Axiocam color charged-coupled device camera and treated on a PentiumIII computer with axioVisionTM software (Carl Zeiss AG, Göttingen, Germany).

RESULTS

Skin tumor development induces recruitment of APRIL-producing granulocytes and APRIL production in keratinocytes
An in vivo pro-tumor role of endogenous APRIL was identified originally by grafting the adenocarcinoma HT29 cell line subcutaneously in immunodeficient mice [9 ]. We therefore looked at APRIL production in human cutaneous tumors. We used an anti-APRIL antibody, Stalk-1, selectively identifying cells producing APRIL in situ. This antibody recognizes the nonsecreted product of APRIL, staying anchored in the membrane of producing cells upon furin cleavage [17 ]. Stalk-1 stained human tissues specifically, as reactivity on human melanoma sections was blocked by the peptide used to raise Stalk-1 in rabbits (Fig. 1A ). An intense staining for Stalk-1 was observed in the epithelium overlying melanoma cells. A similar staining was observed for BCC, and no staining was seen in normal skin (Fig. 1B) or at a distance from the tumor lesion (data not shown). None of the irrelevant polyclonal antibodies tested in this experiment (n=4) stained these epithelia (data not shown). Higher magnification revealed that the staining was usually more intense in the supra-basal layer of keratinocytes (inset), identifying differentiated keratinocytes as APRIL-producing cells. In contrast, none of the BCC and melanoma tumor cells produced APRIL. This indicates that keratinocytes respond to tumor development by producing APRIL locally. In addition to this epithelial staining, stromal cells were stained with Stalk-1. These APRIL-producing cells surrounded tumor nests. Such cells were not detected in the derma of normal skin, indicating that tumor development also induces the recruitment of APRIL-producing cells and/or production of APRIL in dermal-resident cells.


Figure 1
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  		Figure 1. APRIL production in melanoma and BCC. (A) A melanoma lesion was stained with Stalk-1 (identifying in situ APRIL-producing cells) in the presence of a blocking or an irrelevant peptide. (B) Lesions from BCC and normal skin were also stained with Stalk-1. Original magnification was 10x. Arrows indicate Stalk-1-positive cells in the dermis. Insets (40x original magnification) show APRIL-producing cells in the epithelium. The figures are representative of eight BCC, 12 melanomas, and five normal skin sections.

 
We next identified stromal cells producing APRIL in two-color immunofluorescence-staining experiments. Figure 2A shows that all the Stalk-1-positive cells expressed the mature granulocyte marker CD15 in BCC. In addition to CD15, the Stalk-1-positive cells contained elastase-positive granules (Fig. 2B) , identifying them as neutrophils. High magnification analysis confirmed this observation, as a tri-lobular nucleus was observed in these cells (Fig. 2C) . The APRIL-producing neutrophils constitute the main source of APRIL in melanoma (n=4) and BCC (n=8) lesions analyzed. However, a minority of CD15+Stalk-1+ cells in the lesions did not show elastase-positive granules. These cells did not express CD68, excluding monocyte/macrophages, and were identified morphologically as eosinophils (data not shown). In addition, few endothelial cells were stained with Stalk-1 (Fig. 2D) . Taken together, these indicate that APRIL in BCC and melanoma lesions is provided by keratinocytes and mature granulocytes. The majority of the mature granulocytes producing APRIL was neutrophils.


Figure 2
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  		Figure 2. Neutrophils produce APRIL in the tumor stroma. (A) A carcinoma case was analyzed in double-fluorescence stainings with Stalk-1 (green) and an anti-CD15 (1/50, red) or (B) elastase monoclonal antibody (1 µg/ml, red). The merged pictures show a complete overlap between Stalk-1 and CD15 or elastase stainings. (C) Stalk-1-stained cells with tri-lobular nuclei in a BCC lesion (original magnification, 40x). (D) Endothelial cells stained with Stalk-1 (original magnification, 40x). The stainings shown are representative of lesions from four BCC patients.

 
Neutrophils are efficient cells to secrete APRIL
As APRIL is binding to cellular proteoglycans, we assessed the influence of proteoglycans in the secretion of APRIL by producing cells. We transfected 293-T cells, known to express proteoglycans [18 ], with a plasmid encoding secreted APRIL, APRILA88, or secreted APRIL lacking the proteoglycan-binding site APRILH98. Figure 3A shows that a significant fraction of 293 T-transfected cells retained a high level of APRILA88 (peak of cells with a high fluorescence level), and this cell population was absent in APRILH98-transfected cells. The cell retention was confirmed by quantification of secreted APRIL in the supernatant. 293-T cells transfected with APRILH98 secreted ~2.5 µg/ml recombinant protein, and tenfold less secretion was achieved with APRILA88 (Fig. 3B) . We next assessed whether neutrophils, shown above as the major hematopoietic cells producing APRIL in tumor lesions, express proteoglycans. This was achieved by testing APRILA88 binding to the cell surface. Figure 3C shows that the neutrophil cell line HL60 did not bind APRIL, which was also not binding to ex vivo-purified peripheral neutrophils (data not shown). In contrast, the L363 cell line (multiple myeloma cell line expressing syndecan-1) bound APRIL. The latter binding was competed by heparin, indicating a HSPG-dependent interaction. Taken together, these data show that neutrophils are devoid of any detectable proteoglycans able to bind APRIL on their surface. The deficit in expression of proteoglycans binding APRIL by neutrophils renders them fully competent to secrete this molecule.


Figure 3
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  		Figure 3. Neutrophils are fully equipped to secrete APRIL. (A) 293-T cells transfected with APRILA88 or APRILH98 were stained with Aprily-1 (10 µg/ml) after cell permeabilization. Fluorescence was analyzed by flow cytometry. (B) Secreted APRIL was quantified in a sandwich ELISA in two independent supernatants from 293-T cells transfected with APRILA88 or APRILH98. (C) Binding of acrpAPRILA88 (1 µg/ml) was assessed on HL60 and L363 cell lines. Acrp was used as negative control. Competition with heparin was also performed.

 
High concentration of secreted APRIL in tumor lesions
Secreted APRIL was next tracked in tumor lesions with the use of Aprily-2, an antibody selectively binding to the secreted form of APRIL [17 ]. BCC tumor cells were stained with a pan-keratin antibody, used here as a tumor marker (Fig. 4A ). An intense, punctuated staining was observed in the stroma. Secreted APRIL depots were observed in the stroma surrounding the tumor lesions and even in close contacts with the periphery of tumor nests (Fig. 4A) . We also stained lesions, wherein adjacent keratinocytes were producing APRIL. The pan-keratin antibody first identified the epithelium, and Stalk-1 served to identify areas producing APRIL (data not shown). We observed that skin epithelia express syndecan-1 (Fig. 4B) , consistent with a previous report [19 ]. Syndecan-1 is a HSPG able to bind APRIL [2 ]. In this situation, Aprily-2 staining was seen at the epithelial level, concentrating in the basal layer constituted by undifferentiated keratinocytes expressing syndecan-1 (Fig. 4B) . Depots of secreted APRIL were also observed in the stroma (Fig. 4B) . Taken together, these experiments indicate that high concentrations of secreted APRIL are retained in tumor lesions.


Figure 4
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  		Figure 4. High concentration of secreted APRIL in solid tumor lesions. (A) A BCC lesion was stained with pan-keratin (1/100, green) and Aprily-2 (2 µg/ml, red). The merged picture shows depots of secreted APRIL in close proximity or in contacts with tumor cells. Similar stainings were observed for melanoma lesions. (B) A melanoma lesion was stained with anti-syndecan-1 (10 µg/ml, green) and Aprily-2 (red). The merged picture shows depots of secreted APRIL in the basal layer of the epithelium and the stroma. The figures are representative of five BCC and three melanomas.

 
Secreted APRIL binds to solid tumor cells via HSPG interaction
To investigate the interaction of secreted APRIL with tumor cells, we performed in vitro-binding assays with soluble APRIL. Figure 5A shows an efficient binding of soluble APRIL onto carcinoma and melanoma cells. Heparin, a soluble HSPG-competing APRIL/HSPG interaction [2 ], gave a complete binding inhibition, indicating that APRIL binding was mediated by HSPG interactions. Such HSPG-dependent interactions of APRIL were seen with two other carcinomas (Kim-1, HT-29) and four other melanoma cell lines (Mewo, Me300, Me67.8, Me245; data not shown). In fact, all the tumor cell lines tested here bind soluble APRIL, indicating a constitutive expression of HSPG, binding APRIL, by solid tumor cells. We next looked in situ at binding of secreted APRIL to tumor cells from diverse origins. Figure 5B shows Aprily-2 staining located into tumor nests. Higher magnification analysis revealed Aprily-2 staining around morphologically characteristic tumor cells. Similar staining was also seen with melanoma (data not shown). Thus, secreted APRIL also binds to tumor cells in situ.


Figure 5
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  		Figure 5. APRIL binds to solid tumor cells in a HSPG-dependent manner. (A) Flow cytometry analysis of acrp-APRILA88 (1 µg/ml) binding to solid tumor cell lines in the presence or absence of soluble heparin. Data obtained with binding of acrpAPRIL are shown as thick lines in the absence of heparin or thin lines when preincubated with heparin (1/100). Control stainings (Acrp) are shown as dotted lines. (B) Tumor lesions from independent patients and of the indicated origins were stained with Aprily-2. Upper panel shows 10x original magnification; lower panel shows 40x original magnification. An arrow for each case is marking a tumor cell binding secreted APRIL.

 
Stromal cells constitute the main source of APRIL in human solid tumors of diverse origins
To further document APRIL production in solid tumors, microarrayed tissue sections of human solid tumors from diverse origins were stained with Stalk-1. A total of 2159 tumor samples was analyzed. Table 1 shows that APRIL-producing cells were detectable in approximately two-thirds of the lesions (1374/2159). Figure 6A shows representative lesions with no detectable APRIL-producing cells. In more than 85% of the Stalk-1-positive lesions (1176/1374), stromal cells constituted the unique source of APRIL. Representative lesions with stroma as the unique source of APRIL are shown in Figure 6B . It is notable that urothelial carcinoma of the bladder (UCB) and squamous cell carcinoma (SCC) of the larynx showed tumor cells producing APRIL by themselves (Fig. 6C) . UCB and SCC [51/63 (80%) and 138/462 (29%), respectively] showed tumor cells stained with Stalk-1. Higher magnification analysis (inserts) revealed that Stalk-1 staining was focal in these lesions, with only a fraction of tumor cells stained. Finally, lesions wherein tumor cells constituted the unique source of APRIL were extremely rare (20/2159, 0.9%). In contrast to tumor lesions, Stalk-1-stained cells were rare in normal tissues (data not shown), demonstrating up-regulation of APRIL production in solid tumors. Taken together, this microarray analysis revealed that APRIL is produced in a majority of solid tumors from diverse origins. Again, stromal cells constitute the main cellular source of APRIL in these solid tumors.


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  		Table 1. APRIL-Producing Cells in Human Solid Tumors

 

Figure 6
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  		Figure 6. APRIL production in human carcinomas from diverse origins. Tumor lesions from UCB and lung SCC were stained with Stalk-1. Representative sections (10x original magnification) show (A) no APRIL expression, (B) APRIL expression only in stromal cells, and (C) APRIL expression in tumor and stromal cells. Insets (40x original magnification) show the focal expression of APRIL in carcinoma cells.

 
DISCUSSION

In this study, we analyzed APRIL expression in human solid tumors from diverse origins. We observed APRIL-producing cells in approximately two-thirds of the tumor lesions. The reason why some solid tumors were devoid of APRIL-producing cells in this analysis is not known presently. We cannot exclude for the negative cases that sampling, as a result of the tissue microarraying process, has selected negative areas. In the positive lesions, neutrophils present in the stroma were the main source of APRIL. This in situ expression of APRIL by neutrophils is consistent with the in vitro-reported expression in cells from the myeloid lineage and our recent in situ observation in high-grade human B cell lymphoma [17 ]. In addition to neutrophils, differentiating keratinocytes adjacent to tumors produced APRIL. Such production of tumor-modulating molecules has already been described in keratinocytes responding to tumor development [20 ].

Consistent with the presence of APRIL-producing cells, high concentrations of secreted APRIL were observed in tumor lesions. Such concentrations are indicative for a local retention of the secreted molecule. We already observed such local retention of secreted APRIL in high-grade B cell lymphomas without any diffusion to peripheral blood (submitted manuscript). In B cell lymphomas, the retention was a result of HSPG binding secreted APRIL. Considering the similar punctuated staining observed in the present study, APRIL is also likely retained by HSPG in solid tumor lesions.

In our analysis, only a minority (less than 15%) of lesions harbored tumor cells, producing APRIL themselves. It is notable that this was found selectively in SCC from any organs and UCB. In solid tumors from other origins, we did not find a significant number of lesions harboring tumor cells expressing APRIL. Why is APRIL production by tumor cells so restricted? It is notable that APRIL expression by these tumor cells is focal, suggesting a response to an exogenous factor instead of an intrinsic property. In addition to this, APRIL expression by tumor cells was seen in tumors derived from mucosa epithelial cells. These cells may represent transformed epithelial cells responding to their own tumor development by producing APRIL, similarly to skin keratinocytes in cutaneous tumors. For patients with SCC of the head and neck, no significant correlation was observed between APRIL expression by tumor cells and stage, grade, or overall patient survival (unpublished observation). This suggests that APRIL production by tumor cells is not a factor influencing tumor growth and/or severity. However, a role for APRIL in these tumors may be hidden by a paracrine action of APRIL.

What could be the role of APRIL and more specifically, APRIL/HSPG interactions in solid cancers? HSPG, by binding to the extracellular matrix (ECM) and/or soluble ligands, mediates pleiotropic, biological functions. They regulate growth factor signaling, cytoskeleton organization, cell adhesion, and migration [21 ]. As a result of these properties, HSPG have been implicated in solid tumor development [22 ]. Among other examples, syndecan-1 expression is absolutely required for the development of mammary tumors driven by the transgenic expression of the proto-oncogene, Wnt-1, in mice [23 ]. An important part of HSPG functions has been attributed to the role of the heparan sulfate moiety in concentrating ligands for signaling receptors. Such HSPG coreceptor function is doubtful in solid tumors, as the two known-to-date APRIL signaling receptors, TACI and BCMA, have a restricted expression to specific B cell differentiation stages [24 ]. Therefore, direct signaling by the proteic core moiety of HSPG on APRIL binding may be taken into consideration. Such signaling function has already been proposed for HSPG [25 ]. Alternatively, HSPG may modulate cancer cell adhesion and invasion. Indeed, despite the fact that affinity of HSPG binding to ECM components is of low affinity in the micromolar range [21 ], tumor cell adhesion and invasion assays revealed a critical role for HSPG, possibly by serving as coreceptors for integrins [26 ]. Among others, an interesting study showed that solid tumor cell spreading induced upon syndecan-1 ligation, required integrin function [27 ].

The abundant expression of APRIL in a majority of human solid tumors is consistent with an implication in solid cancer development. This implication is likely to be dependent on the HSPG-binding property of APRIL. As a result of the complexity of HSPG involvement in cancer progression [28 ], additional studies are definitely required to fully understand the impact of APRIL up-regulation in solid cancer development. Such studies may reveal a more complex role for APRIL than the tumor-promoting activity known to date.

ACKNOWLEDGEMENTS

This work was supported by Dinu Lipatti/Henri Dubois-Ferrière Foundation. The technical expertise of C. Bosshard and K. Grosdemange is greatly acknowledged. Authors declare that they have no competing financial interest.

Received November 13, 2005; accepted April 24, 2006.

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