APRIL is overexpressed in cancer: link with tumor progression
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BAFF and APRIL share two receptors – TACI and BCMA – and BAFF binds to a third receptor, BAFF-R. Increased expression of BAFF and APRIL is noted in hematological malignancies. BAFF and APRIL are essential for the survival of normal and malignant B lymphocytes, and altered expression of BAFF or APRIL or of their receptors (BCMA, TACI, or BAFF-R) have been reported in various B-cell malignancies including B-cell non-Hodgkin's lymphoma, chronic lymphocytic leukemia, Hodgkin's lymphoma, multiple myeloma, and Waldenstrom's macroglobulinemia.
We compared the expression of BAFF, APRIL, TACI and BAFF-R gene expression in 40 human tumor types – brain, epithelial, lymphoid, germ cells – to that of their normal tissue counterparts using publicly available gene expression data, including the Oncomine Cancer Microarray database.
We found significant overexpression of TACI in multiple myeloma and thyroid carcinoma and an association between TACI expression and prognosis in lymphoma. Furthermore, BAFF and APRIL are overexpressed in many cancers and we show that APRIL expression is associated with tumor progression. We also found overexpression of at least one proteoglycan with heparan sulfate chains (HS), which are coreceptors for APRIL and TACI, in tumors where APRIL is either overexpressed or is a prognostic factor. APRIL could induce survival or proliferation directly through HS proteoglycans.
Taken together, these data suggest that APRIL is a potential prognostic factor for a large array of malignancies.
KeywordsMultiple Myeloma Chronic Lymphocytic Leukemia Bladder Carcinoma Burkitt Lymphoma Heparan Sulfate Proteoglycan
APRIL and BAFF are two members of the TNF family. BAFF is a type II transmembrane protein that can be secreted after proteolytical cleavage from the cell membrane[1, 2]. APRIL is processed intracellularly within the Golgi apparatus by a furin pro-protein convertase prior to secretion of the biologically active form. APRIL can also be expressed as a cell surface fusion protein with TWEAK called TWE-PRIL[4, 5]. Both ligands bind to TACI (transmembrane activator and CAML interactor) and BCMA (B-cell maturation antigen), two members of the TNFR family. BAFF binds additionally to BAFF receptor (BAFF-R). BAFF is involved in the survival of normal and malignant B cells and normal plasmablasts [6, 7, 8]. APRIL is highly expressed in several tumor tissues, stimulates the growth of tumor cells and promotes survival of normal plasmablasts and plasma cells[10, 11].
Evidence has been presented that BAFF/APRIL contribute to malignancies of B cells and plasma cells: non-Hodgkin's lymphoma [12, 13, 14, 15, 16], Hodgkin lymphoma, chronic lymphocytic leukemia[18, 19], multiple myeloma [20, 21, 22, 23, 24] and Waldenstrom's macroglobulinemia.
Recombinant APRIL binds to several cell lines that do not express detectable mRNA for TACI and BCMA and proteoglycans were identified as APRIL-specific binding partners. This binding is mediated by heparan sulfate (HS) side chains and can be inhibited by heparin[26, 27]. Binding of APRIL to proteoglycans or BCMA/TACI involves different regions in APRIL. APRIL binds HS proteoglycans via the lysine-rich region in the N-terminal part, leaving the TNF-like region available to interact with others receptors. Blockade of APRIL/BAFF using human BCMA-Ig in nude mice inhibited the growth of a subcutaneously injected human lung carcinoma cell line (A549) and a human colon carcinoma cell line (HT29). These cell lines express APRIL, but not BAFF, TACI, BCMA or BAFF-R suggesting that HS proteoglycans could mediate the growth response to APRIL. However, BCMA-Fc leaves the APRIL binding HSPG domain intact. This blockade may suggest that the TNF-receptor binding domain is also necessary for activity, and that an additional APRIL-specific receptor might exist. B-cell lymphoma cells can bind large amount of APRIL secreted by neutrophils via proteoglycan binding and the high expression of APRIL in tumor lesion correlates with B-cell lymphoma aggressiveness. More recently, Bischof et al demonstrated that TACI binds also HS proteoglycans like syndecan-1, syndecan-2 and syndecan-4 .
These data demonstrate that BAFF/APRIL are potent growth factors in B cell malignancies. Furthermore, APRIL could be implicated in tumor emergence and/or progression due to its ability to bind HS proteoglycans [26, 27, 28]. Therefore, we looked for the expression of BAFF, APRIL and of their receptors – BAFF-R, BCMA, and TACI – in various cancers, compared to their normal tissue or cell counterparts and in association with disease staging.
We used Oncomine Cancer Microarray database http://www.oncomine.org and Amazonia database http://amazonia.montp.inserm.fr/ to study gene expression of BAFF, APRIL, BCMA, TACI, BAFF-R and HS proteoglycans genes in 40 human tumor types and their normal tissue counterparts as indicated in Table 1 (Additional file 1). Only gene expression data obtained from a single study using the same methodology were compared. All data were log transformed, median centred per array, and the standard deviation was normalized to one per array.
Statistical comparisons were done with Mann-Whitney or Student t-tests.
Results and Discussion
BAFF is overexpressed in solid tumors
APRIL is overexpressed in solid and hematological malignancies
TACI is overexpressed in hematological cancers
Correlations between APRIL and heparan sulfate chain proteoglycans overexpression in tumor cells
Receptors for BAFF and APRIL are expressed exclusively by lymphoid cells. APRIL can bind and promote tumor-cell proliferation of several cell lines that do not express detectable mRNA for TACI and BCMA[9, 64, 65]. Ingold et al and Hendriks at al identified proteoglycans as the APRIL-non specific binding partners. This binding is mediated by HS side chains and can be inhibited by heparin[26, 27]. Only APRIL expression was associated with a bad prognosis in several cancers. APRIL could sustain the survival of malignant cells directly through HS proteoglycans that can deliver signals through their intracellular tails upon binding to ligands[66, 67].
Eleven HS proteoglycans has been identified so far – syndecan 1–4, glypican 1–6, CD44 isoforms containing the alternatively spliced exon v3 – and their gene expression can be evaluated by microarrays (see Additional file 3). Interestingly, at least one HS proteoglycan gene was significantly overexpressed in cancers presenting an overexpression of APRIL compared to their normal counterparts (see Additional file 1). A similar observation was made for cancers showing an association between APRIL expression and the evolution of the disease (see Additional file 1).
HS proteoglycans regulate growth factor signaling, cytoskeleton organization, cell adhesion and migration. HS proteoglycans are implicated in solid tumor development[70, 71]. Syndecan-1 is absolutely required for the development of mammary tumors driven by the transgenic expression of the proto-oncogene Wnt-1 in mice. The important role of HS proteoglycans is attributed in part to its highly negative electric potential, making it able to bind numerous proteins and to function as a coreceptor. However as APRIL activates cells that do not express TACI or BCMA, a direct signaling by the HS proteoglycans core protein is possible as already shown . It may explain the overexpression of APRIL in association with disease aggressiveness in solid tumors which do not express BCMA or TACI. Nevertheless, additional studies are required to understand the exact role of APRIL in solid tumors, the existence of a signaling linked to the interaction of APRIL with HS proteoglycans and the possible existence of a receptor specific to APRIL not yet identified.
The analysis reported here demonstrates that APRIL mRNA is overexpressed in at least 8 cancers compared to their normal counterparts, and within a given tumor category, is associated with a bad prognosis. These observations emphasize the interest using BAFF/APRIL inhibitors in the treatment of patients with cancers. We recently completed a phase I-II clinical trial of Atacicept TACI-Fc inhibitor showing the feasibility and safety of this targeting in multiple myeloma (submitted data). Heparin could be also useful in blocking APRIL binding to surface HS proteoglycan. Of note, we found here always one HS proteoglycan gene overexpressed in tumors that also highly expressed APRIL. A recent study reported that a brief course of subcutaneous low molecular weight heparin favorably influences the survival in patients with advanced malignancy and deserves additional clinical evaluation. Thus, the targeting of APRIL or its interaction with HS proteoglycans may be promising in a large number of cancers.
This work was supported by grants from the Ligue Nationale Contre le Cancer (équipe labellisée 2006), Paris, France, from INCA (n°R07001FN) and from MSCNET European strep (N°E06005FF).
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