Thrombospondin-1 (TSP-1) is a matricellular glycoprotein known for being highly expressed within a tumor microenvironment, where it promotes an aggressive phenotype particularly by interacting with the CD47 cell-surface receptor. While it originates from the stromal compartment in many malignancies, melanoma is an exception as invasive and metastatic melanoma cells overexpress TSP-1. We recently demonstrated that a new molecular agent that selectively prevents TSP-1 binding to CD47, called TAX2, exhibits anti-cancer properties when administered systemically by decreasing viable tumor tissue within subcutaneous B16 melanoma allografts. At the same time, emerging evidence was published suggesting a contribution of TSP-1 in melanoma metastatic dissemination and resistance to treatment. Through a comprehensive systems biology approach based on multiple genomics and proteomics databases analyses, we first identified a TSP-1-centered interaction network that is overexpressed in metastatic melanoma. Then, we investigated the effects of disrupting TSP-1:CD47 interaction in A375 human malignant melanoma xenografts. In this model, TAX2 systemic administrations induce tumor necrosis by decreasing intra-tumoral blood flow, while concomitantly making tumors less infiltrative. Besides, TAX2 treatment also drastically inhibits B16F10 murine melanoma cells metastatic dissemination and growth in a syngeneic experimental model of lung metastasis, as demonstrated by histopathological analyses as well as longitudinal and quantitative µCT follow-up of metastatic progression. Altogether, the results obtained by combining bioinformatics and preclinical studies strongly suggest that targeting TSP-1/CD47 axis may represent a valuable therapeutic alternative for hampering melanoma spreading.
This is a preview of subscription content, log in to check access.
The authors acknowledge supports from Centre National de la Recherche Scientifique (CNRS), Région Champagne-Ardenne and SATT Nord. AJ was recipient of grants from the Ministère de l’Enseignement Supérieur et de la Recherche (2010-2013). The authors acknowledge A. Thomachot for editorial assistance.
Lin X-D, Chen S-Q, Qi Y-L et al (2012) Overexpression of thrombospondin-1 in stromal myofibroblasts is associated with tumor growth and nodal metastasis in gastric carcinoma. J Surg Oncol 106:94–100. doi:10.1002/jso.23037CrossRefPubMedGoogle Scholar
McClenic BK, Mitra RS, Riser BL et al (1989) Production and utilization of extracellular matrix components by human melanocytes. Exp Cell Res 180:314–325CrossRefPubMedGoogle Scholar
Jayachandran A, Anaka M, Prithviraj P et al (2014) Thrombospondin 1 promotes an aggressive phenotype through epithelial-to-mesenchymal transition in human melanoma. Oncotarget 5:5782–5797CrossRefPubMedPubMedCentralGoogle Scholar
Borsotti P, Ghilardi C, Ostano P et al (2015) Thrombospondin-1 is part of a Slug-independent motility and metastatic program in cutaneous melanoma, in association with VEGFR-1 and FGF-2. Pigment Cell Melanoma Res 28:73–81. doi:10.1111/pcmr.12319CrossRefPubMedGoogle Scholar
Rhodes DR, Kalyana-Sundaram S, Mahavisno V et al (2007) Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. Neoplasia 9:166–180CrossRefPubMedPubMedCentralGoogle Scholar
Launay G, Salza R, Multedo D et al (2015) MatrixDB, the extracellular matrix interaction database: updated content, a new navigator and expanded functionalities. Nucleic Acids Res 43:D321–327. doi:10.1093/nar/gku1091CrossRefPubMedGoogle Scholar
Uhlén M, Fagerberg L, Hallström BM, et al (2015) Proteomics. Tissue-based map of the human proteome. Science 347:1260419. doi: 10.1126/science.1260419
Kretschmer L, Beckmann I, Thoms K-M et al (2006) Factors predicting the risk of in-transit recurrence after sentinel lymphonodectomy in patients with cutaneous malignant melanoma. Ann Surg Oncol 13:1105–1112. doi:10.1245/ASO.2006.07.020CrossRefPubMedGoogle Scholar
Kaur S, Soto-Pantoja DR, Stein EV et al (2013) Thrombospondin-1 signaling through CD47 inhibits self-renewal by regulating c-myc and other stem cell transcription factors. Sci Rep. doi:10.1038/srep01673Google Scholar
Lee TK-W, Cheung VC-H, Lu P et al (2014) Blockade of CD47-mediated cathepsin S/protease-activated receptor 2 signaling provides a therapeutic target for hepatocellular carcinoma. Hepatology 60:179–191. doi:10.1002/hep.27070CrossRefPubMedGoogle Scholar