CDB15:0000327 COL1A1 — ITGA2

ABSTRACT: The extracellular matrix (ECM) plays critical roles in tumor progression and metastasis. However, the contribution of ECM proteins to early metastatic onset in the peritoneal cavity remains unexplored. Here, we suggest a new route of metastasis through the interaction of integrin alpha 2 (ITGA2) with collagens enriched in the tumor coinciding with poor outcome in patients with ovarian cancer. Using multiple gene-edited cell lines and patient-derived samples, we demonstrate that ITGA2 triggers cancer cell adhesion to collagen, promotes cell migration, anoikis resistance, mesothelial clearance, and peritoneal metastasis in vitro and in vivo. Mechanistically, phosphoproteomics identify an ITGA2-dependent phosphorylation of focal adhesion kinase and mitogen-activated protein kinase pathway leading to enhanced oncogenic properties. Consequently, specific inhibition of ITGA2-mediated cancer cell-collagen interaction or targeting focal adhesion signaling may present an opportunity for therapeutic intervention of metastatic spread in ovarian cancer.

ABSTRACT: In the past, proteins have been described that may be involved in chondrocyte interactions with extracellular collagen, but little is known about the role of integrins in chondrocyte-collagen interactions. Here we report on the analysis of beta 1-integrin distribution in human fetal cartilage and on the expression of integrins on fetal chondrocytes, using monoclonal and polyclonal antibodies to integrin alpha- and beta-chains. We show the presence of alpha 2-, alpha 5-, alpha 6-, alpha v-, and beta 1-chains on freshly isolated chondrocytes by surface immunofluorescence in the fluorescence-activated cell sorter and by surface iodination followed by immunoprecipitation. Affinity chromatography of bovine chondrocyte membrane proteins on a collagen-Sepharose column followed by immunoprecipitation confirmed the presence of the collagen-binding alpha 2 beta 1-integrin on chondrocytes. Chondrocyte adhesion on native collagens I and II, on fibronectin, and on laminin was completely blocked by anti-beta 1; anti-alpha 2 reduced chondrocyte binding to collagen by only 40-50%; similarly, anti-alpha 1-antibodies were also able to reduce chondrocyte binding to collagen, although alpha 1 could not be unequivocally identified on chondrocytes. Chondrocyte adhesion to fibronectin was Mg(2+)- and Ca(2+)-dependent and could be inhibited by anti-alpha 5 and by RGD peptides. Chondrocyte adhesion to native collagens is Mg(2+)-, but not Ca(2+)-dependent and RGD-independent. Interestingly, although these data point to a role of alpha 2 beta 1 in chondrocyte-collagen interactions in vitro, alpha 2 could not be visualized in sections of human fetal cartilage, in contrast to the beta 1-, alpha v-, and alpha 5-chains which were present. This suggests that alpha 2 beta 1-integrin may be involved in the assembly of a pericellular collagen matrix in vitro, but may not be required for chondrocyte-collagen interactions in intact cartilage.