CDB15:0001489 TNC — ITGB1

ABSTRACT: Tenascin-C is an extracellular matrix molecule that drives progression of many types of human cancer, but the basis for its actions remains obscure. In this study, we describe a cell-autonomous signaling mechanism explaining how tenascin-C promotes cancer cell migration in the tumor microenvironment. In a murine xenograft model of advanced human osteosarcoma, tenascin-C and its receptor integrin α9β1 were determined to be essential for lung metastasis of tumor cells. We determined that activation of this pathway also reduced tumor cell-autonomous expression of target genes for the transcription factor YAP. In clinical specimens, a genetic signature comprising four YAP target genes represents prognostic impact. Taken together, our results illuminate how tumor cell deposition of tenascin-C in the tumor microenvironment promotes invasive migration and metastatic progression.

ABSTRACT: Human umbilical vein endothelial cells were found to attach and partially spread on human tenascin. The attachment of endothelial cells to tenascin results in elongated cells with interconnecting processes and is distinct from the flattened appearance of endothelial cells on fibronectin, collagen, vitronectin or laminin substrata, suggesting a role for tenascin in modulating cell adhesion and motility. Endothelial attachment to tenascin was partially inhibitable by the SRRGDMS peptide derived from human tenascin and completely inhibitable by anti-integrin antibodies to alpha 2 beta 1 and alpha v beta 3. Endothelial cell attachment to tenascin could be inhibited up to 80% with anti-alpha 2 and anti-beta 1 monoclonal antibodies P1E6 and P4C10, respectively, and this was associated with a complete loss in cell spreading. In contrast, pretreatment of endothelial cells with the anti-alpha v beta 3 monoclonal antibody LM609, resulted in a 35% inhibition in cell attachment but did not alter cell spreading. In combination the anti-alpha 2 and anti-alpha v beta 3 antibodies, could completely abrogate cell spreading and attachment to tenascin-coated surfaces. Affinity purification of 125I-labeled endothelial cell extract on a tenascin matrix column followed by immunoprecipitation with monoclonal antibodies to different integrin alpha and beta subunits resulted in the identification of alpha 2 beta 1 and alpha v beta 3 integrins, respectively, as tenascin binding receptors. Collagen affinity-purified alpha 2 beta 1 receptor from endothelial cells bound not only to collagen and laminin but also to tenascin in a radio receptor binding assay. The results demonstrate that alpha 2 beta 1 and alpha v beta 3 mediate distinct endothelial cell interactions with tenascin; cell spreading and cell binding, respectively. Binding by alpha v beta 3 is mediated by the SRRGDMS site on tenascin, whereas the alpha 2 beta 1 binding site remains undefined. The interaction of alpha 2 beta 1 and alpha v beta 3 with tenascin may be regulated in a cell type-specific manner as evidenced by the binding of endothelial cell alpha 2 beta 1 and alpha v beta 3 to tenascin, and the lack of binding by the same receptors on osteosarcoma MG63 to tenascin.

ABSTRACT: In this study we identified tenascin-C (TN-C) and one of its integrin receptors, alpha(v)beta6, in oral squamous-cell carcinoma (SCC) specimens. Neither TN-C nor alpha(v)beta6 are expressed in normal oral mucosa. We also studied 2 human oral squamous-cell carcinoma cell lines: the highly invasive HSC-3 cells, and the poorly invasive SCC-25 cells. We determined that adhesion of these cells to TN-C involves both alpha2 and alpha(v) integrins. Migration on TN-C by oral SCC cells required fibroblast-conditioned medium and did not occur in its absence. This migration was blocked by anti-alpha2 and anti-alpha(v) antibodies and was partially inhibited by antibodies to hepatocyte growth factor, epidermal growth factor and transforming growth factor-beta1. When seeded on TN-C, the poorly invasive SCC-25 cells formed alpha(v)beta6-positive focal contacts; the HSC-3 cells did not. HSC-3, SCC-25 and PTF cells secrete TN-C into the culture medium, as determined by Western blot. However, when HSC-3 cells were inoculated into the floor of the mouth of nude mice, only murine TN-C could be identified in the reactive stroma adjacent to the resulting tumor nests, demonstrating that in vivo, HSC-3 cells do not secrete TN-C. Our results demonstrate that alpha(v)beta6 and tenascin-C are neo-expressed in oral squamous-cell carcinoma, and that the tumor stromal environment is influential in oral SCC behavior.