Abstract
Increasing evidence suggests that a disintegrin and metalloproteinase 15 (ADAM15) have essential roles in the process of cancer metastasis via degradation of the extracellular matrix and binding to integrins. Among them, ADAM15 possesses an Arg-Gly-Asp (RGD) sequence within its disintegrin domain (d.d., hereafter) and binds to RGD recognizing-integrins such as αvβ3 and α5β1 and also interacts with integrin α9β1 in RGD-independent manner. Although these integrins play important roles in the process of cancer metastasis, the role of the interactions between ADAM15 and integrins during processes of cancer metastasis remains to be elucidated. We produced the specific antibody (8F7) that interferes with the interaction of human ADAM15 and integrin receptors and performed in vitro aggregation assay, invasion assay, proliferation assay, proteinase activity assay and cell-cell adhesion assay. 8F7 inhibited tumor cell aggregation, invasion and migration, but not proliferation of breast cancer cells and proteinase activity of ADAM15. Furthermore, the interactions between ADAM15 and integrin receptors induced collective cell migration, phosphorylation of Akt, which was known to promote invasion of breast cancer cells. These data suggested that the binding of ADAM15 to αvβ3 or α9β1 integrins through its d.d. Induces cell aggregation, migration and invasion of human breast cancer cells with concomitant activation of Akt signaling pathway.
Highlights
In western countries, breast cancer is developed in the 10 % of women and 20% of these breast cancer patients died by metastasis (Weigelt et al, 2005)
Cell adhesion assay was performed using recombinant protein of a disintegrin and metalloproteinase 15 (ADAM15) d.d. or mutant d.d.-RAA and CHO cells that express α9 integrin, one of the receptors for
To test whether ADAM15 and integrins were involved in homotypic cell adhesion of breast cancer cells, cell aggregation assay using D3H2LN cells was performed. 8F7, anti-α9β1 or anti-αvβ3 integrin antibody significantly inhibited cell aggregation (Fig. 1H). These results suggested that the interactions between α9β1 or αvβ3 integrin and ADAM15 d.d. mediate cell to cell adhesion of breast cancer cells
Summary
Breast cancer is developed in the 10 % of women and 20% of these breast cancer patients died by metastasis (Weigelt et al, 2005). The process of metastasis consists of various steps, in which tumor cells escape from primary tumor sites by the degradation of the basement membrane which consists of Extracellular Matrix (ECM) including collagen type IV and laminin and invade into blood or lymphatic vessels and reach to target organs and establish metastatic foci. Cell motility and proteolytic activity are necessary for tumor cells to metastasize. Tumor cells control their proteolytic activity at the cell surface by inducing binding of tumor-derived MMP-2 and MMP-9 to αvβ and αvβ integrin, expressed on tumor cell surface, respectively (Bjorklund and Koivunen, 2005; Deryugina and Quigley, 2006)
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