CD44 stimulation induces integrin-mediated adhesion of colon cancer cell lines to endothelial cells by up-regulation of integrins and c-Met and activation of integrins

For cancer metastasis, tumor cells present in the circulation must first ad here to the endothelium. Integrins lymphocyte function-associated antigen ( LFA) 1 and very late antigen 4 play a central role in leukocyte adhesion to the endothelium and subsequent migration into tissues, The majority of tum or cells derived from solid cancers including colorectal cancer do not expr ess suitable adhesion receptors, LFA-1 and very late antigen 4, We investig ated the mechanisms of adhesion and transendothelial migration of cancer ce lls using colorectal carcinoma cell lines, Our results showed the following novel features of CD44 on the cells: (a) colon cancer cells express high l evels of CD44; (b) stimulation of cancer cells by CD44 cross-linking or fra gmented hyaluronan markedly induces the expression of LFA-1s, some of which reveal an activation epitope on the cells; (c) CD44 cross-linking induces F-actin polymerization in the cell cortex; (d) fragmented hyaluronan induce s up-regulation of the activation epitope of LFA-1, which is mediated throu gh protein kinase C; (e) stimulation of CD44 augments the LFA-1-mediated ad hesion of cancer cells to endothelial cells and intercellular adhesion mole cule 1-transfected cells and facilitates transendothelial migration; (f) st imulation of CD44 also induces expression of the hepatocyte growth factor ( HGF) receptor c-Met on cancer cells; and (g) HGF further amplifies the LPA- 1-mediated adhesion of cells prestimulated by CD44-derived signaling. Our r esults indicated that stimulation by CD44 induces "outside-in signaling," w hich consists of a direct pathway via CD44 and an alternate pathway through the induction of c-Met expression via HGF, Such stimuli augment the expres sion and trigger the function of integrins via "inside-out signaling" in co lon cancer cells, which leads to amplification of integrin-mediated adhesio n to the vessel wall and subsequent transendothelial migration.