Adhesion molecules of the
integrin beta1 family are thought to be involved in the malignant progression
renal cell carcinoma (RCC). Still, it is not clear how they contribute to this process. Since the hematogenous phase of tumour dissemination is the rate-limiting step in the metastatic process, we explored
beta1 integrin alterations on several RCC cell lines (A498, Caki1, KTC26) before and after contacting vascular endothelium in a tumour-endothelium (HUVEC) co-culture assay. Notably, alpha2, alpha3 and alpha5
integrins became down-regulated immediately after the tumour cells attached to HUVEC, followed by re-expression shortly thereafter.
Integrin down-regulation on RCC cells was caused by direct contact with endothelial cells, since the isolated endothelial membrane fragments but not the cell culture supernatant contributed to the observed effects.
Integrin loss was accompanied by a reduced
focal adhesion kinase (FAK) expression, FAK activity and diminished binding of tumour cells to matrix
proteins. Furthermore, intracellular signalling
proteins RCC cells were altered in the presence of HUVEC membrane fragments, in particular 14-3-3 epsilon, ERK2, PKCdelta, PKCepsilon and RACK1, which are involved in regulating tumour cell motility. We, therefore, speculate that contact of RCC cells with the vascular endothelium converts
integrin-dependent adhesion to
integrin-independent cell movement. The process of dynamic
integrin regulation may be an important part in tumour cell migration strategy, switching the cells from being adhesive to becoming motile and invasive.