Transient down-regulation of beta1 integrin subtypes on kidney carcinoma cells is induced by mechanical contact with endothelial cell membranes.
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.
Jones
Jon
J
Klinik für Urologie und Kinderurologie, Zentrum der Chirurgie, Johann Wolfgang Goethe-Universität, D-60590 Frankfurt am Main, Germany.
Berkhoff
Stefan
S
Weich
Eva
E
Engl
Tobias
T
Wedel
Steffen
S
Relja
Borna
B
Jonas
Dietger
D
Blaheta
Roman A
RA
D002448:Cell Adhesion; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D015536:Down-Regulation; D042783:Endothelial Cells / Q000201:enzymology / Q000378:metabolism*; D005434:Flow Cytometry; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism*; D018613:Microscopy, Confocal; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000378:metabolism; D014470:Umbilical Cord / Q000166:cytology / Q000201:enzymology
D018797:Cell Cycle Proteins; D019012:Integrin beta1; D051416:Focal Adhesion Protein-Tyrosine Kinases