Expression level of integrin α5 on tumour cells affects the rate of metastasis to the kidney

Tumour metastasis is known clinically to have organ specificity. We hypothesised that integrins might be involved in determining the organ specificity of tumour metastasis. Here, we report the results of spontaneous metastasis tested in nude mice that were inoculated with Chinese hamster ovary (CHO) cells expressing integrin α5β1 at various levels. The growth of the primary tumour inversely correlated with the α5 expression level on CHO cells, which is consistent with a previous report (Schreiner et al, 1991). The rates of pulmonary, lymph node, and adrenal metastases that developed in nude mice were not related to changes of the α5 expression level on CHO cells. Kidney metastasis developed in 40% of nude mice inoculated with α5B2 cells (CHO cells overexpressing α5) and in 20% of mice with CHO-K1 cells (CHO cells expressing native α5), whereas inoculation with CHO-B2 cells (α5-defective mutants) and α5CHO cells with the highest expression of α5 did not lead to development of kidney metastasis. Furthermore, α5CHO, which shows the slowest growth of these cell types, did not lead to primary tumours in nude mice. These findings suggest that there is an appropriate level of α5 expression on tumour cells that leads to metastasis. Microscopic observations revealed that micrometastasis in the kidney was formed in glomeruli. An adhesion assay using frozen sections of the kidney demonstrated that α5B2 cells, but not CHO-B2 cells, effectively adhered to glomeruli. Kidney metastasis in vivo and the adhesion of α5B2 to glomeruli shown ex vivo were significantly suppressed by the administration of GRGDS peptide. Finally, we conclude that the interaction of α5β1 on tumour cells with fibronectin in kidney glomeruli is involved in kidney metastasis and that the tumour has appropriate levels of integrins crucial for metastasis.