Possible significance of VLA-4 (alpha 4 beta 1) for hematogenous metastasis of renal-cell cancer.
Very late antigen-4 (VLA-4) composed of alpha 4 and beta 1, a member of the beta 1-integrin subfamily, facilitates cell-to-cell interaction with vascular cell-adhesion molecule-1 (VCAM-1) on endothelial cells (EC). Attachment of blood-borne tumor cells to EC is a crucial step for hematogenous metastasis, and VLA-4-positive tumor cells can attach to EC by binding to VCAM-1. Renal-cell cancer (RCC) reveals proportionally greater percentages of metastases than other carcinomas at initial diagnosis. We investigated whether VLA-4 is expressed on RCC, and how such expression on RCC correlates with the metastatic potential of RCC. Immunohistochemical staining on 66 primary and 4 metastatic RCC showed that 4 out of 4 metastatic and 5 out of 8 primary RCC from patients with lung and/or brain metastases expressed alpha 4 and beta 1 chains. On the other hand, 13 of 58 RCC without metastases expressed alpha 4 chain, alpha 4 and beta 1 expressions were also detected on 5 out of 5 human RCC cell lines, ACHN, KRC/Y, A498, Caki1 and Caki2, by flow-cytometric analysis. Reverse-transcriptase-polymerase-chain-reaction (RT-PCR), followed by Southern-blot hybridization with cDNA probe for a alpha 4 chain, also confirmed mRNA production in 4 out of 5 RCC cell lines. Furthermore, adhesion of alpha 4-positive RCC cell lines to human umbilical-vein endothelial cells (HUVEC) was augmented by treatment of HUVEC with tumor necrosis factor-alpha (TNF-alpha). This adhesion was inhibited by anti-alpha 4 or anti-VCAM-1 antibodies, suggesting that VLA-4-VCAM-1 interaction was involved in the adhesion between RCC cells and HUVEC. Taken together, VLA-4 on RCC cells might play a crucial role in their hematogenous metastasis.
Tomita
Y
Y
Department of Urology, Niigata University School of Medicine, Japan.
Saito
T
T
Saito
K
K
Oite
T
T
Shimizu
F
F
Sato
S
S
D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000556:secondary*; D002448:Cell Adhesion; D002478:Cells, Cultured; D004727:Endothelium / Q000166:cytology; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000556:secondary*; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating; D016029:Receptors, Very Late Antigen / Q000096:biosynthesis*; D014471:Umbilical Veins / Q000166:cytology
D016029:Receptors, Very Late Antigen