Laminin alpha1 chain in human renal cell carcinomas and integrin-mediated adhesion of renal cell carcinoma cells to human laminin isoforms.
In human tissues, the laminin (Ln) alpha1 chain shows a restricted and developmentally regulated distribution in basement membranes (BMs) of a subset of epithelial tissues, including those of renal proximal convoluted tubules. The present study investigated the distribution of the Ln alpha1 chain in renal cell carcinomas (RCCs) and oncocytomas as well as in xenografted tumours induced in nude mice with four characterized RCC cell lines. These cell lines were also used in cell adhesion studies with purified laminins. By immunohistochemistry it was found that the Ln alpha1 chain is widely present in the BMs of RCCs, all of the specimens presenting immunoreactivity. High-grade RCCs tended to contain more BM-confined and stromal immunoreactivity than low-grade tumours, none of the grade 3 (G3) carcinomas being negative and all of the metastatic specimens showing partial or overall BM immunoreactivity. Double immunolabelling experiments showed that in RCC BMs but not in vessel walls, the Ln alpha1 chain was co-distributed with Ln alpha5, beta1, and beta2 chains, implying the presence of Ln-1/Ln-3 and Ln-10/Ln-11. In papillary RCCs, the Ln alpha1 chain co-localized with Ln-5. The oncocytomas lacked immunoreactivity for the Ln alpha1 chain. Xenografted tumours induced in nude mice showed BM-like deposition of the Ln alpha1 chain. In cell adhesion studies, mouse and human Ln-1 were equally effective in promoting cell adhesion of all RCC cell lines. For each cell line, Ln-10 and Ln-10/11 were equally effective adhesive substrates, all cell lines adhering more avidly to these laminins than to mouse or human Ln-1. As judged by inhibition assays employing specific integrin antibodies, adhesion of normal human renal proximal tubular epithelial (RPTE) cells and RCC cells from a G1 tumour to human Ln-1 was mediated mainly by alpha(6)beta(1) integrin, while only the G1 RCC cells adhered to mouse Ln-1 by using alpha(6)beta(1) integrin. For adhesion to Ln-10, RPTE cells and RCC cells from a G1 tumour used an unidentified beta(1) integrin. Cells from G3 tumours mainly used an alpha(3)beta(1) integrin complex for adhesion to mouse Ln-1 and to human Ln-1 and Ln-10. For all cells, adhesion to the Ln-10/11 mixture was mediated by an unidentified integrin complex or by other adhesion molecules. These results show that laminin trimers containing the alpha1 chain are, in contrast to oncocytomas, abundant in the BMs of RCCs. This is in keeping with their suggested origin from renal proximal tubular epithelium known for its capacity to produce the Ln alpha1 chain. The results also show that RCC cells utilize complex, mainly integrin alpha(3)beta(1)- and integrin alpha(6)beta(1)-mediated, mechanisms for adhesion to laminins. The adhesion to Ln-1 changes from integrin alpha(6)beta(1) to integrin alpha(3)beta(1) upon increasing malignancy and, especially for Ln-10 and Ln-10/11, other adhesion molecules of non-integrin type may contribute to the adhesion.
Rissanen
Jan
J
Institute of Biomedicine/Anatomy, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), FIN-00014 University of Helsinki, Helsinki, Finland. jan.rissanen@helsinki.fi
Korhonen
Matti
M
Lehto
Veli-Pekka
VP
Virtanen
Ismo
I
D018249:Adenoma, Oxyphilic / Q000378:metabolism; D000818:Animals; D001485:Basement Membrane / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D002448:Cell Adhesion; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000378:metabolism*; D007797:Laminin / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism*; D009368:Neoplasm Transplantation; D020033:Protein Isoforms / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D016023:Integrins; D007797:Laminin; D009363:Neoplasm Proteins; D020033:Protein Isoforms; C084098:laminin A