LOSS OF EPITHELIAL DIFFERENTIATION MARKERS AND ACQUISITION OF VIMENTIN EXPRESSION AFTER XENOGRAFT WITH LAMININ-1 ENHANCE MIGRATORY AND INVASIVE ABILITIES OF HUMAN COLON-CANCER CELLS LOVO C5

Clone C5 of the the human colon adenocarcinoma LoVo cell line was subc utaneously injected with Or without exogenous laminin-1 (EHS laminin) into immunosuppressed newborn rats. Cultures were initiated from lung metastases obtained with or without laminin-1 and gave rise to the C5 sublines LM and M4, respectively. The LM subline was mainly composed o f spreading cells whereas most C5 and M4 cells remained round and aggr egated. The mesenchymal marker vimentin was expressed by very rare C5 and M4 cells (<1%), and by many LM cells (about 35%). On the opposite, the epithelial markers villin and dipeptidylpeptidase IV were well ex pressed by C5 cells but not by LM cells. In in vitro migration and inv asion assays, LM cells migrated and invaded basement membrane extract twice as much as the parental C5 clone and the M4 subline, probably in association with vimentin-expressing cells, because invasion of basem ent membrane extract Matrigel by LM cells gave rise to 100% vimentin-p ositive cells (sublines LM 22, LM 23 and LM 24). When subcutaneously i njected, C5 cells induced tumors limited by an interrupted but well or ganized basement membrane, whereas LM cells induced tumor masses, occa sionally limited by a very irregular basement membrane, as observed wh en C5 cells were injected with laminin-1. Gelatin zymographic analysis clearly showed an increased expression of matrix metalloproteinase-2 by LM cells. Our results suggest a specific role of laminin-l on the i n vivo proliferation of highly invasive vimentin-expressing colon carc inoma cells. This proliferation may result from the initial interactio n of C5 cells with large amounts of laminin-1, leading to a selection of vimentin-expressing cells during the metastatic cascade.