TUMOR-DEPENDENT ACTIVATION OF RODENT HEPATIC STELLATE CELLS DURING EXPERIMENTAL MELANOMA METASTASIS

In this work we report the presence of intrametastatic smooth-muscle i so-alpha-actin (SMA)-expressing cells which appeared from the early st ages of the hepatic metastasis process of intrasplenically injected B1 6 melanoma (B16M) cells. They formed a network of stromal cells among B16M cells, a very low percentage of them expressing desmin. In contra st, those parts of liver tissue unaffected by metastasis had perisinus oidal desmin-expressing quiescent hepatic stellate cells (qHSC) which did not express SMA. Exposure of freshly isolated rat quiesent hepatic stellate cells (qHSC) to B16M cell-conditioned medium (B16M-CM) leads to a progressive increase (P < .01) in the number of SMA-expressing c ells, which was accompanied by a parallel reduction in the number of d esmin-expressing cells. In addition, B16M-CM also contained chemotacti c factor(s) which significantly (P < .01) increased (50%) in vitro qHS C migration and stimulated both [H-3]thymidine and [H-3]glucosamine up take in qHSC. Moreover, B16M-CM also significantly (P < .01) enhanced qHSC secretion of matrix metalloproteinase-2 (MMP-2), and unknown chem otactic factor(s) enhancing in vitro migration of B16M cells. The resu lts suggest that B16 melanoma releases qHSC-activating factors, which induce the appearance of metastasis-infiltrating myofibroblasts by a p aracrine mechanism. Such cells showed cytoskeletal alterations which a re associated with enhanced proliferation, glycosaminoglycan synthesis , MMP-2 secretion, and tumor-chemotactic factor production. Thus, tumo r-activated qHSC may play an important role in melanoma cell motility and invasion during hepatic metastasis progression.