Tumor-dependent activation of rodent hepatic stellate cells during experimental melanoma metastasis.
In this work we report the presence of intrametastatic smooth-muscle iso-alpha-actin (SMA)-expressing cells which appeared from the early stages of the hepatic metastasis process of intrasplenically injected B16 melanoma (B16M) cells. They formed a network of stromal cells among B16M cells, a very low percentage of them expressing desmin. In contrast, those parts of liver tissue unaffected by metastasis had perisinusoidal desmin-expressing quiescent hepatic stellate cells (qHSC) which did not express SMA. Exposure of freshly isolated rat quiescent hepatic stellate cells (qHSC) to B16M cell-conditioned medium (B16M-CM) leads to a progressive increase (P < .01) in the number of SMA-expressing cells, which was accompanied by a parallel reduction in the number of desmin-expressing cells. In addition, B16M-CM also contained chemotactic factor(s) which significantly (P < .01) increased (50%) in vitro qHSC migration and stimulated both [3H]thymidine and [3H]glucosamine uptake in qHSC. Moreover, B16M-CM also significantly (P < .01) enhanced qHSC secretion of matrix metalloproteinase-2 (MMP-2), and unknown chemotactic factor(s) enhancing in vitro migration of B16M cells. The results suggest that B16 melanoma releases qHSC-activating factors, which induce the appearance of metastasis-infiltrating myofibroblasts by a paracrine mechanism. Such cells showed cytoskeletal alterations which are associated with enhanced proliferation, glycosaminoglycan synthesis, MMP-2 secretion, and tumor-chemotactic factor production. Thus, tumor-activated qHSC may play an important role in melanoma cell motility and invasion during hepatic metastasis progression.
Olaso
E
E
Department of Cellular Biology and Morphological Sciences, School of Medicine and Dentistry, University of the Basque Country, Leioa, Vizcaya, Spain.
Santisteban
A
A
Bidaurrazaga
J
J
Gressner
A M
AM
Rosenbaum
J
J
Vidal-Vanaclocha
F
F
D000199:Actins / Q000032:analysis / Q000096:biosynthesis; D000818:Animals; D015415:Biomarkers; D002465:Cell Movement; D002478:Cells, Cultured; D002630:Chemotactic Factors / Q000032:analysis; D017077:Culture Media, Conditioned; D003893:Desmin / Q000032:analysis / Q000096:biosynthesis; D018093:Gelatinases / Q000096:biosynthesis; D005944:Glucosamine / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism* / Q000473:pathology*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D008297:Male; D020778:Matrix Metalloproteinase 2; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology*; D008666:Metalloendopeptidases / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D013936:Thymidine / Q000378:metabolism
D000199:Actins; D015415:Biomarkers; D002630:Chemotactic Factors; D017077:Culture Media, Conditioned; D003893:Desmin; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D005944:Glucosamine; D013936:Thymidine