Matrix Vol. 12/1992, pp. 213-220 © 1992 by Gustav Fischer Verlag, Stuttgart The Stimulation of Fibroblasts Collagen Synthesis by Neoplastic Cells is Modulated by the Extracellular Matrix A. NOEL 1 , C. MUNAUT 1 , B. NUSGENS 2 , J. M. FOIDART 1 and CH. M. LAPIERE 2 1 Laboratory ofBiology and 2 Laboratory of Experimental Dermatology, University of Liege, Sart Tilman, B4000 Liege, Belgium. Abstract Human fibroblasts cocultured with neoplastic MCF7 cells produce increased amounts of col- lagen. A maximal stimulation requires direct cell-cell contacts between tumor cells and fibro- blasts. However, this effect could be reproduced, although to a lesser extent, by medium conditioned by MCF7 cells, suggesting that it is mediated by a factor produced by MCF7 cells and secreted, at least partly, under a soluble form (Noel et al., 1992). This Collagen Stimulating Factor ("COSF") present in the culture medium displayed a molecular mass between 3,500 to 10,000 daltons, bound to heparin and appeared to be different from the growth factors described until now. The "COSF" can be released from the surface of MCF7 cells by treatment with heparin. The aim of the present work was to investigate the influence of various extracellular matrix components on the production and the release of "COSF". A 3- to 4-fold enhancement of collagen synthesis was observed in coculture on plastic and collagen type I substrates without significant modification of the non-collagen proteins. The increased collagen synthesis was paralleled by an elevation of specific collagen mRNAs level suggesting a regulation at a pretrans- lationallevel. On the opposite, in the presence of soluble or insoluble laminin, this stimulation was abolished. Similarly, coculture on "reconstituted basement membrane matrix", matrigel, did not increase collagen production. The "COSF" was found to bind to matrigel and could be released from the basement membrane matrix by treatment with heparin. The absence of colla- gen stimulation in the presence of laminin could not be ascribed to a lesser responsiveness of fi- broblasts, an absence of "COSF" secretion by MCF7 cells or its binding to laminin. This absence of collagen stimulating effect was only observed when the two cell types cultured on laminin were in close contacts suggesting the requirement of direct intercellular contacts between tumoral cells and fibroblasts. Key words: collagen, desmoplasia, extracellular matrix, fibroblasts, neoplastic cells. Introduction The microenvironment of malignant cells modulates the growth and the evolution of neoplasm. The major environ- mental factors involved in such a process are the contacts between tumoral cells and the extracellular matrix (ECM), and their interactions with host cells. Growing neoplasms are often surrounded by abundant and excessive connective tissue. This "desmoplastic reaction" accentuated in some invasive carcinoma of the breast (Martinez-Hernandez, 1988) might result from the secretion by cancer cells of growth factors known to modulate the biosynthetic activity of mesenchymal cells as TGF a, PDGF, FGF (Ignotz and Massague, 1986; Ross et al., 1986; Varga et al., 1987).