Enhanced Collagen Production Research Articles

Promotion of collagen production by human fibroblasts with gastric cancer cells in vitro.

To elucidate the histogenesis of gastric scirrhous cancer, the promotion of collagen production by normal human skin fibroblasts (HSF-1) with human gastric cancer cells (KATO-III, MKN-45 and MKN-28) was investigated by direct coculture and parabiotic culture. Argyrophilic collagenous fibers were demonstrated among fibroblasts on both direct cocultures and parabiotic cultures of the fibroblasts with gastric cancer cells. Microscopic examination showed that these fibers appeared earlier and were more abundant and thicker in direct cocultures and parabiotic cultures than in single cultures of fibroblasts. Gastric cancer cells in single or parabiotic culture did not form argyrophilic fibers. For quantitative proof of the promotion of collagen production by fibroblasts with gastric cancer cells, hydroxyproline produced by fibroblasts was measured. Much higher fibroblast hydroxyproline values were obtained in parabiotic cultures with gastric cancer cell lines than in single cultures of HSF-1. Moreover, the rate of collagen synthesis by HSF-1 was much higher than that of any gastric cancer cell line tested. These results demonstrate that gastric cancer cells enhance collagen production by fibroblasts in vitro. This finding suggests that they may produce a factor promoting fibroblast collagen synthesis and that this may contribute to the formation of stromal collagen in human gastric scirrhous cancer.

Human Monocyte Regulation of Connective Tissue Growth

Accelerated fibroblast accumulation, mitosis, and deposition of collagen during fibrotic processes are frequently preceded by intense inflammatory exudates of mononuclear cells which are derived from the peripheral blood. In vitro , we examined the role of human peripheral blood mononuclear cells in activation of human fibroblasts. The adherent mononuclear phagocyte, or monocyte, was found to release mediators which stimulate fibroblast proliferation and enhance collagen production. Adherence to tissue culture dishes in vitro was found to activate the release of these monocyte products, and represents a process which mimics in vivo extravasation of monocytes from the blood vessel into the connective tissue. The release of these mediators is dependent on monocyte protein synthesis, metabolism, and protease activity. Little is known of the role that immunologic sensitization to autologous connective tissue components might play in inducing such inflammatory responses which can result in pathologic fibrotic sequelae. In beginning to explore these possibilities, we have found that levels of antibodies to types I (interstitial) and IV (basement membrane) collagen correlate directly with the extent of pulmonary fibrosis in patients with scleroderma. Furthermore, we can sensitize mice to homologous types I or IV collagen, or laminin (a basement membrane attachment protein), and elicit a delayed type hypersensitivity response which is marked by mononuclear cell infiltration. Cell-mediated immunity to these antigens can be transferred to normal recipients with sensitized T-lymphocytes. We discuss these data and propose a hypothesis for mechanisms of monocyte extravasation → fibroblast activation → fibrosis.