Induction of Hepatocyte Growth Factor/Scatter Factor by Fibroblast Clustering Directly Promotes Tumor Cell Invasiveness

Abstract

For determining the malignant behavior of a tumor, paracrine interactions between stromal and cancer cells are crucial. We previously reported that fibroblast clustering induces cyclooxygenase-2 (COX-2), plasminogen activation, and programmed necrosis, all of which were significantly reduced by nonsteroidal anti-inflammatory drugs (NSAID). We have now found that tumor cell-conditioned medium induces similar fibroblast clustering. Activation of the necrotic pathway in clustering fibroblasts, compared with control monolayer cultures, induced a massive >200-fold production of bioactive hepatocyte growth factor/scatter factor (HGF/SF), which made human carcinoma cells spread and invade a collagen lattice. This response occurred only if a functional, properly processed c-Met receptor was present, which was then rapidly phosphorylated. The invasion-promoting activity was inhibited by a neutralizing HGF/SF antibody. NSAIDs, if added early during fibroblast aggregation, inhibited HGF/SF production effectively but had no effect at later stages of cell aggregation. Our results thus provide the first evidence that aggravated progression of tumors with necrotic foci may involve paracrine reciprocal signaling leading to stromal activation by direct cell-cell contact (i.e., nemosis). (Cancer Res 2005; 65(21): 9914-22)

Effects of Multispecies Probiotic Combination on Helicobacter pylori Infection In Vitro

“…4A, B, and E). However, no cell detachment or structural protein loss, as measured by the sustained expression of actin (3,22), was evident at any time point or with any treatment throughout the study (data not shown). In order to exclude potential pH-dependent activity on H. pylori or epithelial cell viability, the experiments were carried out at neutral pH.…”

Inflammatory environment created by fibroblast aggregates induces growth arrest and phenotypic shift of human myeloma cells

“…As a neat culture the RPMI 8226 cells exhibited the highest growth potential within the panel of analysed cell lines. On the basis of our earlier findings on profuse production of HGF by nemosis-activated skin fibroblasts [18] one would expect that the growth of RPMI 8226 cells will be more busted in the coculture. The RPMI 8226 cells are well documented in the literature to express functionally active receptor tyrosine kinase c-Met on their surface via which the HGF triggered mitogenic signal is transmitted [32].…”

“…Previously, we introduced and characterized a new biological way of mesenchymal cell activation called nemosis [18]. Nemosis, which is triggered solely by cell-cell contacts, is programmed process of cell activation and subsequent death, the most distinctly observed in human dermal fibroblasts [19].…”

Nemosis of fibroblasts is inhibited by benign HaCaT keratinocytes but promoted by malignant HaCaT cells

“…Nonsteroidal anti-inflammatory drugs (NSAIDs) prevented both COX-2 and HGF/SF induction effectively and thus inhibited fibroblast activation and nemosis. Nemosis can also be induced by tumor cell-derived soluble mediators promoting fibroblast clustering (Kankuri et al, 2005).…”