Induction of hepatocyte growth factor/scatter factor by fibroblast clustering directly promotes tumor cell invasiveness.
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).
Kankuri
Esko
E
Institute of Biomedicine, Pharmacology, Haartman Institute, University of Helsinki, Finland. esko.kankuri@helsinki.fi
Cholujova
Dana
D
Comajova
Monika
M
Vaheri
Antti
A
Bizik
Jozef
J
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology; D002449:Cell Aggregation / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D017077:Culture Media, Conditioned; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis*; D006801:Humans; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis; D018874:Spheroids, Cellular; D017154:Stromal Cells / Q000166:cytology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D017077:Culture Media, Conditioned; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met