This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kankuri, E. Articles by Bizik, J. Search for Related Content PubMed PubMed Citation Articles by Kankuri, E. Articles by Bizik, J.

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

¹ Institute of Biomedicine, Pharmacology, ² Haartman Institute, University of Helsinki; ³ Cell Therapy Research Consortium, Third Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland; and ⁴ Laboratory of Tumor Cell Biology, Cancer Research Institute, Bratislava, Slovakia

Requests for reprints: Esko Kankuri, Institute of Biomedicine, Pharmacology, University of Helsinki, P.O. Box 63, FIN-00014 Helsinki, Finland. Phone: 358-9-191-25336; Fax: 358-9-191-25364; E-mail: esko.kankuri{at}helsinki.fi.

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).

This article has been cited by other articles:

				E. Myllyluoma, A.-M. Ahonen, R. Korpela, H. Vapaatalo, and E. Kankuri Effects of Multispecies Probiotic Combination on Helicobacter pylori Infection In Vitro Clin. Vaccine Immunol., September 1, 2008; 15(9): 1472 - 1482. [Abstract] [Full Text] [PDF]

				M. Ye, D. Hu, L. Tu, X. Zhou, F. Lu, B. Wen, W. Wu, Y. Lin, Z. Zhou, and J. Qu Involvement of PI3K/Akt Signaling Pathway in Hepatocyte Growth Factor-Induced Migration of Uveal Melanoma Cells Invest. Ophthalmol. Vis. Sci., February 1, 2008; 49(2): 497 - 504. [Abstract] [Full Text] [PDF]

				L. Beuret, E. Flori, C. Denoyelle, K. Bille, R. Busca, M. Picardo, C. Bertolotto, and R. Ballotti Up-regulation of MET Expression by {alpha}-Melanocyte-stimulating Hormone and MITF Allows Hepatocyte Growth Factor to Protect Melanocytes and Melanoma Cells from Apoptosis J. Biol. Chem., May 11, 2007; 282(19): 14140 - 14147. [Abstract] [Full Text] [PDF]