Published online before print February 26, 2009

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(American Journal of Pathology. 2009;174:1230-1240.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080613

Senescent Peritoneal Mesothelial Cells Promote Ovarian Cancer Cell Adhesion

The Role of Oxidative Stress-Induced Fibronectin

Krzysztof Ksiazek^*, Justyna Mikula-Pietrasik^*, Katarzyna Korybalska^*, Grzegorz Dworacki, Achim Jörres and Janusz Witowski^*

From the Departments of Pathophysiology^* and Clinical Immunology, Poznan University of Medical Sciences, Poznan, Poland; and the Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany

Adhesion of ovarian cancer cells to the peritoneal mesothelium is a key step in the malignant progression of the disease. In an in vitro study, we showed that the adherence of ovarian cancer cells (of the OVCAR-3, SKOV-3, and A2780 cell lines) to senescent human omentum-derived peritoneal mesothelial cells (HOMCs) was greater than to early passage cells. The process was mediated primarily by the increased interaction of the 5β1 integrin on cancer cells with HOMC-associated fibronectin (FN). In comparison with early passage HOMCs, senescent cells exhibited increased FN mRNA expression levels and produced significantly more FN. To assess the effect of senescence-associated oxidative stress on FN release, HOMCs were rendered senescent by exposure to an oxidant, tert-butyl hydroperoxide. Treatment with tert-butyl hydroperoxide resulted in a significant increase in HOMC FN mRNA and protein expression levels. The effect of oxidative stress on FN synthesis was found to be mediated by transforming growth factor-β1, whose signaling pathway was controlled at upstream and downstream levels by p38 MAPK. The activity of p38 MAPK increased markedly in senescent HOMCs. Treatment of HOMCs with antioxidants significantly attenuated senescence-associated increases in p38 MAPK activity, production of both transforming growth factor-β1 and FN, and ovarian cancer cell adhesion. These data indicate that oxidative stress that accompanies senescence may increase FN production by HOMCs and thus facilitate binding and dissemination of ovarian cancer cells.