Colorectal cancer-promoting activity of the senescent peritoneal mesothelium
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Justyna Mikuła-Pietrasik1, Patrycja Sosińska1, Konstantin Maksin2, Małgorzata Kucińska3, Hanna Piotrowska3, Marek Murias3, Aldona Woźniak2, Dariusz Szpurek4, Krzysztof Książek1
1Department of Pathophysiology, Poznań University of Medical Sciences, Poznań, Poland
2Department of Clinical Pathology, Poznań University of Medical Sciences, Poznań, Poland
3Department of Toxicology, Poznań University of Medical Sciences, Poznań, Poland
4Division of Gynecological Surgery, Poznań University of Medical Sciences, Poznań, Poland
Krzysztof Książek, e-mail: email@example.com
Keywords: cellular senescence, gastrointestinal cancers, mesothelial cells, mice xenografts, peritoneal cavity
Received: April 21, 2015 Accepted: July 24, 2015 Published: August 06, 2015
Gastrointestinal cancers metastasize into the peritoneal cavity in a process controlled by peritoneal mesothelial cells (HPMCs). In this paper we examined if senescent HPMCs can intensify the progression of colorectal (SW480) and pancreatic (PSN-1) cancers in vitro and in vivo. Experiments showed that senescent HPMCs stimulate proliferation, migration and invasion of SW480 cells, and migration of PSN-1 cells. When SW480 cells were injected i.p. with senescent HPMCs, the dynamics of tumor formation and vascularization were increased. When xenografts were generated using PSN-1 cells, senescent HPMCs failed to favor their growth. SW480 cells subjected to senescent HPMCs displayed up-regulated expression of transcripts for various pro-cancerogenic agents as well as increased secretion of their products. Moreover, they underwent an epithelial-mesenchymal transition in the Smad 2/3-Snail1-related pathway. The search for mediators of senescent HPMC activity showed that increased SW480 cell proliferation was stimulated by IL-6, migration by CXCL8 and CCL2, invasion by IL-6, MMP-3 and uPA, and epithelial-mesenchymal transition by TGF-β1. Secretion of these agents by senescent HPMCs was increased in an NF-κB- and p38 MAPK-dependent mechanism. Collectively, our findings indicate that in the peritoneum senescent HPMCs may create a metastatic niche in which critical aspects of cancer progression become intensified.
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