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Oncotarget. 2015 Oct 6;6(30):29178-95. doi: 10.18632/oncotarget.4932.

Colorectal cancer-promoting activity of the senescent peritoneal mesothelium.

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Department of Pathophysiology, Poznań„ University of Medical Sciences, Poznań„, Poland.
Department of Clinical Pathology, Poznań„ University of Medical Sciences, PoznaÅń, Poland.
Department of Toxicology, Poznań„ University of Medical Sciences, Poznań„, Poland.
Division of Gynecological Surgery, Poznań„ University of Medical Sciences, Poznań„, Poland.


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.


cellular senescence; gastrointestinal cancers; mesothelial cells; mice xenografts; peritoneal cavity

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