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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.

Author information

1
Department of Pathophysiology, Poznań„ University of Medical Sciences, Poznań„, Poland.
2
Department of Clinical Pathology, Poznań„ University of Medical Sciences, PoznaÅń, Poland.
3
Department of Toxicology, Poznań„ University of Medical Sciences, Poznań„, Poland.
4
Division of Gynecological Surgery, Poznań„ University of Medical Sciences, Poznań„, Poland.

Abstract

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.

KEYWORDS:

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

PMID:
26284488
PMCID:
PMC4745719
DOI:
10.18632/oncotarget.4932
[Indexed for MEDLINE]
Free PMC Article

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