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.
Highlights
The peritoneal cavity is a common site for metastasis of colorectal and pancreatic carcinomas [1]
In the study presented here we comprehensively examined whether senescent human peritoneal mesothelial cells (HPMCs), which are known to accumulate in the peritoneal cavity [24], may promote the progression of colorectal and pancreatic carcinomas in vitro and stimulate the development of peritoneal tumors in a mice xenograft model in vivo
The effect of senescent HPMCs on the progression of colorectal (SW480) and pancreatic cancer (PSN-1) cells was evaluated with regard to a cancer cell response to soluble agents released to the environment by the HPMCs, and to their reaction to direct physical contact with HPMCs in a co-culture
Summary
The peritoneal cavity is a common site for metastasis of colorectal and pancreatic carcinomas [1]. It has been estimated that 40–80% of patients who died from the disease developed intraperitoneal tumors [4]. The same case holds for advanced stages of pancreatic cancer, when 70–80% of nonresectable patients suffered from peritoneal metastases [5]. Peritoneal dissemination of gastrointestinal cancers typically proceeds in two ways: as a result of direct cell detachment from a primary tumor (along with bowel wall penetration in the case of colon carcinoma), or iatrogenically, due to incomplete resection of the primary tumor and/or malignant cell leakage from dissected blood and lymph channels [1, 5, 6]
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