Colorectal cancer-promoting activity of the senescent peritoneal mesothelium.
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.
Department of Pathophysiology, Poznań University of Medical Sciences, Poznań, Poland.
Justyna
J
Mikuła-Pietrasik
Department of Pathophysiology, Poznań University of Medical Sciences, Poznań, Poland.
Patrycja
P
Sosińska
Department of Clinical Pathology, Poznań University of Medical Sciences, PoznaÅń, Poland.
Konstantin
K
Maksin
Department of Toxicology, Poznań University of Medical Sciences, Poznań, Poland.
Mał Gorzata
MG
Kucińska
Department of Toxicology, Poznań University of Medical Sciences, Poznań, Poland.
Hanna
H
Piotrowska
Department of Toxicology, Poznań University of Medical Sciences, Poznań, Poland.
Marek
M
Murias
Department of Clinical Pathology, Poznań University of Medical Sciences, PoznaÅń, Poland.
Aldona
A
Woźniak
Division of Gynecological Surgery, Poznań University of Medical Sciences, Poznań, Poland.
Dariusz
D
Szpurek
Department of Pathophysiology, Poznań University of Medical Sciences, Poznań, Poland.
Krzysztof
K
Książek
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D016922:Cellular Senescence; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019899:Paracrine Communication; D010534:Peritoneal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D010537:Peritoneum / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D013997:Time Factors; D059016:Tumor Microenvironment
cellular senescence; gastrointestinal cancers; mesothelial cells; mice xenografts; peritoneal cavity