title: Senescent peritoneal mesothelium induces a pro-angiogenic phenotype in ovarian cancer cells in vitro and in a mouse xenograft model in vivo.
abstract: It is believed that senescent cells contribute to the progression of primary and metastatic tumors, however, the exact mechanisms of this activity remain elusive. In this report we show that senescent human peritoneal mesothelial cells (HPMCs) alter the secretory profile of ovarian cancer cells (A2780, OVCAR-3, SKOV-3) by increasing the release of four angiogenic agents: CXCL1, CXCL8, HGF, and VEGF. Proliferation and migration of endothelial cells subjected to conditioned medium generated by: cancer cells modified by senescent HPMCs; cancer cells co-cultured with senescent HPMCs; and by early-passage HPMCs from aged donors, were markedly intensified. The same was the case for the vascularization, size and number of tumors that developed in the mouse peritoneum upon injection of ovarian cancer cells with senescent HPMCs. When the identified pro-angiogenic proteins were neutralized in conditioned medium from the cancer cells, both aspects of endothelial cell behavior intensified in vitro in response to senescent HPMCs were markedly reduced. The search for mediators of senescent HPMC activity using specific neutralizing antibodies and recombinant exogenous proteins showed that the intensified angiogenic potential of cancer cells was elicited by IL-6 and TGF-β1. At the transcriptional level, increased proliferation and migration of endothelial cells exposed to cancer cells modified by senescent HPMCs was regulated by HIF-1α, NF-κB/p50 and AP-1/c-Jun. Collectively, our findings indicate that senescent HPMCs may promote the progression of ovarian cancer cells by reprogramming their secretory phenotype towards increased production of pro-angiogenic agents and subsequent increase in the angiogenic capabilities of the vascular endothelium.
authors.affiliation: Department of Pathophysiology, Poznań University of Medical Sciences, Rokietnicka 8 Str., 60-806, Poznań, Poland. jmikula@ump.edu.pl.
authors.forename: Justyna
authors.initials: J
authors.lastname: Mikuła-Pietrasik
authors.affiliation: Department of Pathophysiology, Poznań University of Medical Sciences, Rokietnicka 8 Str., 60-806, Poznań, Poland. psosinska@ump.edu.pl.
authors.forename: Patrycja
authors.initials: P
authors.lastname: Sosińska
authors.affiliation: General Surgery Ward, Centrum Medyczne HCP, 28 czerwca 1956 r. 223/229 Str., 61-485, Poznań, Poland. eryknaumowicz@plusnet.pl.
authors.forename: Eryk
authors.initials: E
authors.lastname: Naumowicz
authors.affiliation: Department of Clinical Pathology, Poznań University of Medical Sciences, Przybyszewskiego 49 Str., 60-355, Poznań, Poland. kmaksin@gmail.com.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Maksin
authors.affiliation: Department of Toxicology, Poznań University of Medical Sciences, Dojazd 30 Str., 60-631, Poznań, Poland. hanna.piotrowska@ump.edu.pl.
authors.forename: Hanna
authors.initials: H
authors.lastname: Piotrowska
authors.affiliation: Department of Clinical Pathology, Poznań University of Medical Sciences, Przybyszewskiego 49 Str., 60-355, Poznań, Poland. aldona.wozniak@wp.pl.
authors.forename: Aldona
authors.initials: A
authors.lastname: Woźniak
authors.affiliation: Division of Gynecological Surgery, Poznań University of Medical Sciences, Polna 33 Str., 60-535, Poznań, Poland. dszpurek@gmail.com.
authors.forename: Dariusz
authors.initials: D
authors.lastname: Szpurek
authors.affiliation: Department of Pathophysiology, Poznań University of Medical Sciences, Rokietnicka 8 Str., 60-806, Poznań, Poland. kksiazek@ump.edu.pl.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Książek
mesh_terms: D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000502:physiology*; D018450:Disease Progression; D004848:Epithelium / Q000473:pathology*; D005260:Female; D064593:Heterografts; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000473:pathology*; D010537:Peritoneum / Q000473:pathology*; D010641:Phenotype
keywords: Angiogenesis; Cellular senescence; Mesothelial cells; Ovarian cancer; Peritoneal cavity