期刊
MOLECULAR CANCER RESEARCH
卷 15, 期 1, 页码 3-14出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-16-0192
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资金
- Cancer Research Society/Pancreatic Cancer Canada/John van Haastrecht Research Grant
- Princess Margaret Center Foundation
- Ontario Institute for Cancer Research/PanCuRx Translational Research Initiative
- Ontario Ministry of Health and Long Term Care
- Terry Fox Foundation STIHR Program in Molecular Pathology of Cancer at CIHR [STP 53912]
Carcinoma-associated fibroblasts (CAF) represent a significant component of pancreatic cancer stroma and are biologically implicated in tumor progression. However, evidence of both cancer-promoting and-restraining properties amongst CAFs suggests the possibility of multiple phenotypic subtypes. Here, it is demonstrated that senescent CAFs promote pancreatic cancer invasion and metastasis compared with nonsenescent control CAFs using in vitro Transwell invasion models and in vivo xenograft mouse models. Screening by gene expression microarray and cytokine ELISA assays revealed IL8 to be upregulated in senescent CAFs. Experimental modulation through IL8 overexpression or receptor inhibition implicates the IL8 pathway as a mediator of the proinvasive effects of senescent CAFs. In a cohort of human pancreatic cancer cases, more abundant stromal senescence as indicated by p16 immunohistochemistry correlated with decreased survival in patients with early-stage disease. These data support senescent fibroblasts as a pathologically and clinically relevant feature of pancreatic cancer. The inhibition of senescent stroma-cancer signaling pathways has the potential to restrain pancreatic cancer progression. (C) 2016 AACR.
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