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Senescent Carcinoma-Associated Fibroblasts Upregulate IL8 to Enhance Prometastatic Phenotypes
Published version of a preprint
Abstract
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. IMPLICATIONS: Findings show that senescent cancer-associated fibroblasts secret excess IL8 to promote pancreatic cancer invasion and metastasis; thus, senescent CAFs represent a phenotypic subtype, challenging conventional assumptions that CAFs are a homogeneous population. Mol Cancer Res; 15(1); 3-14. ©2016 AACR.
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“Intriguingly, it has been reported that upregulation of IL‐8 in senescent carcinoma‐associated fibroblasts promotes invasion and metastasis of pancreatic cancer cells.47”
From Cellular senescence and senescence-associated secretory phenotype via the cGAS-STING signaling pathway in cancer (2020) · cites this paper as [47]
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Metadata
- Authors
- Wang, T., Notta, F., Navab, R., Joseph, J., Ibrahimov, E., Xu, J., Zhu, C.-Q., Borgida, A., Gallinger, S., & Tsao, M.-S.
- Affiliations
- University Health Network (CA)
- Ontario Institute for Cancer Research (CA)
- Mount Sinai Hospital (CA)
- Venue
- Molecular Cancer Research
- Published
- 2016-09-27
- Volume
- 15
- Issue
- 1
- Pages
- 3-14
- ISSN
- 1541-7786 (ISSN-L)
- 1557-3125
- OpenAlex
- W2525061549
- Cited by
- 123
- References
- 56
- Citations by year
- 2026: 7 · 2025: 16 · 2024: 13 · 2023: 12 · 2022: 17 · 2021: 19 · 2020: 14 · 2019: 9 · 2018: 10 · 2017: 6
- FWCI
- 4.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
- Keywords
- cancer-associated fibroblasts, cellular senescence, interleukin-8, pancreatic cancer, tumor stroma, metastasis, tumor invasion, p16, stromal heterogeneity, prognostic factors
- MeSH terms
- Cancer-Associated Fibroblasts, Animals, Female, Humans, Male, Middle Aged, Neoplasm Invasiveness, Neoplasm Metastasis, Pancreatic Neoplasms, Phenotype, Up-Regulation, Interleukin-8, Cellular Senescence, Stromal Cells, Cell Line, Tumor, Cell Proliferation, Mice
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