Senescence‐associated tissue microenvironment promotes colon cancer formation through the secretory factor GDF15
Open accessAbstract
The risk of colorectal cancer (CRC) varies between people, and the cellular mechanisms mediating the differences in risk are largely unknown. Senescence has been implicated as a causative cellular mechanism for many diseases, including cancer, and may affect the risk for CRC. Senescent fibroblasts that accumulate in tissues secondary to aging and oxidative stress have been shown to promote cancer formation via a senescence‐associated secretory phenotype (SASP). In this study, we assessed the role of senescence and the SASP in CRC formation. Using primary human colon tissue, we found an accumulation of senescent fibroblasts in normal tissues from individuals with advanced adenomas or carcinomas in comparison with individuals with no polyps or CRC. In in vitro and ex vivo model systems, we induced senescence using oxidative stress in colon fibroblasts and demonstrated that the senescent fibroblasts secrete GDF15 as an essential SASP factor that promotes cell proliferation, migration, and invasion in colon adenoma and CRC cell lines as well as primary colon organoids via the MAPK and PI3K signaling pathways. In addition, we observed increased mRNA expression of GDF15 in primary normal colon tissue from people at increased risk for CRC in comparison with average risk individuals. These findings implicate the importance of a senescence‐associated tissue microenvironment and the secretory factor GDF15 in promoting CRC formation.
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The senescence-associated tissue microenvironment promotes colon cancer formation in human colon epithelial cells and human-derived colon organoids.
“The senescence‐associated tissue microenvironment promotes colon cancer formation in human colon epithelial cells and in human-derived colon organoids266.”
From SenNet recommendations for detecting senescent cells in different tissues (2024) · cites this paper as [266]
The Results section reports that senescent fibroblasts increased proliferation in colon epithelial cell lines and primary human colon organoids, and increased migration and invasion in the cell lines. It concludes that these effects *may* promote adenoma or colorectal cancer formation; the experiments described do not establish cancer formation in the cells or organoids as the citing sentence states. (LLM, conf=0.87)
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- Authors
- Guo, Y., Ayers, J. L., Carter, K. T., Wang, T., Maden, S. K., Edmond, D., Newcomb P, P., Li, C., Ulrich, C., Yu, M., & Grady, W. M.
- Affiliations
- Fred Hutch Cancer Center (US)
- University of Washington (US)
- Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle Washington
- Huntsman Cancer Institute (US)
- Corresponding author
- Yu, Ming
- Grady, William M.
- ORCID
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2019-08-06
- Volume
- 18
- Issue
- 6
- Pages
- e13013-e13013
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- PMC
- PMC6826139
- OpenAlex
- W2965836614
- Cited by
- 139
- References
- 16
- Citations by year
- 2026: 24 · 2025: 32 · 2024: 17 · 2023: 12 · 2022: 21 · 2021: 16 · 2020: 16 · 2019: 1
- FWCI
- 9.60
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Aging Cell (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (P01CA077852, P30CA042014, P30CA15704, R01189184, R01CA194663, R01CA207371, R01CA220004, U01CA206110, U54CA143862)
- Huntsman Cancer Foundation
- National Cancer Institute (R50 CA233042)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- colorectal cancer, cellular senescence, senescence-associated secretory phenotype, GDF15, senescent fibroblasts, tissue microenvironment, colonic adenoma, oxidative stress, MAPK signaling, PI3K signaling, colon organoids, cancer risk, cell proliferation and invasion
- MeSH terms
- Aging, Cells, Cultured, Colonic Neoplasms, Fibroblasts, Humans, Phenotype, RNA, Messenger, Cellular Senescence, Growth Differentiation Factor 15, HEK293 Cells, Tumor Microenvironment
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