Novel mechanisms of sublethal oxidant toxicity: induction of premature senescence in human fibroblasts confers tumor promoter activity
Abstract
Aging is the highest risk factor for cancer. Although oxidants are thought to contribute to both aging and cancer, the interplay between oxidative stress, aging, and cancer has not been well studied. Human diploid fibroblasts (HDFs) undergo premature senescence in response to sublethal doses of H(2)O(2). To test the hypothesis that senescent or senescent-like HDFs function as a tumor promoter, we have employed an in vitro skin tumor promotion model, in which colony formation is measured using initiated mouse keratinocyte 308 cells seeded at clonal density. 308 cells form colonies when co-cultured with normal HDFs only in the presence of the tumor promoter phorbol 12-myristate 13-acetate (TPA), which induces an average of 5.75 colonies. When co-cultured with H(2)O(2)-treated HDFs, 308 cells form an average of 30.3 colonies. To understand the mechanism behind this phenomenon, we tested whether conditioned medium of HDFs, HDF extracellular matrix (ECM), density of HDFs, or the contact between keratinocytes and HDFs plays a role in 308 cell colony formation. The conditioned medium from prematurely senescent cells resulted in an average of eightfold more 308 cell colonies formed than the conditioned medium from normal HDFs, and the growth-promoting effect of the conditioned medium was trypsin sensitive. The ECM alone was not able to induce 308 cell colony formation. Increasing the density of normal HDFs or contact with normal HDFs but not senescent-like HDFs was inhibitory to the growth of 308 cells. Measurement of Connexin 43 indicated a decreased expression of the protein, which suggests an impaired gap junction communication in senescent-like HDFs. We conclude that H(2)O(2)-treated fibroblasts not only lose contact inhibition of the growth of initiated keratinocytes perhaps related to reduced gap junction communication but also increase production of secreted protein factors to enhance the growth of 308 keratinocytes.
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There is mounting evidence that senescent fibroblasts create a local tissue environment that promotes the growth of initiated or preneoplastic epithelial cells both in culture and in vivo.
“Indeed, there is mounting evidence that senescent fibroblasts create a local tissue environment that promotes the growth of initiated or preneoplastic epithelial cells both in culture and in vivo (Krtolica et al., 2001; Roninson, 2002; Dilley et al., 2003).”
From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Dilley et al., 2003
Co-culture of senescent fibroblasts, induced by various stimuli, can promote the growth and proliferation of benign, pre-malignant, and malignant cells from a range of tumour types.
“Co-culture of senescent fibroblasts, induced by various stimuli (e.g. radiation, DNA damage, replicative exhaustion), can promote the growth and proliferation of benign, pre-malignant, and malignant cells from a range of tumour types.9,12,26,41–44”
From Paracrine roles of cellular senescence in promoting tumourigenesis (2018) · cites this paper as [42]
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- Authors
- Dilley, T. K., Bowden, G. T., & Chen, Q. M.
- Affiliations
- University of Arizona (US)
- Corresponding author
- Chen, Qin M
- ORCID
- Chen, Qin M
- Venue
- Experimental Cell Research
- Publisher
- Elsevier BV
- Published
- 2003-10
- Volume
- 290
- Issue
- 1
- Pages
- 38-48
- ISSN
- 0014-4827 (ISSN-L)
- OpenAlex
- W2154432562
- Cited by
- 64
- References
- 49
- Citations by year
- 2026: 1 · 2024: 4 · 2023: 3 · 2022: 2 · 2021: 1 · 2018: 1 · 2017: 2 · 2016: 4 · 2015: 2 · 2014: 2 · 2013: 3 · 2012: 3
- FWCI
- 1.54
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Experimental Cell Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Burroughs Wellcome Fund
- American Federation for Aging Research
- National Institutes of Health (R01 ES10826)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- premature senescence, hydrogen peroxide, human diploid fibroblasts, tumor promotion, skin tumor promotion, keratinocytes, conditioned medium, extracellular matrix, contact inhibition, gap junctional intercellular communication, connexin 43, oxidative stress, aging and cancer, secreted growth factors
- MeSH terms
- Carcinogens, Cell Adhesion, Cell Communication, Cell Division, Cell Line, Cell Transformation, Neoplastic, Extracellular Matrix, Fibroblasts, Humans, Models, Biological, Neoplasms, Tetradecanoylphorbol Acetate, Tumor Stem Cell Assay, Keratinocytes, Oxidants, Cellular Senescence, Culture Media, Conditioned, Gap Junctions, Connexin 43, Oxidative Stress, Coculture Techniques
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