Cancer and aging: a model for the cancer promoting effects of the aging stroma
Abstract
The incidence of cancer rises exponentially with age in humans and many other mammalian species. Malignant tumors are caused by an accumulation of oncogenic mutations. In addition, malignant tumorigenesis requires a permissive tissue environment in which mutant cells can survive, proliferate, and express their neoplastic phenotype. We propose that the age-related increase in cancer results from a synergy between the accumulation of mutations and age-related, pro-oncogenic changes in the tissue milieu. Most age-related cancers derive from the epithelial cells of renewable tissues. An important element of epithelial tissues is the stroma, the sub-epithelial layer composed of extracellular matrix and several cell types. The stroma is maintained, remodeled and repaired by resident fibroblasts, supports and instructs the epithelium, and is essential for epithelial function. One change that occurs in tissues during aging is the accumulation of epithelial cells and fibroblasts that have undergone cellular senescence. Cellular senescence irreversibly arrests proliferation in response to damage or stimuli that put cells at risk for neoplastic transformation. Senescent cells secrete factors that can disrupt tissue architecture and/or stimulate nearby cells to proliferate. We therefore speculate that their presence may create a pro-oncogenic tissue environment that synergizes with oncogenic mutations to drive the rise in cancer incidence with age. Recent evidence lends support to this idea, and suggests that senescent stromal fibroblasts may be particularly adept at creating a tissue environment that can promote the development of age-related epithelial cancers.
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Senescent fibroblasts secrete high levels of several matrix metalloproteinases, epithelial growth factors, and inflammatory cytokines.
“Senescent fibroblasts secrete high levels of several matrix metalloproteinases, epithelial growth factors, and inflammatory cytokines (reviewed in Krtolica and Campisi [2002]).”
From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Krtolica and Campisi [2002]
p16, and to a lesser extent ARF, are markers expressed predominantly, although not exclusively, by senescent cells.
“p16, and to a lesser extent ARF, join the extremely short list of markers that are expressed predominantly, although not exclusively, by senescent cells (reviewed in Krtolica and Campisi [2002]).”
From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Krtolica and Campisi [2002]
Cells with characteristics of senescence are present at sites of certain age-related pathologies, including atherosclerotic lesions, skin ulcers and arthritic joints, as well as benign and preneoplastic hyperproliferative lesions in the prostate and liver.
“Moreover, these cells are present at sites of certain age-related pathologies, including atherosclerotic lesions, skin ulcers and arthritic joints, as well as benign and preneoplastic hyperproliferative lesions in the prostate and liver (reviewed in Krtolica and Campisi, 2002).”
From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Krtolica and Campisi, 2002
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- Authors
- Krtolica, A., & Campisi, J.
- Affiliations
- Lawrence Berkeley National Laboratory (US)
- Corresponding author
- Campisi, Judith
- ORCID
- Campisi, Judith
- Venue
- The International Journal of Biochemistry & Cell Biology
- Publisher
- Elsevier BV
- Published
- 2002-11
- Volume
- 34
- Issue
- 11
- Pages
- 1401-1414
- ISSN
- 1357-2725 (ISSN-L)
- OpenAlex
- W2027659803
- Cited by
- 295
- References
- 15
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 2 · 2023: 9 · 2022: 8 · 2021: 12 · 2020: 9 · 2019: 6 · 2018: 8 · 2017: 11 · 2016: 14 · 2015: 12 · 2014: 17 · 2013: 12 · 2012: 18
- FWCI
- 1.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The International Journal of Biochemistry & Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Energy
- California Breast Cancer Research Program
- 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
- tumor microenvironment, stroma, cellular senescence, senescence-associated secretory phenotype, stromal fibroblasts, extracellular matrix, oncogenic mutations, epithelial cancers, age-related cancer incidence, oncogenic transformation
- MeSH terms
- Age Factors, Aging, Animals, Epithelial Cells, Fibroblasts, Humans, Neoplasms, Phenotype, Cellular Senescence, Stromal Cells
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