Selective Evolution of Stromal Mesenchyme with p53 Loss in Response to Epithelial Tumorigenesis
Open accessAbstract
Our understanding of cancer has largely come from the analysis of aberrations within the tumor cell population. Yet it is increasingly clear that the tumor microenvironment can significantly influence tumorigenesis. For example, the mesenchyme can support the growth of tumorigenic epithelium. However, whether fibroblasts are subject to genetic/epigenetic changes as a result of selective pressures conferred by oncogenic stress in the epithelium has not been experimentally assessed. Recent analyses of some human carcinomas have shown tumor-suppressor gene mutations within the stroma, suggesting that the interplay among multiple cell types can select for aberrations nonautonomously during tumor progression. We demonstrate that this indeed occurs in a mouse model of prostate cancer where epithelial cell cycle disruption via cell-specific inhibition of pRb function induces a paracrine p53 response that suppresses fibroblast proliferation in associated stroma. This interaction imposes strong selective pressure yielding a highly proliferative mesenchyme that has undergone p53 loss.
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A p53-deficient stroma promotes epithelial cancer progression.
“This activity might explain why a p53-deficient stroma promotes epithelial cancer progression [ 75 , 76 ].”
From Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor (2008) · cites this paper as [76]
T121 is thought to specifically inactivate the three Rb family members.
“The Van Dyke group has published a series of elegant studies in mice expressing a truncated form of the SV40 large T oncoprotein, T121, which is thought to specifically inactivate the three Rb family members87,154–160.”
From Cellular mechanisms of tumour suppression by the retinoblastoma gene (2008) · cites this paper as [159]
Not all mechanisms of cancer initiation are cell autonomous.
“In addition, the analysis of mice expressing T121 in the prostate indicates that loss of Rb family function in epithelial cells triggers signals to surrounding stromal cells, underscoring that not all the mechanisms of cancer initiation are cell autonomous159.”
From Cellular mechanisms of tumour suppression by the retinoblastoma gene (2008) · cites this paper as [159]
Loss of Rb family function in prostate epithelial cells triggers signals to surrounding stromal cells.
“In addition, the analysis of mice expressing T121 in the prostate indicates that loss of Rb family function in epithelial cells triggers signals to surrounding stromal cells, underscoring that not all the mechanisms of cancer initiation are cell autonomous159.”
From Cellular mechanisms of tumour suppression by the retinoblastoma gene (2008) · cites this paper as [159]
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Self-citation
- Authors
- Hill, R., Song, Y., Cardiff, R. D., & Van Dyke, T.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- University of California, Davis (US)
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2005-12
- Volume
- 123
- Issue
- 6
- Pages
- 1001-1011
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2129404018
- Cited by
- 324
- References
- 3
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 2 · 2023: 9 · 2022: 5 · 2021: 8 · 2020: 8 · 2019: 8 · 2018: 9 · 2017: 12 · 2016: 12 · 2015: 9 · 2014: 15 · 2013: 19 · 2012: 26
- FWCI
- 13.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 2821 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Cancer Institute (R01-CA046283, U01-CA84294)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- tumor microenvironment, p53 deficiency, epithelial-fibroblast interaction, paracrine signaling, selection pressure, fibroblast proliferation, prostate cancer, tumor progression, cell cycle disruption, tumor suppressor
- MeSH terms
- S100 Calcium-Binding Protein A4, Actins, Adenocarcinoma, Animals, Antigens, Polyomavirus Transforming, Connective Tissue, Disease Models, Animal, Epithelial Cells, Fibroblasts, Genotype, Keratins, Male, Mice, Transgenic, Models, Biological, Mutation, S100 Proteins, Prostate, Prostatic Neoplasms, Tumor Suppressor Protein p53, Retinoblastoma Protein, Stromal Cells, Gene Deletion, Mice, Knockout, Loss of Heterozygosity, Paracrine Communication, Cell Proliferation, Mice, Keratin-8
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