Prostate Cancer Associated with p53 and Rb Deficiency Arises from the Stem/Progenitor Cell–Enriched Proximal Region of Prostatic Ducts
Open accessAbstract
Recently, we have shown that prostate epithelium–specific deficiency for p53 and Rb tumor suppressors leads to metastatic cancer, exhibiting features of both luminal and neuroendocrine differentiation. Using stage-by-stage evaluation of carcinogenesis in this model, we report that all malignant neoplasms arise from the proximal region of the prostatic ducts, the compartment highly enriched for prostatic stem/progenitor cells. In close similarity to reported properties of prostatic stem cells, the cells of the earliest neoplastic lesions express stem cell marker stem cell antigen 1 and are not sensitive to androgen withdrawal. Like a subset of normal cells located in the proximal region of prostatic ducts, the early neoplastic cells coexpress luminal epithelium markers cytokeratin 8, androgen receptor, and neuroendocrine markers synaptophysin and chromogranin A. Inactivation of p53 and Rb also takes place in the lineage-committed transit-amplifying and/or differentiated cells of the distal region of the prostatic ducts. However, the resulting prostatic intraepithelial neoplasms never progress to carcinoma by the time of mouse death. Interestingly, in an ectopic transplantation assay, early mutant cells derived from either region of the prostatic ducts are capable of forming neoplasms within 3 months. These findings indicate that p53 and Rb are critically important for the regulation of the prostatic stem cell compartment, the transformation in which may lead to particularly aggressive cancers in the context of microenvironment. [Cancer Res 2007;67(12):5683–90]
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Combined loss of Trp53 and Rb produces more tumours in mutant mice.
“When loss of Trp53 and Rb are combined, more tumours develop in mutant mice24,147–149 but it becomes difficult to dissect the respective roles of these two potent tumour suppressors.”
From Cellular mechanisms of tumour suppression by the retinoblastoma gene (2008) · cites this paper as [148]
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- Authors
- Zhou, Z., Flesken-Nikitin, A., & Nikitin, A. Y.
- Affiliations
- Cornell University (US)
- Department of Biomedical Sciences, Cornell University, Ithaca, New York
- Venue
- Cancer Research
- Published
- 2007-06-15
- Volume
- 67
- Issue
- 12
- Pages
- 5683-5690
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2122492394
- Cited by
- 91
- References
- 56
- Citations by year
- 2024: 3 · 2023: 2 · 2021: 1 · 2020: 3 · 2019: 8 · 2018: 4 · 2017: 3 · 2016: 1 · 2015: 5 · 2014: 3 · 2013: 11 · 2012: 7
- FWCI
- 9.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense
- University of Southern California
- National Institutes of Health
- National Cancer Institute (R01CA096823, R01 CA 96823)
- National Center for Research Resources (CA96823, K26RR017595)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Diagnosis and Treatment
- Keywords
- prostate cancer, p53 deficiency, prostatic ducts, Sca-1, neuroendocrine differentiation, luminal differentiation, prostatic intraepithelial neoplasia, androgen withdrawal, androgen receptor, synaptophysin, chromogranin A, carcinogenesis, tumor microenvironment, metastatic cancer, ectopic transplantation
- MeSH terms
- Animals, Cell Transformation, Neoplastic, Immunohistochemistry, Male, Prostatic Neoplasms, Stem Cells, Polymerase Chain Reaction, Tumor Suppressor Protein p53, Retinoblastoma Protein, Mice, Knockout, Mice
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