Characterizing the contribution of stem/progenitor cells to tumorigenesis in the Pten-/-TP53-/- prostate cancer model.

Abstract

Loss of PTEN is one of the most common mutations in prostate cancer, and loss of wild-type TP53 is associated with prostate cancer progression and castrate resistance. Modeling prostate cancer in the mouse has shown that while Pten deletion in prostate epithelial cells leads to adenocarcinoma, combined loss of Pten and TP53 results in rapidly developing disease with greater tumor burden and early death. TP53 contributes significantly to the regulation of stem cell self-renewal, and we hypothesized that loss of Pten/TP53 would result in measurable changes in prostate cancer stem/progenitor cell properties. Clonogenic assays that isolate progenitor function in primary prostate epithelial cells were used to measure self-renewal, differentiation, and tumorigenic potential. Pten/TP53 null as compared with wild-type protospheres showed increased self-renewal activity and modified lineage commitment. Orthotopic transplantation of Pten/TP53 null cells derived from protospheres produced invasive Prostatic Intraepithelial Neoplasia (PIN)/adenocarcinoma, recapitulating the pathology seen in primary tumors. Pten/TP53 null progenitors relative to wild type also demonstrated increased dependence on the AKT/mammalian target of rapamycin complex 1 (mTORC1) and androgen receptor (AR) pathways for clonogenic and tumorigenic growth. These data demonstrate roles for Pten/TP53 in prostate epithelial stem/progenitor cell function, and moreover, as seen in patients with castrate-resistant prostate cancer, suggest for the involvement of an AR-dependent axis in the clonogenic expansion of prostate cancer stem cells.

• Authors: Wassim G Abou-Kheir, Paul G Hynes, Philip L Martin, Rachel Pierce, Kathleen Kelly
• Journal: Stem cells (Dayton, Ohio) (Stem Cells) Vol. 28 Issue 12 Pg. 2129-40 (Dec 2010) ISSN: 1549-4918 [Electronic] England
• PMID: 20936707 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Multiprotein Complexes
• Proteins
• Receptors, Androgen
• Tumor Suppressor Protein p53
• Mechanistic Target of Rapamycin Complex 1
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• PTEN Phosphohydrolase

Topics

• Animals
• Cell Lineage
• Cell Proliferation
• Cell Separation
• Cell Shape
• Colony-Forming Units Assay
• Disease Models, Animal
• Epithelial Cells (enzymology, pathology)
• Gene Deletion
• Immunophenotyping
• Male
• Mechanistic Target of Rapamycin Complex 1
• Mice
• Multiprotein Complexes
• Neoplastic Stem Cells (pathology)
• PTEN Phosphohydrolase (deficiency, metabolism)
• Precancerous Conditions (enzymology, pathology)
• Prostate (metabolism, pathology)
• Prostatic Neoplasms (enzymology, pathology)
• Proteins (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptors, Androgen (metabolism)
• Spheroids, Cellular (pathology)
• TOR Serine-Threonine Kinases
• Tumor Cells, Cultured
• Tumor Suppressor Protein p53 (deficiency, metabolism)