Prostate epithelial PTEN/TP53 loss leads to transformation of multipotential progenitors and epithelial to mesenchymal transition

Philip Martin, Yen Nien Liu, Rachel Pierce, Wassim Abou-Kheir, Orla Casey, Victoria Seng, Daniel Camacho, R. Mark Simpson, Kathleen Kelly

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49 Citations (Scopus)

Abstract

Loss of PTEN and loss of TP53 are common genetic aberrations occurring in prostate cancer. PTEN and TP53 contribute to the regulation of self-renewal and differentiation in prostate progenitors, presumptive tumor initiating cells for prostate cancer. Here we characterize the transformed phenotypes resulting from deletion of the Pten and TP53 tumor suppressors in prostate epithelium. Using the PB-Cre4+Ptenfl/flTP53fl/fl model of prostate cancer, we describe the histological and metastatic properties of primary tumors, transplanted primary tumor cells, and clonal cell lines established from tumors. Adenocarcinoma was the major primary tumor type that developed, which progressed to lethal sarcomatoid carcinoma at approximately 6 months of age. In addition, basal carcinomas and prostatic urothelial carcinomas were observed. We show that tumor heterogeneity resulted, at least in part, from the transformation of multipotential progenitors. CK8+ luminal epithelial cells were capable of undergoing epithelial to mesenchymal transition in vivo to sarcomatoid carcinomas containing osseous metaplasia. Metastasis rarely was observed from primary tumors, but metastasis to lung and lymph nodes occurred frequently from orthotopic tumors initiated from a biphenotypic clonal cell line. Androgen deprivation influenced the differentiated phenotypes of metastases. These data show that one functional consequence of Pten/TP53 loss in prostate epithelium is lineage plasticity of transformed cells.

Original languageEnglish
Pages (from-to)422-435
Number of pages14
JournalAmerican Journal of Pathology
Volume179
Issue number1
DOIs
Publication statusPublished - Jul 2011
Externally publishedYes

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ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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