Prostate Cancer Associated with p53 and Rb Deficiency Arises from the Stem/Progenitor Cell–Enriched Proximal Region of Prostatic Ducts

Abstract

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]

Characterization of the cell of origin for small cell lung cancer

“…This model highlighting a role for RB and p53 in stem/progenitor cell populations is compatible with other mouse models of human cancers associated with loss of RB and p53 function, including in the blood compartment, in bones, in the retina and in the mammary epithelium. [35][36][37][38][39] However, the identity of potential neuroendocrine cell progenitors in adult lung tissue has not yet been established.…”

Basal epithelial stem cells are efficient targets for prostate cancer initiation

“…Clinical observations that the majority of human prostate cancer cells express luminal cell markers have led many to propose that these cells are the source of prostate cancer initiation (8). The neoplasms that develop in the Rb −/− p53 −/− knockout mouse model express the stem cell marker Sca-1 and arise in the proximal region of the gland (9). In a PTEN null mouse model there is a preferential expansion of basal cells compared to luminal cells, suggesting disease in these mice is propagated by basal cells (10).…”

Cancer stem cell markers in common cancers – therapeutic implications

“…Lentiviral targeted knockdown of PTEN by a siRNA construct also caused PIN lesions in prostate cells [49], as did lentiviral overexpression of both AR and Akt, causing prostate cancer [93]. In the Rb À/À , p53 À/À prostate-specific deletion mouse model, SCA-1 was detected in invasive prostate cancer cells [94] at proximal regions of the prostate where murine prostate stem and progenitor cell populations had previously been described [80]. In contrast to PTEN mice, these prostate cancer lesions were positive for luminal and neuroendocrine markers but failed to express basal cell markers.…”