Identification of a Cell of Origin for Human Prostate Cancer

Abstract

Prostate cancer induced in primary human prostate basal cells recapitulates disease initiation and progression in immunodeficient mice.Luminal cells are believed to be the cells-of-origin for human prostate cancer because the disease is characterized by luminal cell expansion and absence of basal cells. Yet functional studies addressing the origin of human prostate cancer have not previously been reported due to a lack of relevant in vivo human models. Here we show that basal cells, from primary benign human prostate tissue, can initiate prostate cancer in immunodeficient mice. The cooperative effects of AKT, ERG, and androgen receptor (AR) in basal cells recapitulated the histological and molecular features of human prostate cancer with loss of basal cells and expansion of luminal cells expressing prostate-specific antigen (PSA) and alpha-methylacylCoA racemase (AMACR). Our results demonstrate that histological characterization of cancers does not necessarily correlate with the cellular origins of the disease.Prostate cancer research has been hindered by an absence of model systems in which the disease is initiated from primary human prostate epithelial cells, precluding investigation of transforming alterations and cells-of-origin. Commonly used human prostate cancer cell lines and xenografts were derived from metastatic lesions. Murine prostate cancer models prohibit testing of species-specific therapies such as monoclonal antibodies against human proteins (1). An ideal model system would be human cell-derived and present as a multifocal disease to accurately represent the heterogeneity of prostate malignancy (2). The

Brief Report: A Bioassay to Identify Primary Human Prostate Cancer Repopulating Cells

“…The development of improved treatments requires advances to our fundamental understanding of three cell types; prostate stem cells, cancer cells of origin, and cancer repopulating cells. Prostatic stem cells and cancer cells of origin are benign populations that were isolated from basal [2][3][4] and luminal cell [5] compartments of primary prostate tissues. However, the imperative is to identify and target cancer repopulating cells, defined as cells from primary PCa's that can regenerate tumors when transplanted in vivo.…”

The complexities of identifying a cell of origin for human prostate cancer

“…In the latest issue of Science, Goldstein et al 2 provide evidence that basal cells are a potential origin of human PCa, thereby substantiating their earlier report that murine basal epithelial stem cells are efficient targets for PCa initiation. 3 So why are these observations notable?…”

“…Since intracellular and extracellular markers have not been correlated, 'no commonly accepted strategy exists to isolate such populations from dissociated human prostate tissue'. 2 The first sequence of data in the Science article by Goldstein and colleagues 2 shows how dispersed cells from human specimens can be sorted by fluorecense-activated cell sorting using CD49f and Trop2 to separate basal cell populations from luminal cell populations. Accordingly Goldstein et al 2 isolated CD49f lo Trop2 hi luminal cells (defined as CK8/18 1 CK5 1/2 CK14 1/2 AR 1 PSA 1 Nkx3.1 1 TMPRSS2 1 ) and CD49f hiTrop2 hi basal cells (defined as CK5 1 p63 1 -CK14 1/2 CK8/18 1/2 ).…”

“…2 The first sequence of data in the Science article by Goldstein and colleagues 2 shows how dispersed cells from human specimens can be sorted by fluorecense-activated cell sorting using CD49f and Trop2 to separate basal cell populations from luminal cell populations. Accordingly Goldstein et al 2 isolated CD49f lo Trop2 hi luminal cells (defined as CK8/18 1 CK5 1/2 CK14 1/2 AR 1 PSA 1 Nkx3.1 1 TMPRSS2 1 ) and CD49f hiTrop2 hi basal cells (defined as CK5 1 p63 1 -CK14 1/2 CK8/18 1/2 ). Although they did not comment on this, the populations are heterogeneous and in particular the basal cell populations will also contain intermediate (transit amplifying) cells.…”

“…The report is notable because it demonstrates that the basal cell populations contain cells that, when mutated, are cancer-initiating. 2 However, in all probability it is likely that there will be more than one cancer cell of origin (as has been demonstrated in breast cancer), 12 and the PCa field will have to consider both luminal and basal cell types in its approaches to the discovery of new therapies for PCa.…”