Prostate cancer originating in basal cells progresses to adenocarcinoma propagated by luminal-like cells

Abstract

The relationship between the cells that initiate cancer and the cancer stem-like cells that propagate tumors has been poorly defined. In a human prostate tissue transformation model, basal cells expressing the oncogenes Myc and myristoylated AKT can initiate heterogeneous tumors. Tumors contain features of acinartype adenocarcinoma with elevated eIF4E-driven protein translation and squamous cell carcinoma marked by activated betacatenin. Lentiviral integration site analysis revealed that alternative histological phenotypes can be clonally derived from a common cell of origin. In advanced disease, adenocarcinoma can be propagated by self-renewing tumor cells with an androgen receptor-low immature luminal phenotype in the absence of basal-like cells. These data indicate that advanced prostate adenocarcinoma initiated in basal cells can be maintained by luminal-like tumor-propagating cells. Determining the cells that maintain human prostate adenocarcinoma and the signaling pathways characterizing these tumor-propagating cells is critical for developing effective therapeutic strategies against this population.

Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer

“…S2). As a positive control, we used a human CRPC model initiated in primary human cells and driven by the combination of Myc and myristoylated/activated AKT (myrAKT) oncogenes that express high levels of NICD1 (36). NICD1 (100 kDa) was observed only in the human metastatic CRPC samples and the Myc/myrAKT human CRPC model (36) but not in the benign tissue or in localized low-to intermediate-risk prostate cancers ( Fig.…”

Prostatic inflammation enhances basal-to-luminal differentiation and accelerates initiation of prostate cancer with a basal cell origin

“…The differentiation of basal cells with preexisting prooncogenic signaling into luminal cells would enhance the susceptibility of luminal cells to transformation by ensuing genetic changes, as demonstrated by our current study and by several previous studies using mouse models (14-16, 19, 61). A very recent study using the prostate regeneration model showed that basal cells even may serve as the origin of prostate cancer stem cells (62). Currently, because of technical limitations, no published study has directly demonstrated that basal cells and luminal cells within the same human PIN lesions share genetic changes.…”

A basal stem cell signature identifies aggressive prostate cancer phenotypes

“…Murine models overexpressing key components of developmental signaling pathways alone or with other genetic alterations can drive a phenotype reminiscent of late-stage prostate cancer (19)(20)(21)(22). Although these studies provide evidence of a relationship between stem-like qualities and an aggressive phenotype, no studies to our knowledge have shown a molecular relationship between aggressive prostate cancer and uncultured stem-like cells from the human prostate.…”