Endocrine Abstracts (2017) 49 S23.1 | DOI: 10.1530/endoabs.49.S23.1

Prolactin regulation of prostate stem cells: potential implications in prostate cancer

Vincent Goffin


France.


Prostate stem cells have been proposed to participate in prostate cancer initiation. Furthermore, based on their androgen-independence, they are suspected to trigger prostate cancer recurrence when the tumor is no longer responsive to anti-androgens. Therefore better understanding the regulation of this particular cell pool may have important therapeutic relevance. In the human prostate, expression of prolactin (PRL) and activation of its major downstream signaling effector Stat5, have been correlated to prostate cancer progression and relapse. To understand these effects, we use the probasin (Pb)-PRL transgenic mouse model which involves prostate-specific expression of PRL. Pb-PRL mice recapitulate many pre-neoplastic features of the human prostate including focal areas of epithelial dysplasia, prostate intra-epithelial neoplasia and moderate inflammation (‘reactive stroma’), together with hypertrophy and ductal dilatation of all prostate lobes. Using various cell lineage-specific markers coupled to immunohistochemistry and cell sorting (FACS), we showed some years ago that the p63+ basal/stem cell compartment (which contains ‘tumor-initiating’ cells) was highly enriched in Pb-PRL prostate tumors (Rouet et al, PNAS 2010). Subsequent studies revealed enrichment of another cell population that we discovered and named ‘LSCmed’ based on its FACS profile (Sackmann Sala et al, Am. J. Pathol 2014). LSCmed are luminal progenitors that exhibit stem-like properties in vitro (prostasphere assay, gland formation in transplantation assays) and importantly, resistance to androgen deprivation in vivo. Transcriptomic profiling showed that LSCmed is a distinct cell entity that differs from the well-known basal and luminal cell populations and that can be identified using a specific gene expression signature. LSCmed are rare in the normal prostate and their amplification in Pb-PRL prostate tumors more likely results from paracrine signals downstream of PRLR/Stat5 signaling than from a direct PRL effect. Strikingly LSCmed represent the major cell component of aggressive, castration-resistant prostate tumors driven by Pten loss, both before and after castration. This is particularly relevant since loss of PTEN is frequently observed in the human prostate oncogenome. In summary, LSCmed represent a newly-identified prostatic cell population that is a strong candidate for mediating cell resistance to androgen-deprivation therapy. Ongoing studies aim to elucidate the mechanisms that that regulate these luminal progenitors and to identify LSCmed(-like) cells in the human prostate.

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