Stem Cells as Hormone Targets That Lead to Increased Cancer Susceptibility

Abstract

Major advances during the past decade have permitted a clearer understanding of processes that regulate stem cell self-renewal and lineage commitment toward differentiated progeny that populate all tissues. Considerable evidence has also accumulated to indicate that aberrations in the stem and progenitor cell populations can lead to increased cancer risk in specific organs systems. It is long recognized that environmental factors play a major role in cancer etiology, and emerging data suggest that endocrine-disrupting chemicals (EDCs) may contribute to an increased cancer risk. Using the prostate gland as a model system, the present review highlights recent data that find that estrogens and EDCs can reprogram prostate stem and progenitor cell populations, leading to increased cancer susceptibility. We propose that stem cell programming during early development in hormone-regulated tissues may lead to heightened sensitivity to early-life EDC exposures and that aberrant stem cell reprogramming by EDCs may contribute to the developmental basis of adult cancer risk.

Figure 1.

Simplified schematic of stem cell and progenitor cell divisions and differentiation hierarchy for the prostate gland. The stem and progenitor cells differentially express ERs and are thus direct targets of estrogenic compounds. Stem cells within their niche are capable of two types of cell divisions: symmetric self-renewal to form two identical daughter cells and asymmetrical division to self-renew a single stem cell as well as generate an immediate daughter progenitor cell. The progenitor cells transiently proliferate and commit to basal and luminal cell lineages. It is presently unclear whether these cells generate the rare neuroendocrine epithelial cells or whether they are derived from a separate stem population. AR, androgen receptor.

Figure 2.

PS cultured from primary prostate epithelial cells of disease-free organ donors as previously described (11). Day 4 (A) and day 7 (B) PS are clonally generated from a stem-like cell capable of self-renewal and growth through transit amplification of daughter progenitor cells to spheres of 40–50 (day 4) to 100–150 (day 7) progenitor cells at progressing stages of commitment. ERα (C) and ERβ (D) immunostaining of day 7 PS reveals most cells are positive for both receptors. E–H, Primary cells were cultured for 10 days with 1 μM BrdU and transferred to Matrigel culture for sphere formation and BrdU washout. At day 4, PSs were immunostained for BrdU (E and G) to identify the label-retaining stem-like cells. PS were coimmunolabeled for ERβ (F) or ERα (H). E and F, Images for two merged PS reveal that long-term label retaining stem cells (E, green) are strongly ERβ+ (F, red), whereas the daughter progenitor cells have lower relative ERβ protein. G and H, Image of a PS immunostained for BrdU (G, red) and ERα (H, green) shows weak ERα in the stem-like BrdU retaining cell and strong ERα+ in the rapidly dividing progenitor cell population. Scale bar, 50 μM. Panels A–D are reprinted with permission from the authors of another report (11).

Figure 3.

Embryonic hESCs grown to prostate organoids in vitro using directed differentiation conditions. A, Tip of prostate organoid duct at day 20 of Matrigel culture, revealing an organized columnar epithelial structure of prostate-like morphology. B, Confocal imaging of distal tip section shows central epithelial cells colabeled for CK8 (red) and androgen receptor (green). C, Colabeling of organoid for CK8 (red) and Nkx3.1 (green) identifies the prostate-like nature of the epithelium. D and E, Organoids were differentiated over 40 days in the absence (D) and presence (E) of 10 nM BPA and immunostained for Trop2 (red) as a marker of putative prostate stem-like cells. The consistent phenotype observed was rare Trop2+ cells in control organoids (D, arrow) and nests of multiple Trop2+ cells in organoids exposed to BPA (E). Scale bar, 100 μM (A) and 20 μM (C and D).

Figure 4.

Model of developmental estrogenic actions on prostate stem cell populations, resulting in an increased carcinogenic susceptibility. Developmental exposure to an estrogenic EDC (eg, BPA) can lead to increased numbers of reprogrammed stem cells, resulting in a modified gland with little overt phenotype. Exposures to secondary estrogens later in life, as occurs in the aging male, are sufficient to drive preneoplastic lesions in the epithelium, which progress to overt neoplasia and cancer over time. Targets of the secondary exposures can be preinitiated differentiated cells of the modified epithelium or reprogrammed stem and progenitor cells retained in the gland over a lifetime.