A Human Fetal Prostate Xenograft Model of Developmental Estrogenization

Abstract

Prostate cancer is a common disease in older men. Rodent models have demonstrated that an early and later-life exposure to estrogen can lead to cancerous lesions, and implicated hormonal dysregulation as an avenue for developing future prostate neoplasia. This study utilizes a human fetal prostate xenograft model to study the role of estrogen in the progression of human disease. Histopathological lesions were assessed in 7, 30, 90, 200, and 400-day human prostate xenografts. Gene expression for cell cycle, tumor suppressors, and apoptosis-related genes (i.e. CDKN1A, CASP9, ESR2, PTEN, and TP53) were performed for 200-day estrogen-treated xenografts. Glandular hyperplasia was observed in xenografts given both an initial and secondary exposure to estradiol in both 200 and 400-day xenografts. Persistent estrogenic effects were verified using immunohistochemical markers for cytokeratin 10, p63, and estrogen receptor-α. This model provides data on the histopathological state of the human prostate following estrogenic treatment, which can be utilized in understanding the complicated pathology associated with prostatic disease and early- and later-life estrogenic exposures.

Development of the human prostate

“…Xenograft studies of human fetal prostates have been carried out previously and support the idea that normal human prostatic development is dependent upon androgens (Yonemura et al, 1995; Sugimura et al, 1988; Saffarini et al, 2013). Such grafts of human fetal prostate also respond to the adverse effect of exogenous estrogen (Yonemura et al, 1995; Sugimura et al, 1988; Saffarini et al, 2015b; Saffarini et al, 2015a). In the present study we carried out the simple experiment of dividing human fetal prostates into right and left halves, which were grafted into DHT-treated or untreated castrated (androgen-deficient) hosts.…”

“…Endogenous estrogens (primarily of maternal origin) elicit squamous metaplasia of the human fetal prostatic epithelium (Zondek and Zondek, 1979). Prostatic squamous metaplasia and other adverse effects have been reported in xenografts of human fetal prostates grown in mouse hosts treated with diethylstilbestrol (DES) or estradiol benzoate (Saffarini et al, 2015b; Saffarini et al, 2015a; Sugimura et al, 1988; Yonemura et al, 1995). Accordingly, ESR1 and ESR2 have been detected in the human fetal prostate (Adams et al, 2002; Shapiro et al, 2005).…”

“…Many of the earlier reports on human fetal prostatic development were published prior to the common use of color photographs, and on the whole, human prostatic development has been inadequately studied both at morphological and molecular levels. Experimental analyses utilizing xenografts detail effects of exogenous estrogens on human fetal prostatic development (Yonemura et al, 1995; Saffarini et al, 2013; Saffarini et al, 2015b; Saffarini et al, 2015a), but this experimental approach has been under utilized.…”

Postnatal exposure to finasteride causes different effects on the prostate of male and female gerbils

“…This finding can be explained by the action of androgens on smooth muscle differentiation. In addition, oestrogens could play a role in stimulating periductal muscle proliferation (Zhou et al, 2011) and could alter its differentiation (Saffarini et al, 2015). They may be implicated in increasing the thickness of smooth muscle (Holterhus et al, 1993; Sanches et al, 2016a).…”

Avaliação dos efeitos da finasterida sobre o desenvolvimento prostático intrauterino e pós-natal inicial de fêmeas e machos do gerbilo da Mongólia ("Meriones unguiculatus")

“…On the other hand, oestrogens could play a role in stimulating the periductal muscle proliferation 50 and could alter its differentiation. 51 They may be implicated in increasing the thickness of smooth muscle. 8,52 Our data show an increased thickness of the periductal smooth muscle in the finasteride-treated group in both males and females, which may indicate an increase in proliferative activity in these cells and a delay in their differentiation.…”