Biomedical subjects

Annemarie A Donjacour

Publications and source records attributed to Annemarie A Donjacour.

6 recordsLinked to original sources

PubMed2004

Hormonal, cellular, and molecular regulation of normal and neoplastic prostatic development.

This review on normal and neoplastic growth of the prostate emphasizes the importance of epithelial-mesenchymal/stromal interactions. Accordingly, during prostatic development urogenital sinus mesenchyme (a) specifies prostatic epithelial identity, (b) induces epithelial bud formation, (c) elicits prostatic bud growth and regulates ductal branching, (d) promotes differentiation of a secretory epithelium, and (e) specifies the types of secretory proteins expressed. In reciprocal fashion, prostatic epithelium induces smooth muscle differentiation in the mesenchyme. Epithelial-mesenchymal interactions during development continue postnatally into adulthood as stromal-epithelial interactions which play a homeostatic role and in so doing reciprocally maintain epithelial and stromal differentiation and growth-quiescence. Prostatic carcinogenesis involves perturbation of these reciprocal homeostatic cell-cell interactions. The central role of mesenchyme in prostatic epithelial development has been firmly established through analysis of tissue recombinants composed of androgen-receptor-positive wild-type mesenchyme and androgen-receptor-negative epithelium. These studies revealed that at the very least ductal morphogenesis, epithelial cytodifferentiation, epithelial apoptosis and epithelial proliferation are regulated by stromal and not epithelial androgen receptors. Likewise, progression from non-tumorigenesis to tumorigenesis elicited by testosterone plus estradiol proceeds via paracrine mechanisms. Thus, stromal-epithelial interactions play critical roles in the hormonal, cellular, and molecular regulation of normal and neoplastic prostatic development.

Animals↗

PubMed2004

Rapid inhibition of cancer cell growth induced by lentiviral delivery and expression of mutant-template telomerase RNA and anti-telomerase short-interfering RNA.

In human cancers, telomeres are commonly maintained by elevated levels of the ribonucleoprotein enzyme telomerase, which contains an intrinsic templating RNA moiety (human telomerase RNA; hTER) and the core protein (human telomerase reverse transcriptase). We developed a lentiviral system for efficient overexpression of mutant-template human telomerase RNA (MT-hTer) to add mutant DNA to telomeres in cancer cells. We show that such MT-hTer overexpression rapidly inhibits cell growth and induces apoptosis in telomerase-positive precancerous or cancer cells but not in telomerase-negative cells. These rapid effects occurred independent of wild-type p53 and telomere length. Tumor growth and progression were significantly decreased in xenografts of human tumor cells overexpressing MT-hTers. Expression of a hairpin short-interfering RNA that specifically targeted the endogenous wild-type hTER template region, but spared the MT-hTers, also caused p53-independent cell growth inhibition and apoptosis, and when coexpressed with MT-hTer, synergistically killed cancer cells. Hence, anti-wild-type-hTER short-interfering RNA and MT-hTers may act through distinct pathways and, particularly in combination, represent a promising approach to anticancer therapies.

Animals↗

PubMed2003

FGF-10 plays an essential role in the growth of the fetal prostate.

Induction and branching morphogenesis of the prostate are dependent on androgens, which act via the mesenchyme to induce prostatic epithelial development. One mechanism by which the mesenchyme may regulate the epithelium is through secreted growth factors such as FGF-10. We have examined the male reproductive tract of FGF-10(-/-) mice, and at birth, most of the male secondary sex organs were absent or atrophic, including the prostate, seminal vesicle, bulbourethral gland, and caudal ductus deferens. Rudimentary prostatic buds were occasionally observed in the prostatic anlagen, the urogenital sinus (UGS) of FGF-10(-/-) mice. FGF-10(-/-) testes produced sufficient androgens to induce prostatic development in control UGS organ cultures. Prostatic rudiments from FGF-10(-/-) mice transplanted into intact male hosts grew very little, but showed some signs of prostatic differentiation. In cultures of UGS, the FGF-10 null phenotype was partially reversed by the addition of FGF-10 and testosterone, resulting in the formation of prostatic buds. FGF-10 alone did not stimulate prostatic bud formation in control or FGF-10(-/-) UGS. Thus, FGF-10 appears to act as a growth factor which is required for development of the prostate and several other accessory sex organs.

Androgens↗

PubMed2003

Hormonal, cellular, and molecular control of prostatic development.

The prostate is a male accessory sex gland found only in mammals that functions to produce a major fraction of seminal fluid. Interest in understanding the biology of the prostate is driven both by the fascinating nature of the developmental processes that give rise to the prostate and by the high incidence in humans of prostatic diseases, including prostatic adenocarcinoma and benign prostatic hyperplasia. This review summarizes the current state of knowledge of the cellular and molecular processes that control prostatic development. Insight into the mechanisms that control prostatic development has come from experimental embryological work as well as from the study of mice and humans harboring mutations that alter prostatic development. These studies have demonstrated a requirement for androgens throughout prostatic development and have revealed a series of reciprocal paracrine signals between the developing prostatic epithelium and prostatic mesenchyme. Finally, these studies have identified several specific gene products that are required for prostatic development. While research in recent years has greatly enhanced our understanding of the molecular control of prostatic development, known genes cannot yet explain in molecular terms the complex biological interactions that descriptive and experimental embryological studies have elucidated in the control of prostatic development.

Androgens↗

PubMed2003

Mouse urogenital development: a practical approach.

A detailed knowledge of the developmental anatomy of the embryonic mouse urogenital tract is required to recognize mutant urogenital phenotypes in transgenic and knock-out mice. Accordingly, the purpose of this article is to review urogenital development in the mouse embryo and to give an illustrated methodological protocol for the dissection of urogenital organ rudiments at 12-13 days of gestation (E12-13) to isolate the urogenital ridge and at E16 to isolate the seminal vesicle, Müllerian duct, Wolffian duct, and prostatic rudiment, the urogenital sinus (UGS). The UGS can be cultured and, in the presence of testosterone, prostatic buds form in vitro. Because of the importance of mesenchymal-epithelial interactions in urogenital development, methods for the isolation of epithelium and mesenchyme from the embryonic urogenital sinus are also described. Urogenital sinus mesenchyme (UGM) and urogenital sinus epithelium (UGE) can be used to construct tissue recombinants that can either be grown in vitro or grafted in vivo for the study of epithelial-mesenchymal interactions in prostatic development.

Animals↗

PubMed2001

Growth, regeneration, and tumorigenesis of the prostate activates the PSCA promoter.

The prostate gland undergoes dramatic changes in growth status during normal physiologic development, following androgen administration to castrate animals, and during tumor development. The prostate stem cell antigen (PSCA, named for its strong sequence homology to the thymocyte marker stem cell antigen 2) is a cell surface molecule associated with human and murine prostate cancer. To help define the regulation of this molecule, we created a transgenic mouse strain, which uses the human PSCA promoter region to control the expression of enhanced green fluorescent protein (GFP). Expression of GFP was detected in mid-gestation following the appearance of prostatic buds from the urogenital sinus. In adult mice, GFP expression was restricted to a subset of cells located in the distal tips of the glands. GFP expression increased during puberty and regeneration driven by androgen and associated with expansive growth of the prostate. GFP-positive cells coexpressed markers associated with both basal and secretory cells in the human prostate. Prostate carcinogenesis driven by T antigen in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model results in an increased percentage and intensity level for PSCA promoter-driven GFP-positive cells. This transgenic system helps define the range of cellular changes associated with altered expression of PSCA, shows that transcriptional control is a major component regulating PSCA levels, and provides a useful tool to study subpopulations of prostate epithelial cells and factors that regulate the PSCA promoter.

Animals↗