7 research outputs found
Mouse models of adrenal tumors responsive to gonadotropin-releasing hormone and gonadotropins
In recent years, several mouse models have been established for
characterization of the molecular pathways involved in adrenocortical
tumorigenesis. Adrenal tumors develop in genetically susceptible mouse
strains after prepubertal gonadectomy, in mice transgenic with oncogenes
(simian virus 40 T antigen), several gene knockouts (such as inhibin or
conditional Gata6F/F), and in mice overexpressing
transcription factor GATA binding protein 4. The gonadal rest-type
adrenal tumor phenotype is regulated by gonadotropins, mainly
luteinizing hormone. Luteinizing hormone/chorionic hormone receptor and
gonadotropin-releasing hormone receptor expression has been found in
human adrenocortical carcinoma, as well as in several mouse adrenal
tumor/adrenocarcinoma models. This mini-review will address recent
advancements in this research topic with respect to the molecular basis
of adrenocortical tumorigenesis, the clinical relevance of these tumor
models, and the potential for future targeted treatment strategies.
Furthermore, the ectopic expression of the luteinizing hormone/chorionic
hormone receptor or gonadotropin-releasing hormone receptor may open up
options for targeted therapy approaches. </p
Revisiting the expression and function of follicle-stimulation hormone receptor in human umbilical vein endothelial cells
Expression of follicle-stimulation hormone receptor (FSHR) is confined
to gonads and at low levels to some extragonadal tissues like human
umbilical vein endothelial cells (HUVEC). FSH-FSHR signaling was shown
to promote HUVEC angiogenesis and thereafter suggested to have an
influential role in pregnancy. We revisited hereby the expression and
functionality of FSHR in HUVECs angiogenesis, and were unable to
reproduce the FSHR expression in human umbilical cord, HUVECs or
immortalized HUVECs (HUV-ST). Positive controls as granulosa cells and
HEK293 cells stably transfected with human FSHR cDNA expressed FSHR
signal. In contrast to positive control VEGF, FSH treatment showed no
effects on tube formation, nitric oxide production, wound healing or
cell proliferation in HUVEC/HUV-ST. Thus, it remains open whether the
FSH-FSHR activation has a direct regulatory role in the angiogenesis of
HUVECs.</p
Mifepristone Treatment Promotes Testicular Leydig Cell Tumor Progression in Transgenic Mice
Simple SummaryRecently, the antiprogestin activity of selective progesterone receptor (PR) modulator mifepristone (MF) has proven unsuccessful as a potential anti-cancer agent in various clinical trials. Herein, we analyzed the effects of MF treatment on Leydig cell tumor (LCT) progression in a transgenic mouse model (inhibin-alpha promoter-driven SV40 T-antigen), as well as on the proliferation of two Leydig tumor cell lines. MF significantly stimulated the proliferation of LCT in vitro. Similarly, a 1-mo MF or P4 treatment stimulated LCT tumor growth in vivo. Only the abundant membrane Pgrmc1 expression was found in LCTs, but no other classical Pgr or nonclassical membrane PRs. Functional analysis showed that PGRMC1 is required for MF and P4 to stimulate the proliferation and invasiveness of LCTs. Our findings provide novel information that the use of MF as an anti-cancer agent should be considered with caution due to its potential PGRMC1 tumor-promoting pathway activation in cancers.The selective progesterone receptor modulator mifepristone (MF) may act as a potent antiproliferative agent in different steroid-dependent cancers due to its strong antagonistic effect on the nuclear progesterone receptor (PGR). Hereby, we analyzed the effects of MF treatment on Leydig cell tumor (LCT) progression in a transgenic mouse model (inhibin-alpha promoter-driven SV40 T-antigen), as well as on LCT (BLTK-1 and mLTC-1) cell proliferation. MF significantly stimulated the proliferation of LCT in vitro. Similarly, a 1-mo MF or P4 treatment stimulated LCT tumor growth in vivo. Traceable/absent classical Pgr or nonclassical membrane PRs alpha, beta, gamma and Pgrmc2, but abundant membrane Pgrmc1 expression, was found in LCTs. MF did not activate glucocorticoid or androgen receptors in LCTs. Functional analysis showed that PGRMC1 is required for MF and P4 to stimulate the proliferation and invasiveness of LCTs. Accordingly, MF and P4 induced PGRMC1 translocation into the nucleus and thereby stimulated the release of TGF beta 1 in LCT cells. MF and P4 treatments upregulated Tgfbr1, Tgfbr2, and Alk1 expression and stimulated TGF beta 1 release in LCT cells. Our findings provide novel mechanistic insights into the action of MF as a membrane PR agonist that promotes LCT growth through PGRMC1 and the alternative TGF beta 1 signaling pathway
Molecular mechanisms underlying mifepristone's agonistic action on ovarian cancer progression
Background: Recent clinical trials on ovarian cancer with mifepristone (MF) have failed, despite in vitro findings on its strong progesterone (P4) antagonist function.Methods: Ovarian cancer human and murine cell lines, cultured high-grade human primary epithelial ovarian cancer (HG-hOEC) cells and their explants; as well as in vivo transgenic mice possessing ovarian cancer were used to assess themolecular mechanism underlying mifepristone (MF) agonistic actions in ovarian cancer progression.Findings: Here in, we show that ovarian cancer cells express traceable/no nuclear P4 receptor (PGR), but abundantly P4 receptor membrane component 1 (PGRMC1). MF significantly stimulated ovarian cancer cell migration, proliferation and growth in vivo, and the translocation of PGRMC1 into the nucleus of cancer cells; the effects inhibited by PGRMC1 inhibitor. The beneficial antitumor effect of high-doses MF could not be achieved in human cancer tissue, and the low tissue concentrations achieved with the therapeutic doses only promoted the growth of ovarian cancers.Interpretation: Our results indicate that treatment of ovarian cancer with MF and P4 may induce similar adverse agonistic effects in the absence of classical nuclear PGRs in ovarian cancer. The blockage of PGRMC1 activity may provide a novel treatment strategy for ovarian cancer.</div