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Mifepristone Treatment Promotes Testicular Leydig Cell Tumor Progression in Transgenic Mice.

ABSTRACT: 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-? 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 ?, ?, ? 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?1 in LCT cells. MF and P4 treatments upregulated Tgfbr1, Tgfbr2, and Alk1 expression and stimulated TGF?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?1 signaling pathway.

SUBMITTER: Ponikwicka-Tyszko D

PROVIDER: S-EPMC7694279 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Mifepristone Treatment Promotes Testicular Leydig Cell Tumor Progression in Transgenic Mice.

Ponikwicka-Tyszko Donata D Chrusciel Marcin M Pulawska Kamila K Bernaczyk Piotr P Sztachelska Maria M Guo Peilan P Li Xiangdong X Toppari Jorma J Huhtaniemi Ilpo T IT Wołczyński Slawomir S Rahman Nafis A NA

Cancers 20201104 11

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-α promoter-driven SV40 T-antigen), as well as on LCT (BLTK-1 and mLTC-1) cell proliferation. MF significantly stimulated the proliferation of LCT i ...[more]

PMID: 33158280

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Project description:OBJECTIVE:To assess the colour Doppler and ultrasound features of testicular Leydig cell tumours (LCTs) in a population of 38 surgically proven lesions. METHODS:From August 2008 to March 2015, we retrospectively included 38 surgically proven LCTs in 36 patients. Clinical data, scrotal colour Doppler, B-mode ultrasound and videos images were reviewed for each patient. The volume, echotexture of the testis, size, shape, echogenicity and the vascularization pattern of the lesion were evaluated. The tumour margins were categorized as either smooth or lobulated. The vascularization was classified as intense, moderate or without any hypervascularization. We defined the vascularization pattern groups as central, peripheral and mixed (the latter meaning both central and peripheral). RESULTS:26 patients were referred for infertility [5 patients were subsequently diagnosed with Klinefelter syndrome (KS) and 5 patients with cryptorchidism]. 28 patients underwent testis-sparing surgery, while 8 patients underwent a radical orchiectomy. The LCTs were mostly infracentimetric (68.4%), with a median size of 7.0?mm (ranging from 4.0 to 11?mm). 50% of the lesions had lobulated margins, and these were significantly larger than the smooth lesions (p?<?0.05). The content of the lesions was markedly homogeneous and hypoechoic. All lesions had sharp demarcations from the adjacent pulp. 36/38 lesions exhibited moderate-to-intense hypervascularization, with a mixed intrinsic and peripheral rim pattern. Larger lesions were more hypervascularized (p?<?0.05). LCTs in patients with KS had atypical features. CONCLUSION:Typical sporadic LCTs appeared as isolated hypoechoic, infracentimetric masses, with a clear demarcation from the adjacent pulp. They presented intrinsic and peripheral rim hypervascularization. ADVANCES IN KNOWLEDGE:By undertaking the largest imaging series of LCT to date (to our knowledge), we reassessed the typical sonographical aspects of LCTs, so as to provide guidance in regard to opting for testis-sparing surgery and for follow-up. LCTs present both intrinsic and rim vascularization detectable by colour Doppler ultrasound. Intrinsic vascularization and lobulated margins are common findings in testicular LCTs.

Project description:BackgroundAlthough metastatic colon cancer is a leading cause of cancer death worldwide, the molecular mechanisms that enable colon cancer cells to metastasize remain unclear. Emerging evidence suggests that metastatic cells develop by usurping transcriptional networks from embryonic stem (ES) cells to facilitate an epithelial-mesenchymal transition (EMT), invasion, and metastatic progression. Previous studies identified HMGA1 as a key transcription factor enriched in ES cells, colon cancer, and other aggressive tumors, although its role in these settings is poorly understood.Methods/principal findingsTo determine how HMGA1 functions in metastatic colon cancer, we manipulated HMGA1 expression in transgenic mice and colon cancer cells. We discovered that HMGA1 drives proliferative changes, aberrant crypt formation, and intestinal polyposis in transgenic mice. In colon cancer cell lines from poorly differentiated, metastatic tumors, knock-down of HMGA1 blocks anchorage-independent cell growth, migration, invasion, xenograft tumorigenesis and three-dimensional colonosphere formation. Inhibiting HMGA1 expression blocks tumorigenesis at limiting dilutions, consistent with depletion of tumor-initiator cells in the knock-down cells. Knock-down of HMGA1 also inhibits metastatic progression to the liver in vivo. In metastatic colon cancer cells, HMGA1 induces expression of Twist1, a gene involved in embryogenesis, EMT, and tumor progression, while HMGA1 represses E-cadherin, a gene that is down-regulated during EMT and metastatic progression. In addition, HMGA1 is among the most enriched genes in colon cancer compared to normal mucosa.ConclusionsOur findings demonstrate for the first time that HMGA1 drives proliferative changes and polyp formation in the intestines of transgenic mice and induces metastatic progression and stem-like properties in colon cancer cells. These findings indicate that HMGA1 is a key regulator, both in metastatic progression and in the maintenance of a stem-like state. Our results also suggest that HMGA1 or downstream pathways could be rational therapeutic targets in metastatic, poorly differentiated colon cancer.

Dataset Information

Mifepristone Treatment Promotes Testicular Leydig Cell Tumor Progression in Transgenic Mice.

Publications

Mifepristone Treatment Promotes Testicular Leydig Cell Tumor Progression in Transgenic Mice.

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