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Tgfbr2 inactivation facilitates cellular plasticity and development of Pten-null prostate cancer.

ABSTRACT: Mutations in tumors can create a state of increased cellular plasticity that promotes resistance to treatment. Thus, there is an urgent need to develop novel strategies for identifying key factors that regulate cellular plasticity in order to combat resistance to chemotherapy and radiation treatment. Here we report that prostate epithelial cell reprogramming could be exploited to identify key factors required for promoting prostate cancer tumorigenesis and cellular plasticity. Deletion of phosphatase and tensin homolog (Pten) and transforming growth factor-beta receptor type 2 (Tgfbr2) may increase prostate epithelial cell reprogramming efficiency in vitro and cause rapid tumor development and early mortality in vivo. Tgfbr2 ablation abolished TGF-? signaling but increased the bone morphogenetic protein (BMP) signaling pathway through the negative regulator Tmeff1. Furthermore, increased BMP signaling promotes expression of the tumor marker genes ID1, Oct4, Nanog, and Sox2; ID1/STAT3/NANOG expression was inversely correlated with patient survival. Thus, our findings provide information about the molecular mechanisms by which BMP signaling pathways render stemness capacity to prostate tumor cells.

SUBMITTER: Zhao W

PROVIDER: S-EPMC6161409 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Tgfbr2 inactivation facilitates cellular plasticity and development of Pten-null prostate cancer.

Zhao Wei W Zhu Qingyuan Q Tan Peng P Ajibade Adebusola A Long Teng T Long Wenyong W Li Qingtian Q Liu Pinghua P Ning Bo B Wang Helen Y HY Wang Rong-Fu RF

Journal of molecular cell biology 20180801 4

Mutations in tumors can create a state of increased cellular plasticity that promotes resistance to treatment. Thus, there is an urgent need to develop novel strategies for identifying key factors that regulate cellular plasticity in order to combat resistance to chemotherapy and radiation treatment. Here we report that prostate epithelial cell reprogramming could be exploited to identify key factors required for promoting prostate cancer tumorigenesis and cellular plasticity. Deletion of phosph ...[more]

PMID: 29228234

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Project description:BACKGROUND:Some, but not all, epidemiologic evidence supports a role for cholesterol, the precursor for steroid hormone synthesis, in prostate cancer. Using a PTEN-null transgenic mouse model of prostate cancer, we tested the effect of modifying serum cholesterol levels on prostate tumor development and growth. We hypothesized that serum cholesterol reduction would lower tumor androgens and slow prostate cancer growth. METHODS:PTENloxP/loxP-Cre+ mice consuming ad libitum high fat, high cholesterol diets (40% fat, 1.25% cholesterol) were randomized after weaning to receive the cholesterol uptake inhibitor, ezetimibe (30?mg/kg/day), or no intervention, and sacrificed at 2, 3, or 4 months of age. Serum cholesterol and testosterone were measured by ELISA and intraprostatic androgens by mass spectrometry. Prostate histology was graded, and proliferation and apoptosis in tumor epithelium and stroma was assessed by Ki67 and TUNEL, respectively. RESULTS:Ezetimibe-treated mice had lower serum cholesterol at 4 months (p?=?0.031). Serum cholesterol was positively correlated with prostate weight (p?=?0.033) and tumor epithelial proliferation (p?=?0.069), and negatively correlated with tumor epithelial apoptosis (p?=?0.004). Serum cholesterol was unrelated to body weight (p?=?0.195). Tumor stromal cell proliferation was reduced in the ezetimibe group (p?=?0.010). Increased serum cholesterol at 4 months was associated with elevated intraprostatic DHEA, testosterone, and androstenedione (p?=?0.043, p?=?0.074, p?=?0.031, respectively). However, cholesterol reduction did not significantly affect adenocarcinoma development at 2, 3, or 4 months of age (0, 78, and 100% in ezetimibe-treated vs. 0, 80, and 100% in mice not receiving ezetimibe). CONCLUSIONS:Though serum cholesterol reduction did not significantly affect the rate of adenocarcinoma development in the PTEN-null transgenic mouse model of prostate cancer, it lowered intraprostatic androgens and slowed tumor growth. These findings support a role for serum cholesterol in promoting prostate cancer growth, potentially via enhanced tumor androgen signaling, and may provide new insight into cholesterol-lowering interventions for prostate cancer treatment.

Dataset Information

Tgfbr2 inactivation facilitates cellular plasticity and development of Pten-null prostate cancer.

Publications

Tgfbr2 inactivation facilitates cellular plasticity and development of Pten-null prostate cancer.

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