Dataset Information

Metformin inhibits metastatic breast cancer progression and improves chemosensitivity by inducing vessel normalization via PDGF-B downregulation.

ABSTRACT:

Background

Vascular maturity and functionality are closely associated with tumor progression and chemosensitivity. The antidiabetic agent metformin has shown its ability to inhibit tumor angiogenesis in metastatic breast cancer models. However, it remains unclear if or how metformin remodels the abnormal vasculature of metastatic breast cancer, while inhibiting angiogenesis.

Methods

Metastatic breast cancer models were constructed to compare microvessel density (MVD), vascular maturity and function, lung metastasis and chemosensitivity in metformin-treated or untreated mice. Protein array assay and transcriptome sequencing were performed for genetic screening. Lentiviral shRNA-PDGF-B transfection was used for observing the contribution of PDGF-B knockdown to metformin's vascular effects.

Results

Metastatic breast cancers were characterized by an excessively angiogenic, immature and morphologically abnormal vasculature. Compared to control, metformin significantly reduced MVD, leakage and hypoxia, and increased vascular mural cells coverage and perfusion, namely, "vessel normalization". Metformin at human blood concentrations had no direct effect on the migration and proliferation of cancer cells. Based on that, reduced lung metastasis of the primary tumor and improved chemosensitization by metformin were assumed to be mediated via metformin's vascular effects. Further results of genetic screening and in vivo experiments showed that the downregulation of platelet-derived growth factor B (PDGF-B) greatly contributed to the metformin-induced vessel normalization.

Conclusions

These findings provide pre-clinical evidences for the vascular mechanism of metformin-induced metastasis inhibition and the chemosensitization of metastatic breast cancers.

SUBMITTER: Wang JC

PROVIDER: S-EPMC6549289 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Metformin inhibits metastatic breast cancer progression and improves chemosensitivity by inducing vessel normalization via PDGF-B downregulation.

Wang Ji-Chang JC Li Guang-Yue GY Wang Bo B Han Su-Xia SX Sun Xin X Jiang Yi-Na YN Shen Yan-Wei YW Zhou Can C Feng Jun J Lu Shao-Ying SY Liu Jian-Lin JL Wang Mao-De MD Liu Pei-Jun PJ

Journal of experimental & clinical cancer research : CR 20190604 1

<h4>Background</h4>Vascular maturity and functionality are closely associated with tumor progression and chemosensitivity. The antidiabetic agent metformin has shown its ability to inhibit tumor angiogenesis in metastatic breast cancer models. However, it remains unclear if or how metformin remodels the abnormal vasculature of metastatic breast cancer, while inhibiting angiogenesis.<h4>Methods</h4>Metastatic breast cancer models were constructed to compare microvessel density (MVD), vascular mat ...[more]

PMID: 31164151

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Project description:Histone-lysine N-methyltransferase EZH2 (EZH2) is the principle component of the polycomb repressive complex 2 (PRC2)/embryonic ectoderm development protein-EZH2 complex, which promotes tumorigenesis by repressing transcription of tumor suppressor genes. EZH2 is considered a key marker in several types of cancer, such as colorectal and prostate cancer. However, the molecular mechanisms and clinical value of EZH2 in lung cancer have not yet been fully investigated. The aim of the present study was to investigate the functions of EZH2 in lung cancer progression and to determine whether treatment with an EZH2 inhibitor enhanced the chemosensitivity of lung cancer cells to cisplatin (CDDP). At the logarithmic growth phase, A549 cells were treated with a small interfering (si)RNA-EZH2, and cell viability was detected using an MTT assay. The degree of apoptosis and cell cycle were detected using flow cytometry. Cell migration and invasion were detected via wound healing and Transwell Matrigel assays. According to information from the Gene Expression Omnibus database, the results of the present study demonstrated that EZH2 was upregulated in lung cancer. Furthermore, overexpression of EZH2 was associated with poor patient prognosis, while EZH2 knockdown inhibited cell viability and migration, and enhanced apoptosis and chemosensitivity in a lung cancer cell line. EZH2 knockdown and treatment of A549 cells using EZH2 inhibitor elevated the inhibitory effects of CDDP on cell viability and apoptosis. Western blot and reverse transcription-quantitative PCR analyses were performed to assess the expression levels of relative protein and mRNA, respectively, in A549 cells treated with siRNA-EZH2 or with CDDP. Overall, the results of the present study demonstrated that high EZH2 expression was associated with poor prognosis, accompanied with a potential impairment of migration and viability in lung cancer cells. These findings suggest that EZH2 may act as a candidate molecular target for gene therapy, and treatment with EZH2 inhibitor may be used to increase chemosensitivity to CDDP agents in lung cancer.

Dataset Information

Metformin inhibits metastatic breast cancer progression and improves chemosensitivity by inducing vessel normalization via PDGF-B downregulation.

Background

Methods

Results

Conclusions

Publications

Metformin inhibits metastatic breast cancer progression and improves chemosensitivity by inducing vessel normalization via PDGF-B downregulation.

Similar Datasets

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