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J Exp Clin Cancer Res. 2019 Jun 4;38(1):235. doi: 10.1186/s13046-019-1211-2.

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

Author information

1
Department of Vascular Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China.
2
Center for Translational Medicine, First Affiliated Hospital of Xi'an Jiaotong University, No. 277 of the Western Yanta Road, Xi'an, 710061, Shaanxi Province, China.
3
Department of Science and Technology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China.
4
Department of Oncological Radiotherapy, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China.
5
Department of Thoracic Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China.
6
Department of Pathology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China.
7
Department of Breast Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China.
8
Department of Medical Oncology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China.
9
Department of Neurosurgery, First Affiliated Hospital of Xi'an Jiaotong University, No. 277 of the Western Yanta Road, Xi'an, 710061, Shaanxi Province, China. maodewang@163.com.
10
Center for Translational Medicine, First Affiliated Hospital of Xi'an Jiaotong University, No. 277 of the Western Yanta Road, Xi'an, 710061, Shaanxi Province, China. liupeijun@mail.xjtu.edu.cn.
11
Key Laboratory for Tumor Precision Medicine of Shaanxi Province, First Affiliated Hospital of Xi'an Jiaotong University, No. 277 of the Western Yanta Road, Xi'an, 710061, Shaanxi Province, China. liupeijun@mail.xjtu.edu.cn.

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.

KEYWORDS:

Chemosensitization; Metastatic breast cancer; Metformin; PDGF-B; Vessel normalization

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