Metformin inhibits metastatic breast cancer progression and improves chemosensitivity by inducing vessel...

Area of Science:

• Oncology
• Vascular Biology
• Pharmacology

Background:

• Tumor vascular maturity and function are critical for cancer progression and treatment response.
• Metformin, an antidiabetic drug, has demonstrated anti-angiogenic properties in metastatic breast cancer.
• The precise mechanisms by which metformin remodels tumor vasculature remain incompletely understood.

Purpose of the Study:

• To investigate the effects of metformin on the abnormal vasculature of metastatic breast cancer.
• To elucidate the role of metformin in normalizing tumor blood vessels and its impact on metastasis and chemosensitivity.

Main Methods:

• Utilized metastatic breast cancer mouse models to assess microvessel density, vascular maturity, function, metastasis, and chemosensitivity.
• Employed protein array assays and transcriptome sequencing for genetic screening.
• Investigated the contribution of platelet-derived growth factor B (PDGF-B) knockdown to metformin's vascular effects using lentiviral shRNA.

Main Results:

• Metastatic breast cancer exhibited immature, hyper-angiogenic vasculature.
• Metformin treatment significantly reduced microvessel density, leakage, and hypoxia, while enhancing vascular mural cell coverage and perfusion, indicating vessel normalization.
• Metformin did not directly affect cancer cell proliferation or migration; its benefits were linked to vascular normalization, including reduced lung metastasis and improved chemosensitization.
• Downregulation of PDGF-B was identified as a significant contributor to metformin-induced vessel normalization.

Conclusions:

• Metformin effectively normalizes the tumor vasculature in metastatic breast cancer.
• These findings provide preclinical evidence for the vascular-targeting mechanism of metformin in inhibiting metastasis and enhancing chemosensitivity.