Suppression of hypoxia-induced excessive angiogenesis by metformin via elevating tumor blood perfusion
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Ji-Chang Wang1,2,*, Guang-Yue Li3,*, Ping-Ping Li2, Xin Sun4, Wei-Ming Li1, Yan Li1, Shao-Ying Lu1 and Pei-Jun Liu2
1Department of Vascular Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, 710061, P.R.China
2Center for Translational Medicine, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, 710061, P.R.China
3Department of Science and Technology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, 710061, P.R.China
4Department of Thoracic Surgery and Oncology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, 710061, P.R.China
*These two authors contributed equally to this work and share co-first authors
Pei-Jun Liu, email: [email protected]
Shao-Ying Lu, email: [email protected]
Keywords: metformin, inhibition of tumor angiogenesis, hypoxia, elevating blood perfusion, HIF-1α
Received: April 09, 2017 Accepted: May 09, 2017 Published: May 19, 2017
The anti-diabetic metformin has been demonstrated to be effective in suppression of tumor progression via multiple mechanisms, in which angiogenic inhibition is involved. Hypoxia is a common feather of malignant tumor and promotes angiogenesis via induction of pro-angiogenic factors. However, the effect of metformin on tumor hypoxia and the association with angiogenic inhibition are still unclear. In the current study, we investigated the effects of metformin on both tumor blood perfusion and hypoxia-induced excessive angiogenesis. In the tumor region adjacent to necrosis, aberrantly excessive angiogenesis resulted from hypoperfusion-induced intense hypoxia and greatly contributed to the high average levels of both microvessel density and vascular branch density. Metformin administration increased the percentage of lectin-perfused vessels and reduced hypoxyprobe-positive area. This metformin-induced amelioration of hypoxia was accompanied by a significant reduction in expressions of both HIF-1α and angiogenesis-associated factors (AAFs). Consequently, inhibited excessive angiogenesis in hypoxic peri-necrotic region was observed in metformin-treated tumor. Further stable knockdown of HIF-1α abrogated hypoxia-induced AAFs in vitro and reduced both microvessel density and area of fitc-conjugated dextran that leaked outside the vascular lumen. Taken together, metformin ameliorated tumor hypoxia and restrained HIF-1α-induced expressions of AAFs through elevating tumor blood perfusion, thus suppressing the excessive tumor angiogenesis.
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