The biguanides metformin and phenformin inhibit angiogenesis, local and metastatic growth of breast cancer by targeting both neoplastic and microenvironment cells
The biguanides metformin and phenformin inhibit angiogenesis, local and metastatic growth of breast cancer by targeting both neoplastic and microenvironment cells
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DOI：
10.1002/ijc.29193
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发表时间：
2015-03-15
影响因子：
6.4
通讯作者：
Bertolini, Francesco
中科院分区：
文献类型：
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作者：
Orecchioni, Stefania;Reggiani, Francesca;Bertolini, Francesco
人类白色脂肪组织(WAT)含有在乳腺癌(BC)血管生成、局部和转移进展中发挥协同作用的前体细胞。常用于治疗2型糖尿病的二甲双胍(Met)可能具有抗BC活性，并被发现在体内抑制血管生成。我们研究了蛋氨酸和另一种双胍类药物苯福明(Phe)在体内外的作用。在体外，双胍类化合物激活AMPK，抑制呼吸链复合体1，并诱导BC和WAT内皮细胞的凋亡。在共培养中，双胍抑制了几种血管生成蛋白的产生。在体内，双胍内酯抑制免疫活性和免疫缺陷小鼠原位注射BC的三重阴性和HER2+BC的局部和转移生长。在HER2+BC基因工程小鼠模型中，双胍抑制了局部和转移性BC的生长。在体内，双胍内酯增加了WAT前体细胞与匹莫硝唑的结合(但不增加HIF-1的表达)，降低了肿瘤微血管密度，改变了血管周细胞/内皮细胞的比例，使肿瘤血管呈现异常增生的表型。无论在体内还是体外，Phe的活性都明显高于Met。考虑到它们的安全性，双胍类药物在高危受试者中预防BC方面值得进一步研究，结合化疗和/或靶向治疗，和/或作为治疗后巩固或维持治疗以防止BC复发。有什么新消息？白色脂肪组织中未分化的前体细胞(WAT)在乳腺癌进展中起协同作用。特别是，它们促进了局部肿瘤的生长、血管生成和转移。本研究表明，双胍类药物二甲双胍和苯福明对这三个过程有抑制作用。苯福明的活性水平最高。这项研究是第一批表明这两种药物通过对乳腺癌细胞的直接活性以及对Wat祖细胞的抗血管生成活性发挥作用的研究之一。这些结论是从三阴性和HER2+乳腺癌模型的体外和体内结果得出的。
The human white adipose tissue (WAT) contains progenitors with cooperative roles in breast cancer (BC) angiogenesis, local and metastatic progression. The biguanide Metformin (Met), commonly used for Type 2 diabetes, might have activity against BC and was found to inhibit angiogenesis in vivo. We studied Met and another biguanide, phenformin (Phe), in vitro and in vivo in BC models. In vitro, biguanides activated AMPK, inhibited Complex 1 of the respiratory chain and induced apoptosis of BC and WAT endothelial cells. In coculture, biguanides inhibited the production of several angiogenic proteins. In vivo, biguanides inhibited local and metastatic growth of triple negative and HER2+ BC in immune-competent and immune-deficient mice orthotopically injected with BC. Biguanides inhibited local and metastatic BC growth in a genetically engineered murine model model of HER2+ BC. In vivo, biguanides increased pimonidazole binding (but not HIF-1 expression) of WAT progenitors, reduced tumor microvessel density and altered the vascular pericyte/endothelial cell ratio, so that cancer vessels displayed a dysplastic phenotype. Phe was significantly more active than Met both in vitro and in vivo. Considering their safety profile, biguanides deserve to be further investigated for BC prevention in high-risk subjects, in combination with chemo and/or targeted therapy and/or as post-therapy consolidation or maintenance therapy for the prevention of BC recurrence.What's new? Undifferentiated progenitor cells in white adipose tissue (WAT) have cooperative roles in breast cancer progression. In particular, they promote local tumor growth, angiogenesis, and metastasisthree processes shown in the present study to be inhibited by the biguanide drugs metformin and phenformin. Phenformin showed the highest levels of activity. The study is among the first to suggest that the two drugs exert their effects through direct activity against breast cancer cells, as well as through anti-angiogenic activity against WAT progenitors. The conclusions were drawn from results obtained in vitro and in vivo in triple negative and HER2+ breast cancer models.