Leptin's Pro-Angiogenic Signature in Breast Cancer.
Leptin's Pro-Angiogenic Signature in Breast Cancer.
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DOI：
10.3390/cancers5031140
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发表时间：
2013-09-06
期刊：
影响因子：
5.2
通讯作者：
Newman G
中科院分区：
文献类型：
--
作者：
Gonzalez-Perez RR;Lanier V;Newman G
肥胖与乳腺癌发病率增加有关。这些病态关系的确切原因和机制尚不清楚。关于瘦素血管生成作用的相互矛盾的数据已经发表。然而，越来越多的证据表明，瘦素在癌症中的促血管生成作用在该疾病中发挥着重要作用。瘦素是脂肪组织分泌的主要脂肪因子，乳腺癌细胞也异常表达瘦素及其受体（OB-R）。瘦素诱导内皮细胞增殖和血管生成分化，上调 VEGF/VEGFR2 并不依赖 VEGF 反式激活 VEGFR2。瘦素诱导两种血管生成因子：IL-1 和 Notch，可增加 VEGF 表达。此外，瘦素诱导血管生成发育所需的蛋白酶和粘附分子的分泌和合成。瘦素的旁分泌作用可以进一步影响基质细胞和肿瘤相关巨噬细胞，它们分别表达 OB-R 并分泌 VEGF 和 IL-1。在乳腺癌中发现瘦素、Notch 和 IL-1 (NILCO) 之间存在复杂的串扰，可诱导 VEGF/VEGFR2。瘦素在肿瘤血管生成中的作用可以放大、冗余和/或补偿 VEGF 信号传导。目前乳腺癌抗血管生成疗法的失败强调了针对乳腺癌中其他促血管生成因子的作用的必要性。瘦素对肿瘤血管生成的影响可能成为乳腺癌的新靶点，尤其是肥胖患者。然而，需要更多的研究来确定瘦素在肿瘤血管生成中的重要性。本综述重点关注瘦素如何促进肿瘤血管生成的最新信息。
Obesity is linked to increased incidence of breast cancer. The precise causes and mechanisms of these morbid relationships are unknown. Contradictory data on leptin angiogenic actions have been published. However, accumulating evidence would suggest that leptin’s pro-angiogenic effects in cancer play an essential role in the disease. Leptin, the main adipokine secreted by adipose tissue, is also abnormally expressed together with its receptor (OB-R) by breast cancer cells. Leptin induces proliferation and angiogenic differentiation of endothelial cells upregulates VEGF/VEGFR2 and transactivates VEGFR2 independent of VEGF. Leptin induces two angiogenic factors: IL-1 and Notch that can increase VEGF expression. Additionally, leptin induces the secretion and synthesis of proteases and adhesion molecules needed for the development of angiogenesis. Leptin’s paracrine actions can further affect stromal cells and tumor associated macrophages, which express OB-R and secrete VEGF and IL-1, respectively. A complex crosstalk between leptin, Notch and IL-1 (NILCO) that induces VEGF/VEGFR2 is found in breast cancer. Leptin actions in tumor angiogenesis could amplify, be redundant and/or compensatory to VEGF signaling. Current failure of breast cancer anti-angiogenic therapies emphasizes the necessity of targeting the contribution of other pro-angiogenic factors in breast cancer. Leptin’s impact on tumor angiogenesis could be a novel target for breast cancer, especially in obese patients. However, more research is needed to establish the importance of leptin in tumor angiogenesis. This review is focused on updated information on how leptin could contribute to tumor angiogenesis.