Proangiogenic contribution of adiponectin toward mammary tumor growth in vivo.
Proangiogenic contribution of adiponectin toward mammary tumor growth in vivo.
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DOI：
10.1158/1078-0432.ccr-08-2649
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发表时间：
2009-05-15
期刊：
影响因子：
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通讯作者：
Scherer PE
中科院分区：
文献类型：
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作者：
Landskroner-Eiger S;Qian B;Muise ES;Nawrocki AR;Berger JP;Fine EJ;Koba W;Deng Y;Pollard JW;Scherer PE
脂肪细胞是乳腺中含量最丰富的成分之一。它们对乳腺肿瘤的生长和生存是必不可少的。在代谢方面，脂联素(APN)是一种更为重要的脂肪衍生因子(“脂肪因子”)。血清APN浓度与体重指数、胰岛素抵抗呈负相关。为了探讨APN与乳腺癌和肿瘤血管生成的关系，我们采用体内实验方法，研究了APN在小鼠乳腺肿瘤病毒(MMTV)-多瘤中T抗原(PYMT)乳腺肿瘤模型中的作用。我们比较了野生型和APN缺失背景下MMTV-PYMT小鼠的肿瘤生长速度。组织学和微正电子发射断层成像显示，在早期没有APN的情况下，肿瘤的生长速度显着降低。PYMT/APN基因敲除小鼠的血管生成减少，导致肿瘤营养缺乏和肿瘤相关细胞死亡。令人惊讶的是，在疾病的更晚期恶性阶段，缺乏APN的小鼠肿瘤生长更具侵略性，导致更大的肿瘤负担，循环内皮祖细胞的动员增加，以及指示更具侵袭性的肿瘤细胞的基因表达指纹。这些观察结果突出了APN在乳腺肿瘤发展和血管生成中的一个新的重要贡献，表明APN在肿瘤血管形成中具有强大的血管模拟特性。然而，在缺乏APN的肿瘤中，这种抗血管生成应激导致适应性反应，通过动员循环内皮祖细胞和发展能够使大量细胞增殖的机制来促进肿瘤生长，尽管微环境长期处于低氧状态。
Adipocytes represent one of the most abundant constituents of the mammary gland. They are essential for mammary tumor growth and survival. Metabolically, one of the more important fat-derived factors (“adipokines”) is adiponectin (APN). Serum concentrations of APN negatively correlate with body mass index and insulin resistance. To explore the association of APN with breast cancer and tumor angiogenesis, we took an in vivo approach aiming to study its role in the mouse mammary tumor virus (MMTV)-polyoma middle T antigen (PyMT) mammary tumor model. We compared the rates of tumor growth in MMTV-PyMT mice in wild-type and APN-null backgrounds. Histology and micro-positron emission tomography imaging show that the rate of tumor growth is significantly reduced in the absence of APN at early stages. PyMT/APN knockout mice exhibit a reduction in their angiogenic profile resulting in nutrient deprivation of the tumors and tumor-associated cell death. Surprisingly, in more advanced malignant stages of the disease, tumor growth develops more aggressively in mice lacking APN, giving rise to a larger tumor burden, an increase in the mobilization of circulating endothelial progenitor cells, and a gene expression fingerprint indicative of more aggressive tumor cells. These observations highlight a novel important contribution of APN in mammary tumor development and angiogenesis, indicating that APN has potent angio-mimetic properties in tumor vascularization. However, in tumors deprived of APN, this antiangiogenic stress results in an adaptive response that fuels tumor growth through mobilization of circulating endothelial progenitor cells and the development of mechanisms enabling massive cell proliferation despite a chronically hypoxic micro-environment.