Obesity promotes breast cancer by CCL2-mediated macrophage recruitment and angiogenesis.
Obesity promotes breast cancer by CCL2-mediated macrophage recruitment and angiogenesis.
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DOI：
10.1158/0008-5472.can-13-0926
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发表时间：
2013-10-01
期刊：
影响因子：
11.2
通讯作者：
Kuperwasser C
中科院分区：
文献类型：
--
作者：
Arendt LM;McCready J;Keller PJ;Baker DD;Naber SP;Seewaldt V;Kuperwasser C
肥胖是最重要的可预防的癌症原因之一，也是绝经后妇女患乳腺癌的最重要风险因素。与苗条的女性相比，肥胖女性更有可能被诊断出患有更大、更高级别的肿瘤，淋巴结转移的发生率增加，以及远处复发的风险增加。然而，肥胖症与乳腺癌发病机制之间的联系还不是很清楚。在这里，我们展示了在肥胖期间，人类和小鼠乳腺组织中的脂肪细胞通过先前未知的CCL2/IL-1β/CXCL12信号通路招募和激活巨噬细胞。激活的巨噬细胞反过来促进间质血管形成和血管生成，甚至在癌症形成之前就是如此。使用一种新的人源化乳腺癌模型概括这些变化足以促进血管生成，并在肿瘤转化之前启动微环境以加速乳腺肿瘤的形成。这些发现提供了脂肪细胞和巨噬细胞在癌症发生前的机制作用，这可能是预防和治疗肥胖相关癌症的关键。
Obesity is one of the most important preventable causes of cancer and the most significant risk factor for breast cancer in postmenopausal women. Compared with lean women, obese women are more likely to be diagnosed with a larger, higher grade tumor, an increased incidence of lymph node metastases, and elevated risk of distant recurrence. However, the mechanisms connecting obesity to the pathogenesis of breast cancer are poorly defined. Here we show that during obesity, adipocytes within human and mouse breast tissues recruit and activate macrophages through a previously uncharacterized CCL2/IL-1β/CXCL12 signaling pathway. Activated macrophages in turn promote stromal vascularization and angiogenesis even prior to the formation of cancer. Recapitulating these changes using a novel humanized breast cancer model was sufficient to promote angiogenesis and prime the microenvironment prior to neoplastic transformation for accelerated breast oncogenesis. These findings provide a mechanistic role for adipocytes and macrophages prior to carcinogenesis that may be critical for prevention and treatment of obesity-related cancer.