Obesity hormone leptin induces growth and interferes with the cytotoxic effects of 5-fluorouracil in colorectal tumor stem cells
Obesity hormone leptin induces growth and interferes with the cytotoxic effects of 5-fluorouracil in colorectal tumor stem cells
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DOI：
10.1677/erc-10-0083
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发表时间：
2010-09-01
影响因子：
3.9
通讯作者：
Surmacz, Eva
中科院分区：
文献类型：
--
作者：
Bartucci, Monica;Svensson, Susanne;Surmacz, Eva
结肠癌的发病率在发达国家有所上升，可能是由于久坐不动的生活方式和高热量饮食。实验和流行病学证据表明，结肠癌的发展与脂肪组织衍生的循环激素之间存在联系。瘦素是一种由脂肪细胞分泌的多能细胞因子，是大脑中食欲和能量平衡的关键调节因子。另一方面，瘦素还控制着周围器官的许多生理和病理过程。近年来对结肠癌细胞系和人类肿瘤的研究表明，瘦素及其受体（ObR）参与结肠癌的发生，可能作为新的生物标志物和药理靶点。在这里，我们首次探讨了瘦素是否会影响结直肠肿瘤干细胞（CTSCs）的生物学。我们发现，我们之前建立和表征的CTSC克隆表达ObR，并通过细胞增殖、细胞外信号相关激酶（ERK）1/2和AKT信号通路的激活、软琼脂中的生长增强以及与E-cadherin过表达相关的球形成改善来响应瘦素。此外，瘦素抵消了5-氟尿嘧啶（一种常见的结肠癌治疗剂）的细胞毒性作用。这些结果表明，肥胖和瘦素水平升高可能通过增加CTSCs的生长和存活来促进结直肠癌。内分泌相关的癌症（2010）17 823-833
The incidence of colon cancer has increased in developed countries, possibly due to sedentary lifestyle and high caloric diet. Experimental and epidemiological evidence suggests a link between colon cancer development and adipose tissue-derived circulating hormones. Leptin, a pluripotent cytokine secreted by adipocytes, is a key regulator of appetite and energy balance acting in the brain. On the other hand, leptin also controls many physiological and pathological processes in peripheral organs. Recent studies in colon cancer cell lines and human tumors suggested that leptin and its receptor (ObR) are implicated in colon carcinogenesis, and may serve as new biomarkers and pharmacological targets. Here, we explored, for the first time, whether leptin can affect the biology of colorectal tumor stem cells (CTSCs). We found that our previously established and characterized CTSC clones express ObR and respond to leptin with cell proliferation, activation of the extracellular signal-related kinase (ERK)1/2 and AKT signaling pathways, enhanced growth in soft agar, and improved sphere formation associated with E-cadherin overexpression. Moreover, leptin counteracted cytotoxic effects of 5-fluorouracil, a common colon cancer therapeutic agent. These results suggest that obesity and increased leptin levels might promote colorectal cancer by increasing growth and survival of CTSCs. Endocrine-Related Cancer (2010) 17 823-833