Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA.
Proc Natl Acad Sci U S A. 2012 Jan 17;109(3):829-34. doi: 10.1073/pnas.1114438109. Epub 2011 Dec 29.
Misregulation of a pluripotency-associated transcription factor network in adult tissues is associated with the expansion of rare, highly malignant tumor-initiating stem cells (TISCs) through poorly understood mechanisms. We demonstrate that robust and selective expression of the receptor for the adipocyte-derived peptide hormone leptin (OB-R) is a characteristic feature of TISCs and of a broad array of embryonic and induced pluripotent stem cells and is mediated directly by the core pluripotency-associated transcription factors OCT4 and SOX2. TISCs exhibit sensitized responses to leptin, including the phosphorylation and activation of the pluripotency-associated oncogene STAT3 and induction of Oct4 and Sox2, thereby establishing a self-reinforcing signaling module. Exposure of cultured mouse embryonic stem cells to leptin sustains pluripotency in the absence of leukemia inhibitory factor. By implanting TISCs into leptin-deficient ob/ob mice or into comparably overweight Lepr(db/db) mice that produce leptin, we provide evidence of a central role for the leptin-TISC-signaling axis in promoting obesity-induced tumor growth. Differential responses to extrinsic, adipocyte-derived cues may promote the expansion of tumor cell subpopulations and contribute to oncogenesis.
成体组织中多能性相关转录因子网络的失调与罕见的、高度恶性的肿瘤起始干细胞（TISC）的扩增有关，其机制尚不清楚。我们证明，瘦素（leptin）的受体在 TISC 以及广泛的胚胎和诱导多能干细胞中具有强烈且选择性的表达，这是由核心多能性相关转录因子 OCT4 和 SOX2 直接介导的。TISC 对瘦素表现出敏感的反应，包括与多能性相关的癌基因 STAT3 的磷酸化和激活，以及 Oct4 和 Sox2 的诱导，从而建立了一个自我强化的信号模块。将培养的小鼠胚胎干细胞暴露于瘦素中，可在没有白血病抑制因子的情况下维持其多能性。通过将 TISC 植入瘦素缺乏的 ob/ob 小鼠或产生瘦素的肥胖 Lepr(db/db) 小鼠中，我们提供了证据表明，瘦素-TISC-信号轴在促进肥胖诱导的肿瘤生长中起着核心作用。对外在的、脂肪细胞来源的信号的不同反应可能促进肿瘤细胞亚群的扩增，并有助于肿瘤发生。
