Malignant Drosophila tumors interrupt insulin signaling to induce cachexia-like wasting.
Malignant Drosophila tumors interrupt insulin signaling to induce cachexia-like wasting.
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DOI：
10.1016/j.devcel.2015.03.001
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发表时间：
2015-04-06
影响因子：
11.8
通讯作者：
Bilder, David
中科院分区：
文献类型：
--
作者：
Figueroa-Clarevega, Alejandra;Bilder, David
肿瘤不仅通过对其局部环境的明显干扰而杀死患者，而且还通过与远处组织的病理生理相互作用而杀死患者。在这里，我们使用果蝇肿瘤模型来研究这种远程相互作用的难以捉摸的机制。将肿瘤移植到成人体内会引起远离肿瘤的脂肪、肌肉和性腺组织的大量消耗，其表型类似于在人类患者中看到的癌症恶病质。有趣的是，恶性肿瘤而非良性肿瘤诱导外周细胞消耗。我们发现胰岛素生长因子结合蛋白（IGFBP）同源物ImpL2是胰岛素信号的拮抗剂，是一种介导消耗的分泌因子。ImpL2足以驱动组织损失，并且在荷瘤宿主的外周组织中胰岛素活性降低。重要的是，在肿瘤中特异性地敲除ImpL2可改善耗损表型。我们提出，肿瘤分泌的IGFBP在远处组织中产生胰岛素抵抗，从而驱动系统性消耗反应。
Tumors kill patients not only through well-characterized perturbations to their local environment, but also through poorly understood pathophysiological interactions with distant tissues. Here we use a Drosophila tumor model to investigate the elusive mechanisms underlying such long-range interactions. Transplantation of tumors into adults induces robust wasting of adipose, muscle and gonadal tissues that are distant from the tumor, phenotypes that resemble the cancer cachexia seen in human patients. Interestingly, malignant but not benign tumors induce peripheral wasting. We identify the Insulin Growth Factor Binding Protein (IGFBP) homolog ImpL2, an antagonist of insulin signaling, as a secreted factor mediating wasting. ImpL2 is sufficient to drive tissue loss, and insulin activity is reduced in peripheral tissues of tumor-bearing hosts. Importantly, knocking downs ImpL2 specifically in the tumor ameliorates wasting phenotypes. We propose that the tumor-secreted IGFBP creates insulin resistance in distant tissues and thus drives a systemic wasting response.
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