新研究：內(nèi)分泌-外分泌信號(hào)促進(jìn)肥胖相關(guān)的胰腺導(dǎo)管腺癌
2020-04-22
來(lái)源：小柯機(jī)器人
美國(guó)耶魯大學(xué)醫(yī)學(xué)院的Mandar Deepak Muzumdar研究組的近期工作表明，內(nèi)分泌-外分泌信號(hào)促進(jìn)肥胖相關(guān)的胰腺導(dǎo)管腺癌。該項(xiàng)研究成果于2020年4月17日在線(xiàn)發(fā)表于《細(xì)胞》雜志。
肥胖是PDAC的主要危險(xiǎn)因素，但是，肥胖如何以及何時(shí)促進(jìn)PDAC的進(jìn)展尚不清楚。
利用原發(fā)小鼠模型，研究人員證明了肥胖在胰腺導(dǎo)管腺癌（PDAC）早期發(fā)展中具有因果關(guān)系和可逆作用，并表明肥胖顯著增強(qiáng)了腫瘤的發(fā)生，而遺傳或飲食誘導(dǎo)的減肥則阻止了癌癥的發(fā)展。
人類(lèi)和鼠樣品的分子分析確定了肥胖的微環(huán)境影響，即促進(jìn)腫瘤發(fā)生，而不是產(chǎn)生新的驅(qū)動(dòng)基因突變，這些影響包括與肥胖相關(guān)腫瘤中胰島細(xì)胞的顯著適應(yīng)性。
具體來(lái)說(shuō)，研究人員確定了響應(yīng)肥胖的肽激素膽囊收縮素（Cck）在β細(xì)胞中的異常表達(dá)，并表明胰島Cck促進(jìn)致癌Kras驅(qū)動(dòng)的胰腺導(dǎo)管腫瘤發(fā)生。
這項(xiàng)研究認(rèn)為，PDAC的進(jìn)展是由局部肥胖相關(guān)的腫瘤微環(huán)境變化驅(qū)動(dòng)的，并且在PDAC的發(fā)展中提示了胰島素以外的內(nèi)分泌-外分泌信號(hào)傳導(dǎo)。
附：英文原文
Title: Endocrine-Exocrine Signaling Drives Obesity-Associated Pancreatic Ductal Adenocarcinoma
Author: Katherine Minjee Chung, Jaffarguriqbal Singh, Lauren Lawres, Kimberly Judith Dorans, Cathy Garcia, Daniel B. Burkhardt, Rebecca Robbins, Arjun Bhutkar, Rebecca Cardone, Xiaojian Zhao, Ana Babic, Sara A. Vayrynen, Andressa Dias Costa, Jonathan A. Nowak, Daniel T. Chang, Richard F. Dunne, Aram F. Hezel, Albert C. Koong, Joshua J. Wilhelm, Melena D. Bellin, Vibe Nylander, Anna L. Gloyn, Mark I. McCarthy, Richard G. Kibbey, Smita Krishnaswamy, Brian M. Wolpin, Tyler Jacks, Charles S. Fuchs, Mandar Deepak Muzumdar
Issue&Volume: 2020-04-17
Abstract: Obesity is a major modifiable risk factor for pancreatic ductal adenocarcinoma (PDAC),yet how and when obesity contributes to PDAC progression is not well understood. Leveragingan autochthonous mouse model, we demonstrate a causal and reversible role for obesityin early PDAC progression, showing that obesity markedly enhances tumorigenesis, whilegenetic or dietary induction of weight loss intercepts cancer development. Molecularanalyses of human and murine samples define microenvironmental consequences of obesitythat foster tumorigenesis rather than new driver gene mutations, including significantpancreatic islet cell adaptation in obesity-associated tumors. Specifically, we identifyaberrant beta cell expression of the peptide hormone cholecystokinin (Cck) in responseto obesity and show that islet Cck promotes oncogenic Kras-driven pancreatic ductal tumorigenesis. Our studies argue that PDAC progression isdriven by local obesity-associated changes in the tumor microenvironment and implicateendocrine-exocrine signaling beyond insulin in PDAC development.
DOI: 10.1016/j.cell.2020.03.062
Source: https://www.cell.com/cell/fulltext/S0092-8674(20)30395-0
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