Pancreatic Tumorigenesis: Oncogenic KRAS and the Vulnerability of the Pancreas to Obesity.
Pancreatic Tumorigenesis: Oncogenic KRAS and the Vulnerability of the Pancreas to Obesity.
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DOI：
10.3390/cancers13040778
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发表时间：
2021-02-13
期刊：
影响因子：
5.2
通讯作者：
Lu W
中科院分区：
文献类型：
--
作者：
Luo Y;Li X;Ma J;Abbruzzese JL;Lu W
胰腺癌是一种生存率低的毁灭性疾病，致癌突变KRAS是其发生和发展的主要驱动因素；然而，针对主要形式的突变KRAS的有效策略/药物尚未出现。值得注意的是，已知肥胖会恶化突变的kras介导的病理，导致PDAC具有高外显率；然而，肥胖和胰腺癌之间的机制联系仍然难以捉摸。最近发现的FGF21作为一种抗肥胖和抗炎症因子以及KRAS的下游靶点，为这一问题提供了新的思路。胰腺导管腺癌（PDAC）是最致命的恶性肿瘤之一，KRAS （Kirsten大鼠肉瘤2病毒癌基因同源物）突变被认为是PDAC发生和发展的关键驱动因素。然而，仅KRAS突变体的影响并不能概括成人中与PDAC发展相关的胰腺病理的全部谱系。从历史上看，突变KRAS被认为是构成活性的；然而，最近的研究表明，内源性突变KRAS的水平并不是完全活跃的，其活性仍然受到上游刺激的上调。肥胖是一种代谢性疾病，可引起慢性、低度炎症（称为间炎症），长期以来一直被临床认为是胰腺癌的主要可改变危险因素。不同的动物模型表明，致肥性高脂肪饮食（HFD）和胰腺炎症可促进高外显率kras介导的PDAC突变体的快速发展。然而，目前尚不清楚为什么内源性突变KRAS水平的胰腺容易受到慢性HFD和炎症的攻击。最近，纤维母细胞生长因子21 （FGF21）作为一种新的抗肥胖和抗炎因子以及突变体KRAS的下游靶点的发现，为这一问题提供了新的思路。本综述旨在提供我们对胰腺在肥胖和相关炎症引起的挑战背景下对kras介导的侵袭性PDAC的易感性的最新认识。
Pancreatic cancer is a devastating disease with a poor survival rate, and oncogenic mutant KRAS is a major driver of its initiation and progression; however, effective strategies/drugs targeting major forms of mutant KRAS have not been forthcoming. Of note, obesity is known to worsen mutant KRAS-mediated pathologies, leading to PDAC with high penetrance; however, the mechanistic link between obesity and pancreatic cancer remains elusive. The recent discovery of FGF21 as an anti-obesity and anti-inflammation factor and as a downstream target of KRAS has shed new light on the problem. Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and KRAS (Kirsten rat sarcoma 2 viral oncogene homolog) mutations have been considered a critical driver of PDAC initiation and progression. However, the effects of mutant KRAS alone do not recapitulate the full spectrum of pancreatic pathologies associated with PDAC development in adults. Historically, mutant KRAS was regarded as constitutively active; however, recent studies have shown that endogenous levels of mutant KRAS are not constitutively fully active and its activity is still subject to up-regulation by upstream stimuli. Obesity is a metabolic disease that induces a chronic, low-grade inflammation called meta-inflammation and has long been recognized clinically as a major modifiable risk factor for pancreatic cancer. It has been shown in different animal models that obesogenic high-fat diet (HFD) and pancreatic inflammation promote the rapid development of mutant KRAS-mediated PDAC with high penetrance. However, it is not clear why the pancreas with endogenous levels of mutant KRAS is vulnerable to chronic HFD and inflammatory challenges. Recently, the discovery of fibroblast growth factor 21 (FGF21) as a novel anti-obesity and anti-inflammatory factor and as a downstream target of mutant KRAS has shed new light on this problem. This review is intended to provide an update on our knowledge of the vulnerability of the pancreas to KRAS-mediated invasive PDAC in the context of challenges engendered by obesity and associated inflammation.
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DOI：
10.1158/1940-6207.capr-13-0065
发表时间：
2013-10
期刊：
Cancer prevention research (Philadelphia, Pa.)
影响因子：
--
作者：
Dawson DW;Hertzer K;Moro A;Donald G;Chang HH;Go VL;Pandol SJ;Lugea A;Gukovskaya AS;Li G;Hines OJ;Rozengurt E;Eibl G
通讯作者：
Eibl G
影响因子：
8.8
作者：
Eser, S.;Schnieke, A.;Schneider, G.;Saur, D.
通讯作者：
Saur, D.
影响因子：
29
作者：
Coate KC;Hernandez G;Thorne CA;Sun S;Le TDV;Vale K;Kliewer SA;Mangelsdorf DJ
通讯作者：
Mangelsdorf DJ
影响因子：
5
作者：
Andersen, Birgitte;Omar, Bilal A.;Ahren, Bo
通讯作者：
Ahren, Bo
影响因子：
64.5
作者：
Chung, Katherine Minjee;Singh, Jaffarguriqbal;Muzumdar, Mandar Deepak
通讯作者：
Muzumdar, Mandar Deepak