Luo Yongde, Li Xiaokun, Ma Jianjia, Abbruzzese James L, Lu Weiqin
The First Affiliated Hospital & School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China.
Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
Cancers (Basel). 2021 Feb 13;13(4):778. doi: 10.3390/cancers13040778.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and (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.
胰腺导管腺癌（PDAC）是最致命的恶性肿瘤之一，（ 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，单独的突变型KRAS的作用并不能概括与成人PDAC发展相关的胰腺病理的全部范围。从历史上看，突变型KRAS被认为是组成型激活的；然而，最近的研究表明，突变型KRAS的内源性水平并非组成型完全激活，其活性仍受上游刺激的上调。肥胖是一种代谢性疾病，会引发一种称为代谢性炎症的慢性低度炎症，长期以来在临床上一直被认为是胰腺癌的主要可改变风险因素。在不同的动物模型中已经表明，致肥胖的高脂肪饮食（HFD）和胰腺炎症会促进具有高外显率的突变型KRAS介导的PDAC的快速发展。然而，尚不清楚为什么具有内源性突变型KRAS水平的胰腺易受慢性HFD和炎症挑战的影响。最近，成纤维细胞生长因子21（FGF21）作为一种新型的抗肥胖和抗炎因子以及突变型KRAS的下游靶点的发现为这个问题提供了新的线索。这篇综述旨在更新我们对在肥胖和相关炎症引发的挑战背景下胰腺易患KRAS介导的侵袭性PDAC的认识。
