Intrapancreatic fat, pancreatitis, and pancreatic cancer.
Intrapancreatic fat, pancreatitis, and pancreatic cancer.
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胰内脂肪、胰腺炎和胰腺癌。
DOI：
10.1007/s00018-023-04855-z
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发表时间：
2023-07-15
影响因子：
8
通讯作者：
Golemis, Erica A.
中科院分区：
文献类型：
--
作者：
Lilly, Anna C.;Astsaturov, Igor;Golemis, Erica A.
胰腺癌通常在晚期才被发现，并且大多数治疗方法都难以治愈，导致生存结果不佳。胰腺癌的发病率正在逐渐增加，这与人口老龄化以及肥胖和胰腺炎发病率的增加有关，而肥胖和胰腺炎是这种癌症的危险因素。风险来源包括全身脂肪细胞发出的脂肪因子信号、胰内脂肪细胞 (IPA) 水平升高、胰腺浸润免疫细胞产生的炎症信号以及胰腺梗阻和腺泡细胞溶解反复循环引起的纤维化环境。一旦癌症形成，胰腺组织的重组通常会将 IPA 排除在肿瘤微环境之外，而肿瘤微环境由嵌入源自癌症相关成纤维细胞 (CAF) 的特殊微环境中的癌细胞组成。虽然癌细胞与 CAF 和免疫细胞的相互作用一直是许多研究的主题，但对癌前生态位中 IPA 的来源和功能的机制研究还很少开发。有趣的是，对胰腺中 IPA 积累和活性的研究进行了广泛回顾，结果表明，出人意料的多种因素导致腺泡组织被 IPA 取代，特别是在作为胰腺癌研究重要工具的小鼠模型中。参与 IPA 积累调节的基因包括 KRAS、MYC、TGF-β、periostin、HNF1 以及导管纤毛和 ER 应激的调节因子等。这些发现强调了研究癌前环境中胰腺损伤因素的重要性，并对胰腺癌小鼠模型数据的解释具有重要意义。
Pancreatic cancer is typically detected at an advanced stage, and is refractory to most forms of treatment, contributing to poor survival outcomes. The incidence of pancreatic cancer is gradually increasing, linked to an aging population and increasing rates of obesity and pancreatitis, which are risk factors for this cancer. Sources of risk include adipokine signaling from fat cells throughout the body, elevated levels of intrapancreatic intrapancreatic adipocytes (IPAs), inflammatory signals arising from pancreas-infiltrating immune cells and a fibrotic environment induced by recurring cycles of pancreatic obstruction and acinar cell lysis. Once cancers become established, reorganization of pancreatic tissue typically excludes IPAs from the tumor microenvironment, which instead consists of cancer cells embedded in a specialized microenvironment derived from cancer-associated fibroblasts (CAFs). While cancer cell interactions with CAFs and immune cells have been the topic of much investigation, mechanistic studies of the source and function of IPAs in the pre-cancerous niche are much less developed. Intriguingly, an extensive review of studies addressing the accumulation and activity of IPAs in the pancreas reveals that unexpectedly diverse group of factors cause replacement of acinar tissue with IPAs, particularly in the mouse models that are essential tools for research into pancreatic cancer. Genes implicated in regulation of IPA accumulation include KRAS, MYC, TGF-β, periostin, HNF1, and regulators of ductal ciliation and ER stress, among others. These findings emphasize the importance of studying pancreas-damaging factors in the pre-cancerous environment, and have significant implications for the interpretation of data from mouse models for pancreatic cancer.
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