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Altered exocrine function can drive adipose wasting in early pancreatic cancer
Nature ( IF 64.8 ) Pub Date : 2018-06-01 , DOI: 10.1038/s41586-018-0235-7
Laura V Danai 1 , Ana Babic 2 , Michael H Rosenthal 2 , Emily A Dennstedt 1 , Alexander Muir 1 , Evan C Lien 1 , Jared R Mayers 1 , Karen Tai 1 , Allison N Lau 1 , Paul Jones-Sali 1 , Carla M Prado 3 , Gloria M Petersen 4 , Naoki Takahashi 4 , Motokazu Sugimoto 4 , Jen Jen Yeh 5 , Nicole Lopez 6 , Nabeel Bardeesy 7 , Carlos Fernandez-Del Castillo 7 , Andrew S Liss 7 , Albert C Koong 8, 9 , Justin Bui 9, 10 , Chen Yuan 2 , Marisa W Welch 2 , Lauren K Brais 2 , Matthew H Kulke 2, 11 , Courtney Dennis 12 , Clary B Clish 12 , Brian M Wolpin 2 , Matthew G Vander Heiden 1, 2, 12
Affiliation  

Malignancy is accompanied by changes in the metabolism of both cells and the organism1,2. Pancreatic ductal adenocarcinoma (PDAC) is associated with wasting of peripheral tissues, a metabolic syndrome that lowers quality of life and has been proposed to decrease survival of patients with cancer3,4. Tissue wasting is a multifactorial disease and targeting specific circulating factors to reverse this syndrome has been mostly ineffective in the clinic5,6. Here we show that loss of both adipose and muscle tissue occurs early in the development of pancreatic cancer. Using mouse models of PDAC, we show that tumour growth in the pancreas but not in other sites leads to adipose tissue wasting, suggesting that tumour growth within the pancreatic environment contributes to this wasting phenotype. We find that decreased exocrine pancreatic function is a driver of adipose tissue loss and that replacement of pancreatic enzymes attenuates PDAC-associated wasting of peripheral tissues. Paradoxically, reversal of adipose tissue loss impairs survival in mice with PDAC. When analysing patients with PDAC, we find that depletion of adipose and skeletal muscle tissues at the time of diagnosis is common, but is not associated with worse survival. Taken together, these results provide an explanation for wasting of adipose tissue in early PDAC and suggest that early loss of peripheral tissue associated with pancreatic cancer may not impair survival.Pancreatic ductal adenocarcinoma in mice induces loss of adipose tissue through altered function of the exocrine pancreas, and supplementing pancreatic enzymes attenuates the wasting of peripheral tissues induced by pancreatic cancer.

中文翻译:

外分泌功能的改变会导致早期胰腺癌的脂肪消耗

恶性肿瘤伴随着细胞和机体代谢的变化1,2。胰腺导管腺癌 (PDAC) 与外周组织消瘦有关,这是一种代谢综合征,会降低生活质量,并已被提议降低癌症患者的存活率 3,4。组织消耗是一种多因素疾病,针对特定循环因素来逆转这种综合征在临床上大多无效5,6。在这里,我们表明脂肪和肌肉组织的损失发生在胰腺癌发展的早期。使用 PDAC 的小鼠模型,我们发现胰腺中的肿瘤生长而不是其他部位的肿瘤生长导致脂肪组织消瘦,这表明胰腺环境中的肿瘤生长导致了这种消瘦表型。我们发现外分泌胰腺功能下降是脂肪组织丢失的驱动因素,并且胰酶的替代会减弱 PDAC 相关的外周组织消耗。矛盾的是,脂肪组织损失的逆转损害了 PDAC 小鼠的生存。在分析 PDAC 患者时,我们发现诊断时脂肪和骨骼肌组织的消耗很常见,但与较差的生存率无关。总之,这些结果为早期 PDAC 中脂肪组织的浪费提供了解释,并表明与胰腺癌相关的外周组织的早期丧失可能不会损害生存。小鼠胰腺导管腺癌通过改变外分泌胰腺的功能诱导脂肪组织的丧失,
更新日期:2018-06-01
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