Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
Dana-Farber Cancer Institute, Boston, MA, USA.
Nature. 2018 Jun;558(7711):600-604. doi: 10.1038/s41586-018-0235-7. Epub 2018 Jun 20.
Malignancy is accompanied by changes in the metabolism of both cells and the organism. 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 cancer. Tissue wasting is a multifactorial disease and targeting specific circulating factors to reverse this syndrome has been mostly ineffective in the clinic. 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.
恶性肿瘤伴随着细胞和机体代谢的变化。胰腺导管腺癌 (PDAC) 与周围组织的消耗有关，这是一种代谢综合征，降低了生活质量，并被提出降低癌症患者的生存率。组织消耗是一种多因素疾病，针对特定的循环因子来逆转这种综合征在临床上大多无效。在这里，我们表明，在胰腺癌的发展过程中，脂肪组织和肌肉组织的丢失很早就发生了。使用 PDAC 的小鼠模型，我们表明，胰腺内的肿瘤生长而不是其他部位的肿瘤生长导致脂肪组织消耗，这表明胰腺内环境中的肿瘤生长导致了这种消耗表型。我们发现，外分泌胰腺功能的降低是脂肪组织丢失的驱动因素，而胰腺酶的替代可以减轻 PDAC 相关的外周组织消耗。矛盾的是，脂肪组织损失的逆转会损害 PDAC 小鼠的生存。在分析 PDAC 患者时，我们发现，在诊断时脂肪组织和骨骼肌组织的消耗很常见，但与较差的生存无关。总之，这些结果为早期 PDAC 中脂肪组织消耗提供了解释，并表明与胰腺癌相关的外周组织的早期丢失可能不会损害生存。
