Dataset Information

Altered exocrine function can drive adipose wasting in early pancreatic cancer.

ABSTRACT: 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.

SUBMITTER: Danai LV

PROVIDER: S-EPMC6112987 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Altered exocrine function can drive adipose wasting in early pancreatic cancer.

Danai Laura V LV Babic Ana A Rosenthal Michael H MH Dennstedt Emily A EA Muir Alexander A Lien Evan C EC Mayers Jared R JR Tai Karen K Lau Allison N AN Jones-Sali Paul P Prado Carla M CM Petersen Gloria M GM Takahashi Naoki N Sugimoto Motokazu M Yeh Jen Jen JJ Lopez Nicole N Bardeesy Nabeel N Fernandez-Del Castillo Carlos C Liss Andrew S AS Koong Albert C AC Bui Justin J Yuan Chen C Welch Marisa W MW Brais Lauren K LK Kulke Matthew H MH Dennis Courtney C Clish Clary B CB Wolpin Brian M BM Vander Heiden Matthew G MG

Nature 20180620 7711

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 sh ...[more]

PMID: 29925948

Similar Datasets

Project description:Background: Malnutrition and cachexia are common in patients with advanced pancreatic ductal adenocarcinoma (PDAC) and have a significant influence on the tolerance and response to treatments. If timely identified, malnourished PDAC patients could be treated to increase their capacity to complete the planned treatments and, therefore, possibly, improve their efficacy. Aims: The aim of this study is to assess the impact of nutritional status, pancreatic exocrine insufficiency (PEI), and other clinical factors on patient outcomes in patients with advanced PDAC. Methods: PAncreatic Cancer MAlnutrition and Pancreatic Exocrine INsufficiency in the Course of Chemotherapy in Unresectable Pancreatic Cancer (PAC-MAIN) is an international multicenter prospective observational cohort study. The nutritional status will be determined by means of Mini-Nutritional Assessment score and laboratory blood tests. PEI will be defined by reduced fecal elastase levels.Main outcomeadherence to planned chemotherapy in the first 12 weeks following the diagnosis, according to patients' baseline nutritional status and quantified and reported as "percent of standard chemotherapy dose delivered."Secondary outcomesrate of chemotherapy-related toxicity, progression-free survival, survival at 6 months, overall survival, quality of life, and the number of hospitalizations.Analysischemotherapy dosing over the first 12 weeks of therapy (i.e., percent of chemotherapy received in the first 12 weeks, as defined above) will be compared between well-nourished and malnourished patients.Sample sizebased on an expected percentage of chemotherapy delivered of 70% in well-nourished patients, with a type I error of 0.05 and a type II error of 0.20, a sample size of 93 patients per group will be required in case of a percentage difference of chemotherapy delivered of 20% between well-nourished and malnourished patients, 163 patients per group in case of a difference of 15% between the groups, and 356 patients per group in case of a 10% difference. Centers from Russia, Romania, Turkey, Spain, Serbia, and Italy will participate in the study upon Local Ethics Committee approval. Discussion: PAC-MAIN will provide insights into the role of malnutrition and PEI in the outcomes of PDAC. The study protocol was registered at clinicaltrials.gov as NCT04112836.

Dataset Information

Altered exocrine function can drive adipose wasting in early pancreatic cancer.

Publications

Altered exocrine function can drive adipose wasting in early pancreatic cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets