Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development

Nat Med. 2014 Oct;20(10):1193-1198. doi: 10.1038/nm.3686. Epub 2014 Sep 28.

Abstract

Most patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed with advanced disease and survive less than 12 months. PDAC has been linked with obesity and glucose intolerance, but whether changes in circulating metabolites are associated with early cancer progression is unknown. To better understand metabolic derangements associated with early disease, we profiled metabolites in prediagnostic plasma from individuals with pancreatic cancer (cases) and matched controls from four prospective cohort studies. We find that elevated plasma levels of branched-chain amino acids (BCAAs) are associated with a greater than twofold increased risk of future pancreatic cancer diagnosis. This elevated risk was independent of known predisposing factors, with the strongest association observed among subjects with samples collected 2 to 5 years before diagnosis, when occult disease is probably present. We show that plasma BCAAs are also elevated in mice with early-stage pancreatic cancers driven by mutant Kras expression but not in mice with Kras-driven tumors in other tissues, and that breakdown of tissue protein accounts for the increase in plasma BCAAs that accompanies early-stage disease. Together, these findings suggest that increased whole-body protein breakdown is an early event in development of PDAC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Amino Acids, Branched-Chain / blood*
  • Animals
  • Carcinoma, Pancreatic Ductal / blood*
  • Carcinoma, Pancreatic Ductal / etiology
  • Case-Control Studies
  • Cohort Studies
  • Disease Models, Animal
  • Disease Progression
  • Female
  • Humans
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Pancreatic Neoplasms / blood*
  • Pancreatic Neoplasms / etiology
  • Prospective Studies
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Risk Factors
  • Time Factors

Substances

  • Amino Acids, Branched-Chain
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)