Metabolic reprogramming of stromal fibroblasts through p62-mTORC1 signaling promotes inflammation and tumorigenesis

Cancer Cell. 2014 Jul 14;26(1):121-135. doi: 10.1016/j.ccr.2014.05.004. Epub 2014 Jul 4.

Abstract

The tumor microenvironment plays a critical role in cancer progression, but the precise mechanisms by which stromal cells influence the epithelium are poorly understood. Here we show that p62 levels were reduced in the stroma of several tumors and that its loss in the tumor microenvironment or stromal fibroblasts resulted in increased tumorigenesis of epithelial prostate cancer cells. The mechanism involves the regulation of cellular redox through an mTORC1/c-Myc pathway of stromal glucose and amino acid metabolism, resulting in increased stromal IL-6 production, which is required for tumor promotion in the epithelial compartment. Thus, p62 is an anti-inflammatory tumor suppressor that acts through the modulation of metabolism in the tumor stroma.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / deficiency
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Amino Acids / metabolism
  • Animals
  • Cell Communication
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology
  • Coculture Techniques
  • Energy Metabolism*
  • Fibroblasts / enzymology*
  • Fibroblasts / metabolism
  • Glucose / metabolism
  • HEK293 Cells
  • Heat-Shock Proteins / deficiency
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism*
  • Humans
  • Inflammation / enzymology*
  • Inflammation / genetics
  • Inflammation / pathology
  • Inflammation Mediators / metabolism
  • Interleukin-6 / metabolism
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism*
  • Neoplasm Invasiveness
  • Oxidative Stress
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism
  • Prostatic Hyperplasia / enzymology
  • Prostatic Hyperplasia / genetics
  • Prostatic Hyperplasia / pathology
  • Prostatic Intraepithelial Neoplasia / enzymology
  • Prostatic Intraepithelial Neoplasia / genetics
  • Prostatic Intraepithelial Neoplasia / pathology
  • Prostatic Neoplasms / enzymology*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / pathology
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • RNA Interference
  • Sequestosome-1 Protein
  • Signal Transduction*
  • Stromal Cells / enzymology*
  • Stromal Cells / pathology
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*
  • Time Factors
  • Transfection
  • Tumor Microenvironment

Substances

  • Adaptor Proteins, Signal Transducing
  • Amino Acids
  • Heat-Shock Proteins
  • IL6 protein, human
  • Inflammation Mediators
  • Interleukin-6
  • MYC protein, human
  • Multiprotein Complexes
  • Myc protein, mouse
  • Proto-Oncogene Proteins c-myc
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • Sqstm1 protein, mouse
  • interleukin-6, mouse
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Glucose