Bone marrow adipocytes promote tumor growth in bone via FABP4-dependent mechanisms

Oncotarget. 2013 Nov;4(11):2108-23. doi: 10.18632/oncotarget.1482.

Abstract

Incidence of skeletal metastases and death from prostate cancer greatly increases with age and obesity, conditions which increase marrow adiposity. Bone marrow adipocytes are metabolically active components of bone metastatic niche that modulate the function of neighboring cells; yet the mechanisms of their involvement in tumor behavior in bone have not been explored. In this study, using experimental models of intraosseous tumor growth and diet-induced obesity, we demonstrate the promoting effects of marrow fat on growth and progression of skeletal prostate tumors. We reveal that exposure to lipids supplied by marrow adipocytes induces expression of lipid chaperone FABP4, pro-inflammatory interleukin IL-1β, and oxidative stress protein HMOX-1 in metastatic tumor cells and stimulates their growth and invasiveness. We show that FABP4 is highly overexpressed in prostate skeletal tumors from obese mice and in bone metastasis samples from prostate cancer patients. In addition, we provide results suggestive of bi-directional interaction between FABP4 and PPARγ pathways that may be driving aggressive tumor cell behavior in bone. Together, our data provide evidence for functional relationship between bone marrow adiposity and metastatic prostate cancers and unravel the FABP4/IL-1β axis as a potential therapeutic target for this presently incurable disease.

Publication types

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

MeSH terms

  • Adipocytes / metabolism*
  • Adipocytes / pathology
  • Animals
  • Bone Marrow / metabolism*
  • Bone Marrow / pathology
  • Bone Neoplasms / genetics
  • Bone Neoplasms / metabolism*
  • Bone Neoplasms / secondary*
  • Cell Growth Processes / physiology
  • Cell Line, Tumor
  • Fatty Acid-Binding Proteins / genetics
  • Fatty Acid-Binding Proteins / metabolism*
  • Humans
  • Interleukin-1beta / metabolism
  • Male
  • Mice
  • PPAR gamma / metabolism
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology*
  • Transfection
  • Tumor Cells, Cultured
  • Up-Regulation

Substances

  • FABP4 protein, human
  • Fatty Acid-Binding Proteins
  • Interleukin-1beta
  • PPAR gamma