Macrophage inhibitory cytokine-1 (MIC-1/GDF15) gene deletion promotes cancer growth in TRAMP prostate cancer prone mice

PLoS One. 2015 Feb 19;10(2):e0115189. doi: 10.1371/journal.pone.0115189. eCollection 2015.

Abstract

The divergent TGF-β superfamily member, macrophage inhibitory cytokine-1 (MIC-1/GDF15), is overexpressed by most cancers, including prostate cancer (PCa). Whilst its circulating levels are linked to cancer outcome, the role MIC-1/GDF15 plays in cancer development and progression is incompletely understood. To investigate its effect on PCa development and spread, we have used TRAMP prostate cancer prone mice bearing a germline deletion of MIC-1/GDF15 (TRAMPMIC-/-). On average TRAMPMIC-/- mice died about 5 weeks earlier and had larger prostatic tumors compared with TRAMP mice that were wild type for MIC-1/GDF15 (TRAMPMIC+/+). Additionally, at the time of death or ethical end point, even when adjusted for lifespan, there were no significant differences in the number of mice with metastases between the TRAMPMIC+/+ and TRAMPMIC-/- groups. However, consistent with our previous data, more than twice as many TRAMP mice overexpressing MIC-1/GDF15 (TRAMPfmsmic-1) had metastases than TRAMPMIC+/+ mice (p<0.0001). We conclude that germ line gene deletion of MIC-1/GDF15 leads to increased local tumor growth resulting in decreased survival consistent with an overall protective role for MIC-1/GDF15 in early primary tumor development. However, in advancing disease, as we have previously noted, MIC-1/GDF15 overexpression may promote local invasion and metastatic spread.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gene Deletion
  • Growth Differentiation Factor 15 / deficiency*
  • Growth Differentiation Factor 15 / genetics
  • Growth Differentiation Factor 15 / metabolism*
  • Male
  • Mice
  • Mice, Transgenic
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology*

Substances

  • Growth Differentiation Factor 15

Grants and funding

This work was supported in part by grants from Cancer Council New South Wales (http://www.cancercouncil.com.au/) and The National Health and Medical Research Council of Australia (NHMRC) (https://www.nhmrc.gov.au/). DAB is a National Health and Medical Research Council Biomedical Career Development Fellow. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.