Transforming Growth Factor-Beta Signaling in Cancer-Induced Cachexia: From Molecular Pathways to the Clinics

Cells. 2022 Aug 28;11(17):2671. doi: 10.3390/cells11172671.

Abstract

Cachexia is a metabolic syndrome consisting of massive loss of muscle mass and function that has a severe impact on the quality of life and survival of cancer patients. Up to 20% of lung cancer patients and up to 80% of pancreatic cancer patients are diagnosed with cachexia, leading to death in 20% of them. The main drivers of cachexia are cytokines such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), macrophage inhibitory cytokine 1 (MIC-1/GDF15) and transforming growth factor-beta (TGF-β). Besides its double-edged role as a tumor suppressor and activator, TGF-β causes muscle loss through myostatin-based signaling, involved in the reduction in protein synthesis and enhanced protein degradation. Additionally, TGF-β induces inhibin and activin, causing weight loss and muscle depletion, while MIC-1/GDF15, a member of the TGF-β superfamily, leads to anorexia and so, indirectly, to muscle wasting, acting on the hypothalamus center. Against this background, the blockade of TGF-β is tested as a potential mechanism to revert cachexia, and antibodies against TGF-β reduced weight and muscle loss in murine models of pancreatic cancer. This article reviews the role of the TGF-β pathway and to a minor extent of other molecules including microRNA in cancer onset and progression with a special focus on their involvement in cachexia, to enlighten whether TGF-β and such other players could be potential targets for therapy.

Keywords: TGF-β; cachexia; cancer-related syndrome.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cachexia* / metabolism
  • Humans
  • Mice
  • Pancreatic Neoplasms* / complications
  • Pancreatic Neoplasms* / metabolism
  • Quality of Life
  • Transforming Growth Factor beta* / metabolism
  • Transforming Growth Factors

Substances

  • Transforming Growth Factor beta
  • Transforming Growth Factors

Grants and funding

This research was partly funded by CCA Foundation 2018 Grant (to E.G.), AIRC grant IG-24444 (to E.G.) and AIRC grant IG-19927 (to R.P.), AIRC grant IG-20074 (to M.T.) and KWF Dutch Cancer Society (KWF grant#11957).