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Review
. 2021 Jan 1;12(4):1125-1132.
doi: 10.7150/jca.50376. eCollection 2021.

GDF15/GFRAL Pathway as a Metabolic Signature for Cachexia in Patients with Cancer

Darakhshan Sohail Ahmed  1   2 , Stéphane Isnard  1   2   3 , John Lin  1   2 , Bertrand Routy  4   5 , Jean-Pierre Routy  1   2   6
Affiliations
Free PMC article
Review

GDF15/GFRAL Pathway as a Metabolic Signature for Cachexia in Patients with Cancer

Darakhshan Sohail Ahmed et al. J Cancer. .
Free PMC article

Abstract

Cachexia is a metabolic mutiny that directly reduces life expectancy in chronic conditions such as cancer. The underlying mechanisms associated with cachexia involve inflammation, metabolism, and anorexia. Therefore, the need to identify cachexia biomarkers is warranted to better understand catabolism change and assess various therapeutic interventions. Among inflammatory proteins, growth differentiation factor-15 (GDF15), an atypical transforming growth factor-beta (TGF-β) superfamily member, emerges as a stress-related hormone. In inflammatory conditions, cardiovascular diseases, and cancer, GDF15 is a biomarker for disease outcome. GDF15 is also implicated in energy homeostasis, body weight regulation, and plays a distinct role in cachexia. The recent discovery of its receptor, glial cell line-derived neurotrophic factor (GDNF) family receptor α-like (GFRAL), sheds light on its metabolic function. Herein, we critically review the mechanisms involving GDF15 in cancer cachexia and discuss therapeutic interventions to improve outcomes in people living with cancer.

Keywords: GDF15; GFRAL; Inflammation; cachexia; cancer.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
The central pathway of cancer cachexia involving GDF15 and GFRAL with RET proto-oncogene as a coreceptor. AP: area postrema; NTS: nucleus of solitary tract; GDF15: growth differentiation factor15; GFRAL: GDNF family receptor alpha-like; RET: rearranged during transfection proto-oncogene, a co-receptor to GFRAL; Erk: extracellular-signal-regulated kinase; Akt: Ak strain transforming; (PLC)γ: phospholipase C-gamma; LBM: Lean body mass; FM: fat mass
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