A recent Nature Metabolism study reports that circulating lactate levels are positively associated with weight loss in cancer cachexia patients. Mouse model experiments also revealed that adipose-specific G-protein-coupled receptor 81 (GPR81) is a key mediator of the catabolic effects of lactate.
Study: Activation of GPR81 by lactate drives tumor-induced cachexia. Image Credit: Pixel-Shot / Shutterstock.com
What is cachexia?
Cachexia is a complicated metabolic syndrome that is associated with rapid body weight loss, including loss of fat and muscle mass.
Patients with cancer cachexia often develop anemia, fatigue, asthenia, and anorexia, which deteriorate their quality of life and reduce their tolerance to cancer therapies. As a result, cachexia accounts for around 20% of patients with cancer-related deaths.
To date, the precise mechanism responsible for the development of cancer cachexia is not well understood. Previous studies have shown that inflammatory cytokines, such as interleukin 6 (IL-6), tumor necrosis factor (TNF), interferon γ (IFN-γ), and transforming growth factor-β, induce the remodeling of adipose and muscle due to accelerated growth of cancer cells, all of which contribute to the pathogenesis of cancer cachexia.
Anti-inflammation treatments have not been associated with positive effects in alleviating cancer cachexia. Therefore, more research is needed to better understand the association between tumor manifestations and poor host metabolism.
About the study
The current study focuses on causally identifying the connecting factors between tumors and extensive catabolism in cancer cachexia. To determine serum lactate levels, samples collected from lung adenocarcinoma patients were used to calibrate the Biosen C-Line glucose lactate analyzer.
The systemic metabolic changes associated with cachexia were profiled using a mouse xenograft model of Lewis lung cancer (LLC) cells. Mice with tumor burden exhibited significant weight loss with reduced white adipose tissue (WAT).
Study findings
Metabolomics screening of a mouse model of cancer cachexia identified lactate as the top differential metabolite. The identity of this metabolite was corroborated by the peak in the mass spectrum, which was compared to the standard.
Lactate levels were strongly correlated with reduced body weight, particularly among patients with lung adenocarcinoma with cancer cachexia. Higher circulating and adipose interstitial lactate levels were observed before body weight loss. Additionally, the wasting phenotype lactate infusion results were similar to those induced by the tumor.
An osmotic minipump-mediated lactate infusion led to a persistent average increase of circulating lactate without a change in blood pH; however, d-lactate exhibited did not appear to influence weight loss. The sustained high lactate levels in many cancer patients were negatively associated with their prognosis.
Adipose GPR81 was identified as the primary mediator of lactate’s pro-catabolic effects. More specifically, GPR81 deficiency was found to block lactate infusion- and tumor-triggered cachectic manifestations, thus establishing lactate/GPR81 as the key connection between metabolic reprogramming in cancer cachexia and tumors.
The catabolic remodeling of WAT has also been identified as an early pathological event in cancer cachexia. In mouse models, depletion of key enzymes in lipolysis alleviated cachectic phenotypes, thereby confirming the crucial role of adipose tissue wasting in cancer cachexia.
A lactate-stimulated cachectic pathway activated the GPR81-Gαi/o-Gβγ-RhoA/ROCK1-p38 signaling cascade, not accompanied by the upregulation of parathyroid hormone-related protein (PTHrP). To trigger WAT browning and lipolysis, chronic elevation of blood lactate is sufficient.
Additionally, phosphoproteomics data showed the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) in the GPR81−/− iWAT. This activation of ERK1/2 in GPR81-deficient mice could influence persistent adipogenesis, thereby muting lactate- and tumor-induced adipose wasting.
Conclusions
The current study identified host GPR81 as the key mediator of cancer cachexia, with lactate activating GPR81 to ultimately support tumor growth. This observation aligns with previous studies reporting the inhibition of GPR81 expression suppressing the growth of pancreatic and breast cancer cells. The experimental findings strongly suggest that the palliation of cachectic symptoms in GPR81−/− is mediated through GPR81 deficiency in the host.
Both in vitro and in vivo experiments associated with tumor growth revealed that the lack of GPR81 expression in LLC cells repressed cancer proliferation. Thus, lactate/GPR81 contributes to both cancer progression and cachexia, which deteriorates disease outcomes.
Mechanistically, lactate activates GPR81, which induces adipose metabolic remodeling through Gαi/o-Gβγ–RhoA/ROCK1–p38 signaling cascade. This leads to muscle dystrophy and systemic hypercatabolism.
Taken together, the study findings indicate that GPR81 could be targeted and blocked to alleviate metabolic impairments involved in cancer cachexia.
Journal reference:
- Liu, X., Li, S., Cui, Q., et al. (2024) Activation of GPR81 by lactate drives tumor-induced cachexia. Nature Metabolism. doi:10.1038/s42255-024-01011-0
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