Cachexia is a complex metabolic syndrome associated with rapid loss of body weight, mainly loss of fat and lean muscle. Patients with cancer cachexia often develop anemia, fatigue, asthenia and anorexia, which worsen their quality of life and reduce their tolerance to anticancer therapies. As a result, cachexia accounts for approximately 20% of patients with cancer-related deaths. To date, experts know that the precise mechanism responsible for the development of cancer cachexia is not complete. Previous studies have shown that inflammatory cytokines such as interleukin 6 (IL-6), tumor necrosis factor (TNF-alpha), interferon gamma (IFN-γ), and transforming growth factor (TGF-β) they induce the remodeling of adipose and muscle tissue due to the accelerated growth of tumor cells, which contribute to the pathogenesis of tumor cachexia.
A latest molecular study conducted by scientists from Beijing University focused on the causal identification of the factors linking tumors and extensive catabolism in tumor cachexia. To determine serum lactate levels, samples collected from patients with lung adenocarcinoma were used to calibrate the Biosen C-Line glucose-lactate analyzer. Systemic metabolic changes associated with cachexia were profiled using a mouse xenograft model of Lewis lung cancer (LLC) cells. Tumor-burdened mice showed significant weight loss with a reduction in white adipose tissue (WAT). Metabolomic screening of a mouse model of tumor cachexia identified lactate as the major differential metabolite. The identity of this metabolite was confirmed by the peak in the mass spectrum.
Lactate levels were strongly correlated with body weight reduction, particularly among lung adenocarcinoma patients with tumor cachexia. Higher levels of circulating and interstitial adipose lactate were observed before body weight loss. Furthermore, the results of lactate infusion of the wasting phenotype were similar to those induced by the tumor. A minipump-mediated osmotic L-lactate infusion led to a persistent mean increase in circulating lactate without a change in blood pH; however, exposed D-lactate does not appear to affect weight loss. Sustained high lactate levels in many cancer patients were negatively associated with their prognosis. This indicates that having too much lactic acid in the case of tumor pathologies simulates a tiredness/asthenia effect similar to that of having performed very intense physical exercise.
To study the potential clinical relevance of lactate in human cancer cachexia, the team collected serum samples from patients with lung adenocarcinoma. Principal component analysis of serum metabolites clustered samples from patients with cachexia as well as those without cachexia. Serum lactate level was also markedly elevated in patients with cachexia and closely correlated with body weight loss, confirming the importance of lactate in the progression of the condition. The researchers noted that the lactate level in patients decreased significantly after surgical removal of the lung tumor, suggesting that the tumor was the main cause of the elevated serum lactate. But how does lactic acid do all this? The membrane receptor GPR81 has been identified as the primary mediator of the pro-catabolic effects of lactate.
Ten years ago Ge et al. pioneered the identification of GPR81, a G protein-coupled receptor (GPCR) capable of binding lactate and transmitting information intracellularly. When GPR81 is bound by lactate, the α subunits immediately undergo a structural conversion with energy generated by the GTP-GDP switch, which in turn influences downstream signaling molecules (second messengers). GPR81 inhibits the activation of the protein kinase A (PKA) system by decreasing the concentration of cAMP. In normal human tissues, GPR81 is most highly expressed in adipose tissue, where it regulates inter- and intracellular transport and, most importantly, inhibits lipolysis when intracellular lactate concentrations are excessive. As research progressed, the identification of multiple lactate receptors emerged, with GPR132 playing a prominent role.
Instead of it, more specifically GPR81 deficiency was found to block cachectic manifestations triggered by lactate infusion and tumor, thus establishing the lactate/GPR81 duo as the key connection between metabolic reprogramming in tumor cacheXxia. Catabolic remodeling of the 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, thus confirming the crucial role of adipose tissue loss in tumor cachexia. In particular, in cancer cachexia the mitochondrial uncoupling protein (UCP-1) is always very high. This cellular protein literally “uncouples” mitochondrial energy metabolism, causing the energy gradient needed for both respiration and energy production to be lost. The latter is dissipated as heat and lost energy potential.
Through the GPR81 receptor, lactate activated the Gαi/o-Gβγ-RhoA-ROCK1-p38 signaling cascade, unaccompanied by upregulation of parathyroid hormone-related protein (PTHrP). p38 is a stress MAP kinase; active p38 has been shown to facilitate nuclear translocation of the transcription factor ATF2 by phosphorylation, leading to increased UCP-1 expression. To trigger WAT browning and lipolysis in the samples, a chronic increase in blood lactate was sufficient. To be sure that GPR81 was the candidate responsible for these biological effects, the scientists ascertained that other potential lactic acid sensors (MCT1, MCT4, GPR4 and GPR132) were either genetically eliminated or pharmacologically inhibited), arriving at the conclusion that none of the previous sensors contribute to the “tumor” effects of lactic acid.
Taken together, the study results indicate that GPR81 could be targeted and blocked to alleviate metabolic and organ wasting involved in cancer cachexia.
Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Chemistry.
Scientific references
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