Many disease states have been traced back to thousands of years ago; times when physicians like Hippocrates and Imhotep were still around. The vast majority of these pathological conditions have been identified and remedied since, but one major illness that has been dated back to Ancient Greece still hasn’t been given a reliable treatment: cachexia12. Cachexia is a syndrome characterized by involuntary weight loss due to muscle wasting and fat loss in patients with chronic illnesses1. This review will specifically highlight cachexia’s role in cancer: cancer cachexia, referred to as “CC.” CC affects about 70% of advanced-stage cancer patients, and accounts for 30% of all cancer-related deaths2. Despite its prevalence, there are no existing FDA-approved drugs or therapeutics to combat this malignancy. While CC encompasses both muscle and fat loss, muscle has historically been the focal point in CC research, leaving adipose tissue (AT) neglected and less understood. Previous research focusing solely on muscle loss has proved unsuccessful in improving patient outcomes. Scientists at the Johns Hopkins University School of Medicine gave patients a drug that exclusively uses muscle as its therapeutic target, overlooking AT entirely. While patients did show an increase in lean or muscle mass, the lack of meaningful data on fat mass underscores their narrowed approach3. This highlights the need for a more holistic approach when it comes to addressing CC. If researchers begin to acknowledge both muscle and AT in their studies, there will be a very hopeful future for therapies towards CC.
Clinicians first thought CC to be a food intake issue where patients were simply not eating enough. As a result, they tried nutritional intervention, giving patients high-fat diets to promote weight gain, but this approach proved unsuccessful4 and patients still were losing weight. This failed intervention suggested that CC is a much deeper issue and led clinicians to take to more complex analyses.
Physicians and scientists began to collect fat deposits and blood samples from patients with CC and have since found this syndrome to be the result of disruptions in metabolism and immune function5. Central to these disruptions is systemic inflammation, the key driver of CC. In cancer, both tumor-derived factors and host immune signaling play significant roles in this sustained inflammatory environment, disrupting tissue homeostasis and energy balance. This chronic inflammatory state drives major metabolic changes that underlie CC: enhanced fat breakdown, muscle breakdown, and disrupted hormone signaling6.
Previous research has identified cytokines, or pro-inflammatory signals, that disrupt homeostasis at both the cellular and structural levels in patients with CC7. CC-mediated fat loss happens through a process driven by these same cytokines: lipolysis, where triglycerides, or the energy packages stored in fat cells, are broken down and released into the bloodstream. Among these cytokines is tumor necrosis factor-α (TNF-α)8, which was the first cachectic factor to be found circulating in the blood and fat depots of patients with CC. TNF-α works through the NF-κB pathway, which suppresses the activity of G0/G1 switch protein 2 (G0S2). G0S2 normally blocks fat breakdown by inactivating the enzyme known to kick off lipolysis, so its suppression removes this protective brake.10. TNF-α has also been shown to upregulate other inflammatory signals that further drive this lipolytic process: when TNF-α binds to its receptor, leukemia inhibitory factor (LIF), which is another inflammatory molecule, has been shown to increase in concentration. LIF runs through the JAK/STAT pathway, which in turn upregulates another inflammatory protein interleukin-6 (IL-6) in the fat cell. Both LIF and IL-6 are known to drive fat loss, and TNF-α attracting these molecules demonstrates that inflammation not only removes the brakes in fat breakdown by inactivating G0S2, but also steps on the gas11 by signaling for other inflammatory cytokines to exacerbate this lipolysis process.
Interestingly, these same signals produced by TNF-α also set off internal fat‑cell pathways, such as p38 mitogen‑activated protein kinase (p38 MAPK), that activate the uncoupling protein‑1 (UCP1). When UCP1 is active, it makes white fat behave more like brown fat, which burns energy instead of storing it, a process called beiging9. The beiging of white fat cells increases non-shivering thermogenesis, or heat production without muscle movement, via UCP1-mediated mitochondrial uncoupling, leading to energy wasting and fat loss, which worsens the patient’s condition. Understanding exactly how this fat‑burning shift happens, and how it interacts with other inflammatory and metabolic changes in cancer cachexia, remains an open question.
To create effective therapeutic options for patients with CC, future research must answer several key questions. To begin, we do not yet know if fat loss is always followed by loss of muscle, or vice versa, in CC; how would knowing this change treatments? What does inflammation of fat do to the rest of the body in CC, and does it worsen muscle loss too? Can anti-inflammatory drugs interact with diet or exercise to block fat breakdown in CC? These remaining questions reflect the reason why more work in adipocyte biology in CC is needed today. We urge scientists interested in a new branch of study, immunometabolism, to begin digging deep into these questions and help make CC a more accurately-studied process.
References
- Berardi, Emanuele et al. “A Pound of Flesh: What Cachexia Is and What It Is Not.” Diagnostics (Basel, Switzerland) vol. 11,1 116. 12 Jan. 2021, doi:10.3390/diagnostics11010116
- Mariean, Claudia Raluca et al. “Cancer Cachexia: New Insights and Future Directions.” Cancers vol. 15,23 5590. 26 Nov. 2023, doi:10.3390/cancers15235590
- Boccia, Ralph & Croot et al. “Effects of enobosarm on muscle wasting and physical function in patients with cancer: A double-blind, randomised controlled phase 2 trial.” The Lancet Oncology vol. 14. 10.1016/S1470-2045(13)70055-X.
- Van de Worp, Wouter R P H et al. “Nutritional Interventions in Cancer Cachexia: Evidence and Perspectives From Experimental Models.” Frontiers in nutrition vol. 7 601329. 22 Dec. 2020, doi:10.3389/fnut.2020.601329
- More, Tushar H et al. “Metabolomics analysis reveals novel serum metabolite alterations in cancer cachexia.” Frontiers in oncology vol. 14 1286896. 20 Feb. 2024, doi:10.3389/fonc.2024.1286896
- Schcolnik-Cabrera, Alejandro et al. “Understanding tumor anabolism and patient catabolism in cancer-associated cachexia.” American journal of cancer research vol. 7,5 1107-1135. 1 May. 2017
- Malla, Jyothirmai et al. “What Role Do Inflammatory Cytokines Play in Cancer Cachexia?.” Cureus vol. 14,7 e26798. 12 Jul. 2022, doi:10.7759/cureus.26798
- Patel, Hetal J, and Bhoomika M Patel. “TNF-α and cancer cachexia: Molecular insights and clinical implications.” Life sciences vol. 170 (2017): 56-63. doi:10.1016/j.lfs.2016.11.033
- Cao, Wenhong et al. “p38 mitogen-activated protein kinase is the central regulator of cyclic AMP-dependent transcription of the brown fat uncoupling protein 1 gene.” Molecular and cellular biology vol. 24,7 (2004): 3057-67. doi:10.1128/MCB.24.7.3057-3067.2004
- Hayden, Matthew S, and Sankar Ghosh. “Regulation of NF-κB by TNF family cytokines.” Seminars in immunology vol. 26,3 (2014): 253-66. doi:10.1016/j.smim.2014.05.004
- Cabrera-Rivera, Graciela L et al. “Increased TNF-α production in response to IL-6 in patients with systemic inflammation without infection.” Clinical and experimental immunology vol. 209,2 (2022): 225-235. doi:10.1093/cei/uxac055
- Morita-Tanaka, Satomi et al. “The landscape of cancer cachexia in advanced non-small cell lung cancer: a narrative review.” Translational lung cancer research vol. 12,1 (2023): 168-180. doi:10.21037/tlcr-22-561