Cancer therapy and cachexia
Tuba Mansoor Thakir, Alice R. Wang, Amanda R. Decker-Farrell, Miriam Ferrer, Rohini N. Guin, Sam Kleeman, Llewelyn Levett, Xiang Zhao, Tobias Janowitz
Tuba Mansoor Thakir, Alice R. Wang, Amanda R. Decker-Farrell, Miriam Ferrer, Rohini N. Guin, Sam Kleeman, Llewelyn Levett, Xiang Zhao, Tobias Janowitz
View: Text | PDF
Review

Cancer therapy and cachexia

Abstract

A central challenge in cancer therapy is the effective delivery of anticancer treatments while minimizing adverse effects on patient health. The potential dual impact of therapy is clearly illustrated in cancer-associated cachexia, a multifactorial syndrome characterized by involuntary weight loss, systemic inflammation, metabolic dysregulation, and behavioral alterations such as anorexia and apathy. While cachexia research often focuses on tumor-driven mechanisms, the literature indicates that cancer therapies themselves, particularly chemotherapies and targeted treatments, can initiate or exacerbate the biological pathways driving this syndrome. Here, we explore how therapeutic interventions intersect with the pathophysiology of cachexia, focusing on key organ systems including muscle, adipose tissue, liver, heart, and brain. We highlight examples such as therapy-induced upregulation of IL-6 and growth-differentiation factor 15, both contributing to reduced nutrient intake and a negative energy balance via brain-specific mechanisms. At the level of nutrient release and organ atrophy, chemotherapies also converge with cancer progression, for example, activating NF-κB in muscle and PKA/CREB signaling in adipose tissue. By examining how treatment timing and modality align with the natural trajectory of cancer cachexia, we underscore the importance of incorporating physiological endpoints alongside tumor-centric metrics in clinical trials. Such integrative approaches may better capture therapeutic efficacy while preserving patient well-being.

Authors

Tuba Mansoor Thakir, Alice R. Wang, Amanda R. Decker-Farrell, Miriam Ferrer, Rohini N. Guin, Sam Kleeman, Llewelyn Levett, Xiang Zhao, Tobias Janowitz

×

Figure 3

Mechanistic pathways underlying tumor- and therapy-induced cachexia across key organs.

Options: View larger image (or click on image) Download as PowerPoint
Mechanistic pathways underlying tumor- and therapy-induced cachexia acro...
Examples of converging molecular pathways through which tumors and cancer therapies drive cachexia-associated changes in five major organ systems: muscle, liver, fat, brain, and heart. Arrows indicate the connected mechanistic pathway resulting in physiological dysfunction in each organ, ultimately leading to a convergent effect. For example, in the brain, elevated GDF-15 or IL-6 levels, resulting from tumor progression or chemotherapy, are detected by neurons in the area postrema, resulting in the activation of circuitry that leads to food avoidance and behavior changes driven by hormone signaling (42, 43, 94, 96). In the heart, tumor- and therapy-driven activation of TGF-β signaling promotes cardiac fibrosis and heart failure (181–184). In the liver, tumor- and therapy-induced ROS accelerate fibrosis and impair liver function (47, 109, 139, 185, 186). In muscle, tumors and chemotherapy agents (e.g., doxorubicin, cisplatin) activate the NF-κB axis (inflammatory pathways), leading to atrophy via upregulation of MuRF1 and atrogin-1 (187–192). In adipose tissue, lipolytic enzymes (HSL, ATGL) and β3-adrenergic/PKA/CREB signaling promote lipid mobilization and thermogenesis, leading to energy wasting and fat loss (31–37, 39, 40). These molecular pathways collectively unmask or exacerbate cachexia and contribute to multi-organ dysfunction and failure during cancer progression and therapy. The figure illustrates only selected examples and does not represent a comprehensive set of molecular pathways or causalities. ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; MMP2, matrix metallopeptidase 2; COL1A1, collagen type I alpha 1; COL3A1, collagen type III alpha 1; CGI-58, comparative gene identification-58; FFA, free fatty acid; PKA, protein kinase A; CREB, cAMP response element-binding protein; C/EBPβ, CCAAT/enhancer binding protein beta; UCP1, uncoupling protein 1; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PRDM16, PR domain containing 16; CPT1, carnitine palmitoyltransferase I; PDK4, pyruvate dehydrogenase kinase 4.