IL-6–mediated cardiac and vascular dysfunction in cancer cachexia
A Antunes Goncalves, Y Qilang Ye, D Chistopher Dostal, M K P Mandana Karamali Palangtschi, E Eva Harakaly-Bottka, B K P Bruno K. Podesser, P Peter Pokreisz, K Xaver Koenig, K Attila KissAbstract
Introduction/Background
Cachexia is a multifactorial metabolic syndrome that occurs in multiple diseases such as heart failure (HF) and cancer. Elevated levels of the inflammatory cytokine IL-6 contributes to tissue wasting across multiple organs in cachexia as well as is strongly linked to worse outcome of HF.
Purpose
To identify the role of tumor derived IL-6 in a progression of cardiac and vascular dysfunction in mice model of cancer and cachexia.
Methods
Male BALB/c mice (10–12 weeks old) were inoculated into the right flank with 1×106 mouse colon-26 carcinoma (C26) or tumor specific silenced IL6 (C26shIL6) cells, PBS served as control (n=8, all groups). Cardiac function and body composition (echocardiography and echo-MRI) were assessed at baseline, day 10, and endpoint. Vascular endothelial function was evaluated by myography. Multi-organ molecular fingerprints were assessed by histological, molecular, and biochemical approaches.
Results
C26 tumour-bearing mice developed a cachectic phenotype characterized by loss of fat (4.77 g vs 1.87 g), lean mass (25 g vs 20 g) and marked systemic inflammation, including elevated neutrophil-to-lymphocyte ratio, and activated platelets (p<0.001) compared to control. Both tumour groups showed trends toward impaired LV systolic and diastolic function at the end-point measurements. Cardiac bulk RNA sequencing with subsequent enrichment analysis in C26 mice demonstrated downregulation of mitochondrial function and metabolic pathways, alongside upregulation of inflammatory and cell death signalling; these changes were partially normalized by IL-6 silencing. Consistently, cardiac (LV) respirometry showed impaired mitochondrial respiration, with reduced complex I–III activity and markedly decreased OXPHO capacity (p<0.001 vs PBS).This was accompanied by the elevation of phospho-STAT3, phospho-MLKL, SUMO1, RIPK1, and RIPK3 were significantly (p<0.001 vs PBS group). These alterations were partially reversed in C26shIL6 group. Endothelial dysfunction was evidenced by a rightward shift in ACh EC50 values (-7.33 vs -6.91, p<0.001 vs PBS and C26shIL6 group), increased endothelial activation markers gene expression (P-selectin, VCAM-1, ICAM-1) in aorta from C26 mice. Immunofluorescence analysis of CD31 in aortic segments demonstrated a significant reduction in endothelial signal in C26 group (p<0.05), which was partially restored in C26shIL6.
Conclusion
Cancer cachexia drives a distinct cardio-oncology phenotype marked by systemic inflammation, peripheral endothelial dysfunction, mitochondrial failure, and necroptotic signalling, culminating in early LV impairment reminiscent of HF. IL-6 links tumour burden to cardiac metabolic and vascular injury; its silencing partially reverses these alterations, supporting IL-6–targeted strategies in cancer-associated HF.