The Combination of Low Skeletal Muscle Mass and High Tumor Interleukin-6 Associates with Decreased Survival in Clear Cell Renal Cell Carcinoma

Abstract

Clear cell renal carcinoma (ccRCC) is frequently associated with cachexia which is itself associated with decreased survival and quality of life. We examined relationships among body phenotype, tumor gene expression, and survival. Demographic, clinical, computed tomography (CT) scans and tumor RNASeq for 217 ccRCC patients were acquired from the Cancer Imaging Archive and The Cancer Genome Atlas (TCGA). Skeletal muscle and fat masses measured from CT scans and tumor cytokine gene expression were compared with survival by univariate and multivariate analysis. Patients in the lowest skeletal muscle mass (SKM) quartile had significantly shorter overall survival versus the top three SKM quartiles. Patients who fell into the lowest quartiles for visceral adipose mass (VAT) and subcutaneous adipose mass (SCAT) also demonstrated significantly shorter overall survival. Multiple tumor cytokines correlated with mortality, most strongly interleukin-6 (IL-6); high IL-6 expression was associated with significantly decreased survival. The combination of low SKM/high IL-6 was associated with significantly lower overall survival compared to high SKM/low IL-6 expression (26.1 months vs. not reached; p < 0.001) and an increased risk of mortality (HR = 5.95; 95% CI = 2.86–12.38). In conclusion, tumor cytokine expression, body composition, and survival are closely related, with low SKM/high IL-6 expression portending worse prognosis in ccRCC.

Increased expression of PSME2 is associated with clear cell renal cell carcinoma invasion by regulating BNIP3‑mediated autophagy

“…IL-6 is a tumor cytokine associated with mortality. High mRNA expression levels of IL-6 were associated with decreased survival time in patients with ccRCC (67,68). TNF-α is a core adjustor of a complex cytokine network, which not only mediates the pro-inflammatory response, but also regulates the interaction between cells, cell differentiation and cell death (69).…”

REVOLUTION (Routine EValuatiOn of people LivIng with caNcer)—Protocol for a prospective characterisation study of patients with incurable cancer

“…In order to improve care, spur therapeutic innovation, provide meaningful endpoints for trials and direct future research, work must be done to explore how the tumour influences the clinical phenotype. Characterisation of this interaction may also provide prognostic information, allowing planning of investigations, treatment and referral to palliative medicine services [ 1 ].…”

Interleukin-6: Molecule in the Intersection of Cancer, Ageing and COVID-19

“…This process seems to be strongly influenced by IL-6 and TNF-α, which affect adipocytes, hepatocytes and striated muscle fibres, where both factors induce skeletal muscle atrophy, lipolysis, the "browning" of white adipocytes and ketogenesis in the liver [20,102,103]. It seems that there is a direct association between the high level of IL-6 produced by the malignant tissue, low skeletal muscle mass, and the survival of the patient [104]. In addition to these severe metabolic problems, IL-6 can cross the blood-brain barrier, where it is recognised by groups of hypothalamic and hippocampal neurons controlling food intake and causing depression [105,106].…”