What Role Do Inflammatory Cytokines Play in Cancer Cachexia?

Abstract

A tumor extends its effects beyond its local site, and one such effect is cancer cachexia which is caused by a state of systemic inflammation in response to cancer. Though the prominent effect of cancer cachexia is seen on skeletal muscles, it shows deterioration in other organs' smooth muscle, adipose tissue, blood, bone marrow, liver, and immunity. Interleukin (IL)-6 plays an imminent role along with tissue necrosis factor-alpha, IL-1 beta, interferon-gamma, myostatin, adiponectin, growth differentiation factor-15, activin A, etc. These cytokines through nuclear factor-kappa beta, mitogen-activated protein kinase, suppressor of mothers against decapentaplegic, and Janus activated kinase/signal transducer and activator of transcription pathway activate genes inducing ubiquitin-proteosome system and reactive oxidative species. Apart from these, they participate in causing anemia and immunosuppression. Adipose tissue acts as a source of cytokines and place of action of cytokines leading to lipolysis. Moreover, these cytokines act at the hypothalamic-pituitary-adrenal axis change metabolism and add to anorexia which already exists in cancer patients. The involvement of multiple cytokines necessitates the development and testing of anti-cytokines in combinations.

Keywords: adipose tissue; anorexia; cachexia; cytokines; skeletal muscle.

Figure 1. The various sources of inflammatory cytokines which result in cancer cachexia.

Source: Image created by the authors. CRP: C-reactive protein; GDF-15: growth and differentiation factor-15; IL: interleukin; LMF: lipid mobilizing factor; NK cells: natural killer cells; PIF: proteolysis-inducing factor; Th1 cells: T-helper 1 cells; TNF-alpha: tissue necrosis factor-alpha; T reg cells: regulatory T cells