The role of inflammatory pathways in cancer-associated cachexia and radiation resistance

Abstract

Dysregulated inflammatory responses are key contributors to a multitude of chronic ailments, including cancer. Evidence indicates that disease progression in cancer is dependent on the complex interaction between the tumor and the host microenvironment. Most recently, the inflammatory response has been suggested to be critical, as both the tumor and microenvironment compartments produce cytokines that act on numerous target sites, where they foster a complex cascade of biologic outcomes. Patients with cancer-associated cachexia (CAC) suffer from a dramatic loss of skeletal muscle and adipose tissue, ultimately precluding them from many forms of therapeutic intervention, including radiotherapy. The cytokines that have been linked to the promotion of the cachectic response may also participate in radiation resistance. The major changes at the cytokine level are, in part, due to transcriptional regulatory alterations possibly due to epigenetic modifications. Herein we discuss the role of inflammatory pathways in CAC and examine the potential link between cachexia induction and radiation resistance.

Figure 1

Multiple downstream effects of TNF-α signaling in radiation resistance and CAC. Cachexia-inducing tumors promote the circulation of multiple proinflammatory cytokines, either by directly releasing these factors or by promoting host cells to release these cytokines. One of the more important cytokines implicated is TNF-α. Treatment with ionizing radiation can elicit cellular signaling by two distinct mechanisms: (i) nuclear activation—the damaged DNA activates the DNA repair machinery that arrests the cell cycle and (ii) cytoplasmic activation—ionizing radiation can generate ROS, which can activate RTKs, which in turn initiate downstream prosurvival signaling pathways. These signaling cascades then converge on transcription factors such as NF-κB. In addition, TNF-α is released by the tumor and can act through the TNFR and downregulateG₀S₂, which binds to and negatively regulates adipose triglyceride lipase (ATGL) activity. ATGL is important in catalyzing the conversion of triacylglycerol (TAG) into diacylglycerol (DAG) and free fatty acids (FFA). Therefore, TNF-α can increase ATGL activity and promote increased release of FFA. G₀S₂ could potentially play a role in ionizing radiation–mediated DNA damage response/cell-cycle arrest. It would be of interest to analyze the DNA damage response in adipose tissue and its possible effect on lipid metabolism (26).