Chemoradiation abrogates inflammation, induces sickness behavior, activates hypoxia signaling pathways, and causes mitochondrial dysfunction in a syngeneic murine model of head and neck cancer

Abstract

As cancer-related symptoms are similar to those of sickness associated with inflammation, it has been proposed that they are also mediated by increased inflammatory cytokines in the brain. However, there is still limited evidence for this relationship. The current study evaluated the alternative possibility that cancer-related symptoms are associated with changes in gene expression indicative of hypoxia signaling and mitochondrial abnormalities using PCR Arrays. Mice were injected or not with heterotopic tonsil epithelial cells transfected with Ras, E6/E7 of HPV16 and were exposed or not to 3 rounds of cisplatin (5.28 mg/kg) and radiotherapy (8 Gy). Tumor-bearing mice showed increased brain and liver inflammatory cytokine mRNA expression that was associated with decreased burrowing. Chemoradiation in non-tumor-bearing mice decreased burrowing but did not induce liver or brain inflammatory cytokine expression. Chemoradiation in tumor-bearing mice reduced burrowing and attenuated liver and brain inflammation, presumably by reducing tumor volume. Both the tumor and its treatment were associated gene expression changes indicative of mitochondrial dysfunction and HIF-1 α activation in liver and brain, with evidence of an additive effect of tumor and chemoradiation on brain mitochondrial dysfunction. Although correlative at this stage, these findings indicate that targeting mitochondrial dysfunction following cancer and cancer therapy may be a strategy for prevention of cancer-related symptoms. Ongoing work is exploring whether this can be achieved without interfering with the tumor response to chemoradiation.