Abstract
Zucker obese rats are highly sensitive to colon cancer and possess a plethora of metabolic abnormalities including elevated levels of cytokine tumor necrosis factor‐α (TNF‐α). The main objective of this study was to determine if physiologically elevated TNF‐α affects colonic tumor phenotype with regard to an altered TNF‐α signaling pathway. Zucker obese (fa/fa, homozygous recessive for dysfunctional leptin receptors), Zucker lean (Fa/fa, Fa/Fa) and Sprague–Dawley (SD) rats were injected twice with azoxymethane (10 mg/kg) over 2 weeks. After 30 weeks, the animals were terminated and physiological and tumor parameters were assessed. Obese rats had notably higher body and organ weights as well as plasma TNF‐α, insulin and leptin levels than lean or SD animals. A 100% tumor incidence and significantly higher tumor size, multiplicity and burden were found in obese rats compared to the lean group that had 47.8% tumor incidence. The SD group had the lowest tumor incidence (20.0%). Tumors from obese animals had higher protein levels of TNF‐α, TNF‐α‐receptor‐2 (TNFR2), nuclear transcription factor‐κB (NF‐κB) and IκB‐kinaseβ (IKKβ) compared to lean animals. In both obese and lean groups, expression levels of these proteins were higher in tumors than in surrounding, normal‐appearing colonic mucosae. These findings support an important role for TNF‐α signaling in tumorigenesis and demonstrate that tumors growing in an obese state had significantly different expression levels of TNFR2 and NF‐κB, proteins known to play a critical role in growth and survival, than those growing in the lean state. It is concluded that the physiological state of the host intricately affects tumor phenotype.