Elevated expression of tumor necrosis factor-± signaling molecules in colonic tumors of Zucker obese (fa/fa) rats

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-± (TNF-±). The main objective of this study was to determine if physiologically elevated TNF-± affects colonic tumor phenotype with regard to an altered TNF-± 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-±, 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-±, TNF-±-receptor-2 (TNFR2), nuclear transcription factor-°B (NF-°B) and I°B-kinase (IKK) 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-± signaling in tumorigenesis and demonstrate that tumors growing in an obese state had significantly different expression levels of TNFR2 and NF-°B, 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. © 2010 UICC.