Elevated expression of tumor necrosis factor-alpha signaling molecules in colonic tumors of Zucker obese (fa/fa) rats.
Zucker obese rats are highly sensitive to colon cancer and possess a plethora of metabolic abnormalities including elevated levels of cytokine tumor necrosis factor-alpha (TNF-alpha). The main objective of this study was to determine if physiologically elevated TNF-alpha affects colonic tumor phenotype with regard to an altered TNF-alpha 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-alpha, 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-alpha, TNF-alpha-receptor-2 (TNFR2), nuclear transcription factor-kappaB (NF-kappaB) and IkappaB-kinasebeta (IKKbeta) 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-alpha signaling in tumorigenesis and demonstrate that tumors growing in an obese state had significantly different expression levels of TNFR2 and NF-kappaB, 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.
Jain
Swati S
SS
Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada.
Bird
Ranjana P
RP
D000818:Animals; D001397:Azoxymethane; D001772:Blood Cell Count; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000378:metabolism*; D005260:Female; D016328:NF-kappa B / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D000097782:NF-kappaB-Inducing Kinase
D001397:Azoxymethane; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D000097782:NF-kappaB-Inducing Kinase