Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada.
Int J Cancer. 2010 Nov 1;127(9):2042-50. doi: 10.1002/ijc.25232.
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.
肥胖 Zucker 大鼠对结肠癌高度敏感，并且存在多种代谢异常，包括细胞因子肿瘤坏死因子-α（TNF-α）水平升高。本研究的主要目的是确定生理水平升高的 TNF-α是否会影响结肠肿瘤表型，特别是改变 TNF-α信号通路。肥胖 Zucker 大鼠（fa/fa，瘦素受体功能障碍的纯合隐性）、瘦 Zucker 大鼠（Fa/fa，Fa/Fa）和 Sprague-Dawley（SD）大鼠在 2 周内两次注射氧化偶氮甲烷（10mg/kg）。30 周后，处死动物并评估生理和肿瘤参数。肥胖大鼠的体重和器官重量以及血浆 TNF-α、胰岛素和瘦素水平明显高于瘦大鼠或 SD 大鼠。与瘦大鼠相比，肥胖大鼠的肿瘤发生率为 100%，肿瘤大小、多发性和负担明显更高，而瘦大鼠的肿瘤发生率为 47.8%。SD 大鼠的肿瘤发生率最低（20.0%）。与瘦大鼠相比，肥胖大鼠的肿瘤 TNF-α、TNF-α受体-2（TNFR2）、核转录因子-κB（NF-κB）和 IκB 激酶β（IKKβ）的蛋白水平更高。在肥胖和瘦大鼠中，这些蛋白的表达水平在肿瘤中均高于周围正常外观的结肠黏膜。这些发现支持 TNF-α信号在肿瘤发生中的重要作用，并表明在肥胖状态下生长的肿瘤与在瘦状态下生长的肿瘤相比，TNFR2 和 NF-κB 的表达水平有显著差异，这些蛋白在生长和存活中起着关键作用。结论是宿主的生理状态会微妙地影响肿瘤表型。
