Pro & Anti-Inflammatory Cytokines in Colorectal Cancer

描述(申请人提供)：慢性炎症与结直肠癌的病因有关。实验研究表明，强大的促炎细胞因子，即肿瘤坏死因子-1、白介素1和白介素6具有致癌作用。其他细胞因子和细胞因子受体，如可溶性肿瘤坏死因子受体I和II(sTNF-R1和sTNF-R2)，IL-1受体拮抗剂(IL-1ra)和干扰素(干扰素)-γ，具有抗炎和抗肿瘤作用。据推测，促炎和抗炎反应之间的失衡有利于促炎细胞因子的产生，与结直肠癌的风险有关。这一假设从未在人类身上进行过检验。这项拟议的研究将被整合到NIH资助的正在进行的病例队列研究中，该研究是在妇女健康倡议(WHI)内进行的，这是一项针对绝经后妇女的大型前瞻性研究。这项正在进行的病例队列研究从血清学和遗传学水平研究了乳腺癌、子宫内膜癌和结直肠癌的风险与胰岛素、胰岛素样生长因子-I、雌二醇和脂肪因子的关系。本研究将以500例结直肠癌发病病例和900例亚队列研究对象为研究对象，研究(1)血浆促炎细胞因子(TNF-α、IL-1和IL-6)、抗肿瘤干扰素-γ和抗炎可溶性细胞因子受体(sTNF-R1、sTNF-R2和IL-1ra)水平，以及(2)参与这些细胞因子信号转导途径的基因多态性在结直肠癌发病机制中的作用。此外，结合正在进行的病例队列研究的现有数据，我们将评估细胞因子、胰岛素、IGF-I、雌激素和脂肪因子之间的相互关系，并探索它们对结直肠癌风险的交互作用。这项研究的结果可能有助于识别易患慢性炎症和肿瘤发展的绝经后妇女。这些高危个体可能受益于预防结直肠癌的预防性非甾体抗炎药。这项研究考察了促炎和抗炎反应之间的不平衡是否与结直肠癌的风险有关，这些反应有利于促炎细胞因子的产生。这项研究的结果可能有助于识别易患慢性炎症和肿瘤发展的绝经后妇女。这些高危个体可能受益于预防结直肠癌的预防性非甾体抗炎药。公共卫生相关性：这项研究调查了促炎和抗炎反应之间的不平衡是否与结直肠癌的风险有关，这些反应有利于促炎细胞因子的产生。这项研究的结果可能有助于识别易患慢性炎症和肿瘤发展的绝经后妇女。这些高危个体可能受益于预防结直肠癌的预防性非甾体抗炎药。

DESCRIPTION (provided by applicant): Chronic inflammation is implicated in the etiology of colorectal cancer. Experimental studies have shown that the potent proinflammatory cytokines, namely tumor necrosis factor (TNF)-?, interleukin (IL)-1?, and IL-6, have oncogenic effects. Other cytokines and cytokine receptors, such as soluble TNF receptor types I and II (sTNF-R1 and sTNF-R2), IL-1 receptor antagonist (IL-1Ra), and interferon (IFN)-gamma, are anti-inflammatory and anti-tumor. It is hypothesized that imbalance between the pro- and anti-inflammatory responses, which favors production of the proinflammatory cytokines, is associated with the risk of colorectal cancer. This hypothesis has never been tested in humans. This proposed study will be integrated in an ongoing NIH-funded case-cohort study conducted within the Women's Health Initiative (WHI), a large prospective study of postmenopausal women. The ongoing case-cohort study examines how the risk of breast, endometrial, and colorectal cancers is associated with insulin, IGF-I, estradiol, and adipokines assessed at both serologic and genetic levels. The 500 incident colorectal cancer cases and the 900 subcohort subjects in this case-cohort study will be the subjects of this proposed study, in which (1) plasma levels of proinflammatory cytokines (TNF-?, IL-1?, and IL-6), the anti-tumor IFN-gamma, and anti-inflammatory soluble cytokine receptors (sTNF-R1, sTNF-R2, and IL- 1Ra), and (2) polymorphisms of genes involved in the signal transduction pathways of these cytokines will be examined for their roles in the etiology of colorectal cancer. In addition, combining existing data from the ongoing case-cohort study, we will evaluate the inter- relationships among cytokines, insulin, IGF-I, estrogen, and adipokines as well as explore their interactive effects on the risk of colorectal cancer. The results of this study may help to identify the postmenopausal women who are susceptible to chronic inflammation and tumor development. These high-risk individuals may benefit from prophylactic NSAIDS for prevention of colorectal cancer. This study examines if imbalance between the pro- and anti-inflammatory responses, which favors production of the proinflammatory cytokines, is associated with the risk of colorectal cancer. The results of this study may help to identify the postmenopausal women who are susceptible to chronic inflammation and tumor development. These high-risk individuals may benefit from prophylactic NSAIDS for prevention of colorectal cancer. PUBLIC HEALTH RELEVANCE: This study examines if imbalance between the pro- and anti-inflammatory responses, which favors production of the proinflammatory cytokines, is associated with the risk of colorectal cancer. The results of this study may help to identify the postmenopausal women who are susceptible to chronic inflammation and tumor development. These high-risk individuals may benefit from prophylactic NSAIDS for prevention of colorectal cancer.