Pro & Anti-Inflammatory Cytokines in Colorectal Cancer

描述（由申请人提供）：慢性炎症与结直肠癌的病因有关。实验研究表明，强有力的促炎细胞因子，即肿瘤坏死因子（TNF）-β，白细胞介素（IL）-1 β，和IL-6具有致癌作用。其它细胞因子和细胞因子受体，如可溶性TNF受体I型和II型（sTNF-R1和sTNF-R2）、IL-1受体拮抗剂（IL-1Ra）和干扰素（IFN）-γ，是抗炎和抗肿瘤的。据推测，促炎和抗炎反应之间的不平衡，这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得到过验证。这项拟议的研究将被纳入一项正在进行的NIH资助的病例队列研究，该研究在妇女健康倡议（WHI）中进行，这是一项针对绝经后妇女的大型前瞻性研究。正在进行的病例队列研究探讨了乳腺癌、子宫内膜癌和结直肠癌的风险与胰岛素、IGF-I、雌二醇和脂肪因子在血清学和遗传学水平上的相关性。本病例-队列研究中的500例新发结直肠癌病例和900例亚队列受试者将成为本拟定研究的受试者，其中（1）血浆促炎细胞因子（TNF-？，IL-1？，和IL-6）、抗肿瘤IFN-γ和抗炎可溶性细胞因子受体（sTNF-R1、sTNF-R2和IL-1Ra），以及（2）参与这些细胞因子的信号转导途径的基因的多态性，将检查它们在结肠直肠癌病因学中的作用。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，并探讨它们对结直肠癌风险的相互作用。本研究的结果可能有助于确定绝经后妇女谁是易患慢性炎症和肿瘤的发展。这些高危人群可能受益于预防性NSAIDS预防结直肠癌。这项研究检查了促炎和抗炎反应之间的不平衡，这有利于促炎细胞因子的产生，是否与结直肠癌的风险有关。本研究的结果可能有助于确定绝经后妇女谁是易患慢性炎症和肿瘤的发展。这些高危人群可能受益于预防性NSAIDS预防结直肠癌。公共卫生相关性：这项研究检查了促炎和抗炎反应之间的不平衡，这有利于促炎细胞因子的产生，是否与结直肠癌的风险有关。本研究的结果可能有助于确定绝经后妇女谁是易患慢性炎症和肿瘤的发展。这些高危人群可能受益于预防性NSAIDS预防结直肠癌。

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.