Targeting CCL20-CCR6 Interactions in Colorectal Cancer

在美国，近1/20的人在一生中会被诊断出患有结直肠癌，超过1/3的人会被诊断出患有结直肠癌。 这些人会死于疾病。事实上，结直肠癌是第二大癌症相关原因， 死亡在这个国家。预防和治疗方面的进展对艾滋病毒/艾滋病的影响有限。 发病率和生存率。结肠直肠癌的新治疗策略显然是必要的。趋化 已经成为肿瘤促进炎症和癌症之间的关键联系。CCR 6是唯一 炎症趋化因子CCL 20的已知受体，而炎症趋化因子CCL 20又是CCR 6的唯一已知配体。 一些证据表明，炎症趋化因子CCL 20与其受体之间的相互作用可能是一个潜在的机制。 受体CCR 6在结直肠癌的发生和发展中起关键作用。相关 有证据表明CCR 6和CCL 20可能在促进结直肠肿瘤生长中发挥作用， 侵袭和转移。然而，到目前为止，除了我们的初步结果外，缺乏体内 在完整的结肠直肠癌背景下破坏CCL 20-CCR 6相互作用的效果的数据 免疫系统我们已经证明了CCL 20和CCR 6在人结肠中均上调， 癌的我们发现CCR 6的缺乏与腺瘤的显著减少有关， 在自发性肠癌发生模型中， 同系可移植肿瘤模型。我们已经观察到通过CCR 6的CCL 20信号传导诱导了 进一步分泌CCL 20，这反过来又促进结肠直肠癌细胞的增殖和迁移。 除了CCL 20-CCR 6相互作用的上皮细胞效应之外，基质效应由CCL 20-CCR 6相互作用的细胞因子证实。 事实上，在肿瘤攻击实验中，移植的结肠癌细胞在两种细胞中都表达CCR 6， 然而，在CCR 6缺陷的宿主小鼠中生长延迟。我们发现CCR 6缺乏是 与巨噬细胞迁移到腺瘤和移植结肠癌的减少有关。我们 已经进一步证明CCL 20-CCR 6相互作用确实诱导单核细胞/巨噬细胞迁移 在体外和体内。此外，我们已经观察到移植的结肠癌肿瘤的生长， 由于肿瘤巨噬细胞耗尽而延迟。最后，我们发现肿瘤巨噬细胞分泌 炎症介质，其反过来诱导结肠癌细胞的增殖。总的来说， 初步结果表明，CCL 20-CCR 6信号通过直接作用于 肿瘤性癌细胞以及通过对肿瘤基质细胞如巨噬细胞的作用。我们有 最近开始测试一种新的口服小分子CCR 6抑制剂。我们的初步数据显示 这种分子可以抑制CCL 20自动反馈回路，结直肠癌细胞增殖， 体外单核细胞迁移。因此，我们假设CCL 20和CCR 6之间的靶向相互作用是 有效治疗结肠直肠癌。为了验证这一假设，并进一步阐明 CCR 6和CCL 20在结直肠癌中的作用，我们的目标是：1）建立靶向CCL 20-CCR 6的影响 结直肠癌中肿瘤上皮细胞的相互作用; 2）建立靶向治疗的结果 CCL 20-CCR 6相互作用对结直肠癌中促肿瘤基质的影响;以及3）确定CCL 20-CCR 6相互作用对结直肠癌中促肿瘤基质的功效。 靶向人类结肠直肠癌的预防相关模型中的CCL 20-CCR 6相互作用。的 提出的研究将阐明趋化因子受体CCR 6及其配体CCL 20在 结肠直肠癌我们相信，这些研究将确定临床相关性和治疗 CCR 6和CCL 20之间的相互作用在这种疾病中的重要性，并为 在人类患者中成功靶向该途径。

Nearly 1 in 20 people in the U.S. will be diagnosed with colorectal cancer in their lifetime, and over 1/3 of these will die from the disease. In fact, colorectal cancer is the second leading cause of cancer-related deaths in this country. Advances in prevention and treatment have made only a modest impact on incidence and survival. Novel treatment strategies for colorectal cancer are clearly needed. Chemokines have emerged as a crucial link between tumor-promoting inflammation and cancer. CCR6 is the only known receptor for the inflammatory chemokine CCL20, which in turn is the only known ligand for CCR6. Several lines of evidence suggest that interactions between the inflammatory chemokine CCL20 and its receptor CCR6 play a key role in the development and progression of colorectal cancer. Correlative evidence has suggested a possible role of CCR6 and CCL20 in promoting colorectal tumor growth, invasion and metastasis. To date, however, beyond our preliminary results, there is a paucity of in vivo data on the effect of disrupting CCL20-CCR6 interactions in colorectal cancer in the setting of an intact immune system. We have demonstrated that both CCL20 and CCR6 are upregulated in human colon cancers. We have found that deficiency of CCR6 is associated with a dramatic decrease in adenoma formation in a model of spontaneous intestinal carcinogenesis and a marked decrease in tumor growth in a syngeneic transplantable tumor model. We have observed that CCL20 signaling through CCR6 induces further secretion of CCL20, and this in turn promotes proliferation and migration in colorectal cancer cells. In addition to the epithelial cell effects of CCL20-CCR6 interactions, a stromal effect is evidenced by the fact that in the tumor challenge experiments, the transplanted colon cancer cells expressed CCR6 in both arms, yet growth was delayed in CCR6-deficient host mice. We have found that CCR6 deficiency is associated with decreased macrophage migration into adenomas and transplanted colon cancers. We have further demonstrated that CCL20-CCR6 interactions indeed induce monocyte/macrophage migration in vitro and in vivo. Furthermore, we have observed that growth of transplanted colon cancer tumors is delayed by depletion of tumor macrophages. Lastly, we have found that tumor macrophages secrete inflammatory mediators, which in turn induce proliferation of colon cancer cells. In aggregate our preliminary results imply that CCL20-CCR6 signaling promotes colorectal cancer through a direct effect on neoplastic cancer cells as well as through effects on tumor stromal cells such as macrophages. We have recently begun to test a novel, orally-available small molecule CCR6 inhibitor. Our preliminary data show that this molecule can inhibit the CCL20 auto feedback loop, colorectal cancer cell proliferation, and monocyte migration in vitro. Thus we hypothesize that targeting interactions between CCL20 and CCR6 is effective for the treatment of colorectal cancer. To test this hypothesis and to further elucidate the role of CCR6 and CCL20 in colorectal cancer, we aim to: 1) establish the impact of targeting CCL20-CCR6 interactions on the neoplastic epithelial cells in colorectal cancer; 2) establish the outcome of targeting CCL20-CCR6 interactions on tumor-promoting stroma in colorectal cancer; and 3) establish the efficacy of targeting CCL20-CCR6 interactions in translationally relevant models of human colorectal cancer. The proposed studies will shed light on the role of the chemokine receptor CCR6 and its ligand CCL20 in colorectal cancer. We believe that these studies will determine the clinical relevance and therapeutic importance of interactions between CCR6 and CCL20 in this disease and should pave the way to successful targeting of this pathway in human patients.