Targeting CCL20-CCR6 Interactions in Colorectal Cancer

在美国，近20%的人会在一生中被诊断出患有结直肠癌，超过三分之一的人 这些人会死于这种疾病。事实上，结直肠癌是与癌症有关的第二大原因。 这个国家的死亡人数。在预防和治疗方面的进步仅对 发病率和存活率。显然需要针对结直肠癌的新的治疗策略。趋化因子 已经成为促进肿瘤的炎症和癌症之间的关键联系。CCR6是唯一的 已知的炎性趋化因子CCL20的受体，而CCR6是唯一已知的配体。 多条证据表明，炎性趋化因子CCL20与其相互作用 受体CCR6在结直肠癌的发生发展中起关键作用。相关 有证据表明，CCR6和CCL20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，体内还缺乏 阻断CCL20-CCR6相互作用在结直肠癌中的作用 免疫系统。我们已经证明CCL20和CCR6在人的结肠中表达上调 癌症。我们发现CCR6的缺失与腺瘤的急剧减少有关。 自发性小肠癌变模型的形成和小鼠肿瘤生长的显著减少 同基因可移植肿瘤模型。我们观察到CCL20通过CCR6信号诱导 进一步分泌CCL20，进而促进结直肠癌细胞的增殖和迁移。 除了CCL20-CCR6相互作用的上皮细胞效应外，还有一种间质效应是由 在肿瘤攻击实验中，移植的结肠癌细胞在两者中都表达CCR6 然而，CCR6缺陷的宿主小鼠的生长被延迟。我们发现CCR6缺陷是 与巨噬细胞向腺瘤和移植结肠癌的迁移减少有关。我们 进一步证明CCL20-CCR6相互作用确实诱导单核/巨噬细胞迁移 在体外和体内。此外，我们观察到移植的结肠癌肿瘤的生长是 因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 炎性介质，进而诱导结肠癌细胞增殖。总计我们的 初步结果提示，CCL20-CCR6信号通过直接作用于 通过对肿瘤间质细胞，如巨噬细胞的作用。我们有 最近开始测试一种新型的口服小分子CCR6抑制剂。我们的初步数据显示 该分子可以抑制CCL20自动反馈环，抑制结直肠癌细胞的增殖，以及 单核细胞体外迁移。因此，我们假设CCL20和CCR6之间的靶向相互作用为 对治疗结直肠癌有效。来检验这一假说，并进一步阐明 CCR6和CCL20在结直肠癌中的作用，我们的目标是：1)建立靶向CCL20-CCR6的影响 结直肠癌中肿瘤上皮细胞的相互作用；2)建立靶向结果 CCL20-CCR6在结直肠癌促肿瘤间质中的相互作用；以及3)建立 在翻译相关的人类结直肠癌模型中靶向CCL20-CCR6相互作用。这个 拟议的研究将阐明趋化因子受体CCR6及其配体CCL20在 结直肠癌。我们相信这些研究将确定临床相关性和治疗效果。 CCR6和CCL20之间的相互作用在本病中的重要性，并应为 在人类患者中成功地靶向了这一途径。

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.