The role of Interleukin 17RB signaling in colorectal cancer progression

尽管在检测、手术和化疗方面取得了重要进展，但结直肠癌(CRC)仍排在第二位 美国癌症死亡原因。这些死亡中的大多数是由于癌症的进展和随后的 转移性疾病的发展和治疗耐药。新的目标，理想的目标是其抑制可能 抑制肿瘤生长、转移和治疗耐药仍然是迫切需要的。积累有关使用情况的数据 对非类固醇抗炎药物的研究表明，抑制炎症显著降低了 癌症死亡，特别是在结直肠癌中，表明炎症可能是癌症进展和 结肠炎相关癌症罕见病例以外的转移。我们推测许多人显然是“非-- “炎性”实体瘤有惊人的能力招募免疫细胞并上调炎症。 介质--一种名为“肿瘤引发的炎症”(TEI)的现象。然而，确切的分子和细胞 炎症如何调节癌症进展、转移和治疗耐药的机制还不完全 理解，推迟癌症新靶点的识别和验证。 在我们的初步研究中，我们特异性地确定了IL-17B及其受体IL-17RB途径如下：1) 炎症、CAC和CRC的上调；2)与人类患者的不良预后相关，以及与 抑制特异性抗肿瘤免疫反应所需的免疫检查点的表达；3) 对CAC和CRC进展和炎症是必不可少的4)失活减少的分子途径 CAC和CRC，而其他已知的炎症介质仍然存在，这是一条控制这两种疾病的途径 癌细胞和髓系细胞的微环境。这表明IL-17B/RB信号是一个关键的调节因子 TEI与结直肠癌肿瘤发生的关系。在这里，我们将通过定义IL-17B/RB的贡献来检验这一假设 对结直肠癌进展、转移和治疗反应的信号传导，并评估其作用机制。 使用模仿人类CAC和CRC疾病的多等位基因复合遗传小鼠模型。就像IL-17RB一样 在上皮性(癌)细胞和髓系细胞的表达，我们开发了新的条件模型的IL- 每种细胞类型的17RB缺失，使我们能够剖析IL-17RB信号在TEI中的细胞类型特异性作用。 本项目的具体目标如下：(1)明确IL-17RB信号的贡献和它的 结直肠癌发生机制的研究。(2)阐明IL-17Rb在结直肠癌发生发展中的作用 转移。(3)。评估IL-17RB的治疗靶向性以抑制炎症和结直肠癌的发生。 总体而言，这些研究将为通过靶向IL-2来具体抑制炎症奠定理论基础。 17RB通路作为抑制结直肠癌生长、进展和转移的策略。我们的长期目标是做得更好 了解结直肠癌进展过程中炎症环境的成分，从而定义分子 预测原发和复发转移的因素，从而改善对结直肠癌的预防和治疗。

Despite important advances in detection, surgery and chemotherapy, colorectal cancer (CRC) is the second cause of cancer death in the U.S. Most of these deaths are due to cancer progression and the subsequent development of metastatic disease and therapy resistance. New targets, ideally targets whose inhibition could suppress tumor growth, metastasis and therapy resistance, are still sorely needed. Accumulating data on usage of non-steroidal anti-inflammatory drugs reveals that inhibition of inflammation remarkably lowers the risk of cancer death, especially in CRC, indicating that inflammation may be a critical driver of cancer progression and metastasis beyond rare cases of colitis-associated cancer. We postulated that many apparently “non- inflammatory” solid tumors have a surprising ability to recruit immune cells and upregulate inflammatory mediators- a phenomenon named “tumor-elicited inflammation” (TEI). However, the exact molecular and cellular mechanisms of how inflammation regulates cancer progression, metastasis and therapy resistance are not fully understood, delaying identification and validation of new targets in cancer. In our preliminary studies, we specifically identified the IL-17B, and its receptor IL-17RB, pathway as: 1) upregulated in inflammation, CAC and CRC; 2) correlated with poor prognosis in human patients, and with expression of immune checkpoints that are required for inhibition of specific anti-tumor immune responses; 3) essential for CAC and CRC progression and inflammation 4) a molecular pathway whose inactivation reduced CAC and CRC, while other known inflammatory mediators are still present 5) a pathway, which controls both cancer cells and myeloid cell of microenvironment. This suggested that IL-17B/RB signaling is a key regulator of TEI and CRC tumorigenesis. Here we will test this hypothesis by defining the contribution of IL-17B/RB signaling to CRC progression, metastasis and response to therapy, and evaluting its mechanism of action, using multi-allele composite genetic murine models that mimic human CAC and CRC disease. As IL-17RB is expressed by both epithelial (cancer) cells and myeloid cells, we developed novel, conditional models of IL- 17RB deficiency in each cell type to allow us to dissect the cell-type-specific roles of IL-17RB signaling in TEI. Specific Aims for this project are the following: (1) Define the contribution for IL-17RB signaling and its mechanism action in CRC tumorigenesis. (2) Delineate the role of IL-17RB in CRC progression and metastasis. (3). Evaluate therapeutic targeting of IL-17RB to curb inflammation and CRC tumorigenesis. Overall these studies will establish a rationale for the specific inhibition of inflammation by targeting the IL- 17RB pathway as a strategy to halt CRC growth, progression and metastasis. Our long-term goal is to better understand the components of the inflammatory milieu in CRC progression, and thus define molecular predictors of primary and recurrent metastasis, leading to improved prevention and treatment of CRC.