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）仍是第二大恶性肿瘤。 这些死亡中的大多数是由于癌症的进展和随后的 转移性疾病和治疗抗性的发展。新的目标，理想的目标，其抑制可以 抑制肿瘤生长、转移和治疗抗性。积累使用数据 非甾体抗炎药的研究表明，抑制炎症可显著降低 癌症死亡，特别是CRC，表明炎症可能是癌症进展的关键驱动因素， 结肠炎相关癌症的罕见病例之外的转移。我们假设，许多显然“非- 炎性”实体瘤具有令人惊讶的招募免疫细胞和上调炎性细胞的能力。 介质-称为“肿瘤引起的炎症”（TEI）的现象。然而，确切的分子和细胞 炎症如何调节癌症进展、转移和治疗抗性的机制尚不完全清楚。 这可能会延迟癌症新靶点的识别和验证。 在我们的初步研究中，我们特别鉴定了IL-17 B及其受体IL-17 RB途径：1） 在炎症、CAC和CRC中上调; 2）与人类患者的不良预后相关， 表达抑制特异性抗肿瘤免疫应答所需的免疫检查点; 3） 对于CAC和CRC进展和炎症是必需的4）其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5）一个途径，控制这两个 癌细胞和骨髓细胞的微环境。这表明IL-17 B/RB信号传导是一个关键的调节器， TEI和CRC肿瘤发生。在这里，我们将通过定义IL-17 B/RB的贡献来检验这一假设。 向CRC进展、转移和对治疗的反应发出信号，并评估其作用机制， 使用模拟人类CAC和CRC疾病的多等位基因复合遗传小鼠模型。由于IL-17 RB是 由上皮（癌）细胞和髓样细胞表达，我们开发了新的，条件性的IL-1模型。 在每种细胞类型中的IL-17 RB缺陷，使我们能够剖析TEI中IL-17 RB信号传导的细胞类型特异性作用。 本项目的具体目的如下：（1）定义IL-17 RB信号转导及其对IL-17 RB信号转导的贡献。 在CRC肿瘤发生中的作用机制。(2)阐明IL-17 RB在CRC进展中的作用， 转移（三）、评估IL-17 RB的治疗靶向以抑制炎症和CRC肿瘤发生。 总的来说，这些研究将建立通过靶向IL-10特异性抑制炎症的基本原理。 17 RB通路作为阻止CRC生长、进展和转移的策略。我们的长期目标是更好地 了解CRC进展中炎症环境的组成部分，从而定义分子 预测原发和复发转移，从而改善CRC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.