The role of Interleukin 17RB signaling in colorectal cancer progression

白介素 17RB 信号在结直肠癌进展中的作用

• 批准号: 9612878
• 负责人: Sergei I. Grivennikov
• 金额: $ 51.2万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-03 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9612878
• 关键词: Alleles; Backcrossings; Biological Markers; Cancer Biology; Cancer Etiology; Carcinoma; Cause of Death; Cells; Cessation of life; Colon Carcinoma; Colorectal Cancer; Data; Detection; Deterioration; Development; Disease; Epithelial; Fluorouracil; Genetic; Glare; Goals; Growth; Human; Immune; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Interleukin-17; Interleukins; Knock-out; Knowledge; Malignant Neoplasms; Mediating; Modeling; Molecular; Mono-S; Myelogenous; Myeloid Cells; Names; Nature; Neoplasm Metastasis; Non-Steroidal Anti-Inflammatory Agents; Oncogenes; Operative Surgical Procedures; Pathway interactions; Patients; Prevention; Preventive; Recurrence; Regulation; Resistance; Role; Shapes; Signal Transduction; Site; Solid Neoplasm; Testing; Therapeutic; Time; Validation; anti-tumor immune response; cancer cell; cancer risk; cell type; chemotherapy; colitis associated cancer; colon cancer patients; colorectal cancer metastasis; colorectal cancer progression; colorectal cancer treatment; cytokine; defined contribution; immune checkpoint; improved; inflammatory milieu; interleukin-17B; microbial; mouse model; neutralizing antibody; novel; outcome forecast; promoter; receptor; recruit; response; standard of care; therapeutic target; tumor; tumor growth; tumor microenvironment; tumor progression; tumorigenesis

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.

尽管在检测，手术和化学疗法方面取得了重要进展，但结直肠癌（CRC）是第二个 美国癌症死亡的原因大多数是由于癌症的进展和随后的 转移性疾病和抗治疗性的发展。新目标，理想的目标，其抑制作用 仍然需要抑制肿瘤生长，转移和耐药性。累积用法数据 非甾体类抗炎药物的抑制作用显着降低了 癌症死亡，特别是在CRC中，表明感染可能是癌症进展和 罕见的结肠炎相关癌症的转移。我们假设许多显然“非 - 炎症”实体瘤具有募集免疫细胞和上调炎症的惊喜能力 介体 - 一种名为“肿瘤引起的感染”的现象（TEI）。但是，精确的分子和细胞 炎症如何调节癌症进展，转移和耐药性的机制尚未完全 了解，延迟鉴定和验证癌症的新靶标。 在我们的初步研究中，我们专门鉴定了IL-17B及其受体IL-17RB，途径为：1） 更新炎症，CAC和CRC； 2）与人类患者的预后不良相关，与 抑制特异性抗肿瘤免疫调查的免疫切除点的表达； 3） CAC和CRC进展和炎症必不可少 CAC和CRC，而其他已知的炎症介质仍然存在5）一条途径，该途径都控制 微环境的癌细胞和髓样细胞。这表明IL-17B/RB信号是一个关键调节器 TEI和CRC肿瘤发生。在这里，我们将通过定义IL-17B/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，并评估其作用机理， 使用模仿人类CAC和CRC疾病的多代价复合遗传鼠模型。就像IL-17RB一样 通过上皮（癌）和髓样细胞表达，我们开发了新颖的IL-条件模型 每种细胞类型中的17RB缺乏，使我们能够剖析IL-17RB信号在TEI中的细胞类型特异性作用。 该项目的具体目标如下：（1）定义IL-17RB信号及其的贡献 CRC肿瘤发生中的机理作用。 （2）描述IL-17RB在CRC进展中的作用 转移。 （3）。评估IL-17RB的治疗靶向对遏制注射和CRC肿瘤发生的靶向。 总体而言，这些研究将通过靶向IL-来确定对炎症的特异性抑制作用的理由。 17RB途径是制止CRC生长，进展和转移的策略。我们的长期目标是改善 了解CRC进展中炎症环境的成分，从而定义分子 原发性和复发转移的预测因子，从而改善了CRC的预防和治疗。