Microenvironment Interleukin-17 and Colorectal Cancer Treatment Resistance

 描述（由申请人提供）：尽管临床进展，但结直肠癌（CRC）仍然是全世界癌症相关死亡的主要原因。由于CRC治愈的最大障碍之一是手术后无法对辅助化疗实现持久反应，因此分析治疗耐药的机制既及时又具有临床意义。癌症起始细胞（CIC）有助于肿瘤血管生成、侵袭/转移和治疗抗性。我们发现了一种新的现象，即化疗激活癌症相关成纤维细胞（CAF），释放外源性信号，主要是白细胞介素17 A（IL 17 A），通过增加CRC CIC增殖，迁移，肿瘤生长和化疗耐药性重塑肿瘤微环境。这些作用在体外和体内均通过IL 17 A抑制而减轻，表明了干预的潜在靶点。IL-1刺激导致Act 1向IL-17 R募集，并在结肠上皮细胞中激活多种增殖和细胞存活途径（包括NF-κ B、JNK、p38、ERK），但IL-17 A在CIC中的作用尚不明确。在评估人类IL 17 A时，我们发现CRC患者的表达不同，表达增加与预后不良相关。这些观察结果表明IL 17 A影响患者的结果，但这种影响的细节尚不清楚。基于这一背景，我现在将研究一种关键细胞因子（IL 17 A）在CIC维持和治疗耐药性中的作用。我推测，IL 17 A，来自于激活CAFs在肿瘤微环境中，重塑细胞层次结构，促进CIC的维持和治疗抗性。在第一个目标中，我将阐明IL 17 R-Act 1轴增强人类CIC肿瘤发生和化疗耐药性的分子机制。在第二个目标中，我将确定在CRC中使用培养的人CIC和体内小鼠CRC模型靶向IL 17 A诱导的信号传导的治疗益处，采用包括化疗、IL 17抑制和MEK/ERK抑制的组合疗法。最后，我将探索IL 17在离体人CRC标本中的作用与遗传和临床特征的相关性，以开发生物标志物谱。拟议的工作将深入了解推动CRC治疗耐药性的分子机制，测试新的治疗组合，并确定适合这些治疗的适当患者人群，所有这些都将导致改善CRC患者生存率的长期目标。

 DESCRIPTION (provided by applicant): Despite clinical advances, colorectal cancer (CRC) remains a leading cause of cancer-related death throughout the world. As one of the greatest barriers to CRC cure is the inability to achieve a durable response to adjuvant chemotherapy after surgery, it is both timely and clinically relevant to dissect the mechanisms underlying therapeutic resistance. Cancer initiating cells (CICs) contribute to tumor angiogenesis, invasion/metastasis, and therapeutic resistance. We identified a novel phenomenon that chemotherapy activates cancer associated fibroblasts (CAFs), with release of extrinsic signals, mainly interleukin 17A (IL17A), which remodels the tumor microenvironment by increasing CRC CIC proliferation, migration, tumor growth, and chemoresistance. These effects were mitigated by IL17A inhibition both in vitro and in vivo, suggesting a potential target for intervention. IL-1 stimulation leads to recruitment of Act1 to IL-17R and elicits multiple proliferative and cell survival pathways (including NF-kB, JNK, p38, ERK) in colon epithelial cells, but the role of IL17A in CICs is uncharacterized. When evaluating IL17A in humans, we found expression varies among CRC patients and increased expression is associated with worse outcomes. These observations suggest IL17A influences patient outcome, but details of this effect are not understood. Based on this background, I will now investigate the role of a critical cytokine (IL17A) in CIC maintenance and therapeutic resistance. I hypothesize that IL17A, derived from activated CAFs in the tumor microenvironment, remodels the cellular hierarchy and promotes CIC maintenance and therapy resistance. In the first aim, I will elucidate the molecular mechanism by which the IL17R-Act1 axis enhances human CIC tumorigenesis and chemoresistance. In the second aim, I will determine the therapeutic benefit of targeting IL17A-induced signaling in CRC using human CICs in culture and in vivo mouse CRC models, employing combination therapies including chemotherapy, IL17 inhibition, and MEK/ERK inhibition. Lastly, I will explore the effects of IL17 in ex vivo human CRC specimens with correlation to genetic and clinical characteristics to develop a biomarker profile. The proposed work will provide insight to molecular mechanisms driving CRC treatment resistance, test novel treatment combinations, and identify an appropriate patient population suited for these treatments, all of which will lead toward the long-term goal of improving survival for CRC patients.