Toll-like Receptor Regulation of Pancreatic Tumorigenesis

胰腺肿瘤发生的 Toll 样受体调节

• 批准号: 8635316
• 负责人: George Miller
• 金额: $ 34.12万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8635316
• 关键词: Adenocarcinoma; Affect; Apoptotic; Binding; Biochemical; Cancer Etiology; Cell Cycle; Cells; Cessation of life; Chronic; Clinical; Clinical Trials; Cyclin D1; Data; Dendritic Cells; Development; Disease; Disease Outcome; Ductal Epithelial Cell; Elements; Epithelial; Epithelial Cells; Fibrosis; Genes; Growth Factor; HC phosphatase; Human; Individual; Inflammation; Inflammation Mediators; Inflammatory; Insulin-Like Growth Factor II; Interleukin-6; Investigation; Island; Lead; Ligands; Ligation; Link; MAP Kinase Gene; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mediator of activation protein; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mus; Mutagenesis; Mutate; Natural Immunity; Neoplasms; Nutrient; Oncogenic; Outcome; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Diseases; Pancreatic Ductal Carcinoma; Pancreatic carcinoma; Pathologic; Pathway interactions; Pattern; Pattern recognition receptor; Phenotype; Phosphorylation; Platelet-Derived Growth Factor; Prevention; Production; Receptor Activation; Receptor Inhibition; Receptor Signaling; Regulation; Risk; Role; STAT3 gene; Signal Transduction; Sterility; Stimulus; TLR4 gene; TLR7 gene; Testing; Therapeutic; Therapeutic Intervention; Toll-Like Receptor Pathway; Toll-like receptors; Translations; Tumor Suppressor Genes; Work; base; c-myc Genes; cancer therapy; carcinogenesis; cell injury; cell transformation; chronic pancreatitis; cyclin B1; cytokine; in vivo; inhibitor/antagonist; insight; macrophage; neoplastic; notch protein; novel; pancreatic neoplasm; pancreatic tumorigenesis; prevent; public health relevance; receptor expression; research study; therapy development; toll-like receptor 4; tumor; tumor growth; tumor microenvironment; tumor progression; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Pancreatic adenocarcinoma is distinct from most epithelial-based cancers in that the tumor mass is overwhelmingly composed of fibro-inflammatory stroma. The role of the pancreatic tumor stroma has recently risen in profile and has been shown to be essential for both tumor growth and invasiveness. Thus, targeting the stroma is an attractive approach to experimental therapeutics; however, the regulators of stromal expansion and the biochemical crosstalk between the inflammatory stromal compartment and the transformed epithelial compartment are poorly understood. In this proposal we will determine whether Toll-like receptor (TLR) ligation is a primary driver of stromal inflammation and epithelial mutagenesis in pancreatic carcinoma and elucidate the novel downstream signaling mechanisms and inflammatory cellular subsets that mediate its effects. We have found that the pancreatic cancer tumor microenvironment is rife with the byproducts of sterile inflammation that can act as ligands for TLRs. This observation - combined with our preliminary work demonstrating that TLRs are markedly upregulated on a diverse array of cells infiltrating human and murine pancreatic carcinomas - led us to postulate that TLR ligation drives stromal advancement. Moreover, we propose that TLR inhibition can potentially prevent or treat early pancreatic cancer by abrogating inflammatory desmoplasia. In Aim 1 we will determine the relationship between clinico-pathologic features and outcome in human pancreatic cancer and TLR expression as well as determine whether the progression of human chronic pancreatitis to pancreatic cancer is correlated with TLR expression levels. We will also test the effects of TLR activation on pancreatic carcinogenesis in murine models. In Aim 2 we will examine the effect of TLR inhibition on pancreatic tumorigenesis and determine whether TLR activation has direct mutagenic effects within the epithelial compartment in addition to promoting peri-tumoral fibro-inflammation. In Aim 3 we will investigate the specific cellular and biochemical mediators of tumor progression downstream of TLR activation. We postulate the TLR ligation on peri-tumoral dendritic cells and macrophages leads to intense inflammation via canonical NF-?B and MAP-Kinase pathways. Our robust preliminary data further suggest that TLR-mediated inflammation in these cells provide IL-6 and other pro-inflammatory cytokines that promote STAT3 phosphorylation in the Kras-mutated epithelial cells leading to Notch activation in both epithelial and stromal compartments. This is the first investigation of a TLR-STAT3-Notch interface in pancreatic disease. Additionally, bolstered by preliminary data, we propose that this reciprocal activation loop promotes a distinctly aggressive oncogenic phenotype in the epithelial compartment, characterized by dysregulated expression of numerous cell cycle regulators (p16, p21, p27, p53, Cyclin B1, Cyclin D1) and oncogenic genes (c-myc, Rb, and SHPTP1). We believe that the experiments in this proposal will provide important insight into the regulation of peritumoral inflammation and stromal-epithelial cross-talk in pancreatic cancer and provide the scientific basis for the translation of our work to promising clinical trials utilizing clinical-grade TLR inhibitors.

描述（由申请人提供）：胰腺癌与大多数上皮性癌症的不同之处在于肿瘤块绝大多数由纤维炎性间质组成。胰腺肿瘤间质的作用最近在轮廓中上升，并且已被证明对于肿瘤生长和侵袭性都是必不可少的。因此，靶向间质是实验治疗的一种有吸引力的方法;然而，对间质扩张的调节剂以及炎性间质区室和转化的上皮区室之间的生化串扰知之甚少。在这项提议中，我们将确定Toll样受体（TLR）连接是否是间质细胞增殖的主要驱动因素。 胰腺癌中的炎症和上皮突变，并阐明新的下游信号传导机制和介导其作用的炎性细胞亚群。我们发现胰腺癌肿瘤微环境中充满了无菌炎症的副产物，这些副产物可以作为TLR的配体。这一观察结果-结合我们的初步工作表明TLR在浸润人类和小鼠胰腺癌的多种细胞上显著上调-使我们假设TLR连接驱动基质进展。此外，我们认为TLR抑制可能通过消除炎性结缔组织增生来预防或治疗早期胰腺癌。在目的1中，我们将确定人类胰腺癌的临床病理特征和结果与TLR表达之间的关系，以及确定人类慢性胰腺炎向胰腺癌的进展是否与TLR表达水平相关。我们还将在小鼠模型中测试TLR激活对胰腺癌发生的影响。在目标2中，我们将检查TLR抑制对胰腺肿瘤发生的影响，并确定TLR激活除了促进肿瘤周围纤维炎症外，是否在上皮隔室内具有直接致突变作用。在目标3中，我们将研究TLR激活下游肿瘤进展的特异性细胞和生化介质。我们假设TLR连接肿瘤周围的树突状细胞和巨噬细胞导致强烈的炎症，通过典型的NF-？B和MAP激酶途径。我们稳健的初步数据进一步表明，这些细胞中TLR介导的炎症提供IL-6和其他促炎细胞因子，其促进Kras突变的上皮细胞中的STAT 3磷酸化，导致上皮和基质区室中的Notch活化。这是首次研究胰腺疾病中TLR-STAT 3-Notch界面。此外，初步数据的支持下，我们提出，这种相互激活循环促进了一个明显的侵略性的致癌表型在上皮隔室，其特征是许多细胞周期调节因子（p16，p21，p27，p53，细胞周期蛋白B1，细胞周期蛋白D1）和致癌基因（c-myc，Rb和SHPTP 1）的表达失调。我们相信，这项建议中的实验将为肿瘤周围炎症和基质-上皮串扰的调节提供重要的见解 在胰腺癌中，并为我们的工作转化为利用临床级TLR抑制剂的有前途的临床试验提供科学依据。