Toll-like Receptor Regulation of Pancreatic Tumorigenesis

胰腺肿瘤发生的 Toll 样受体调节

• 批准号: 9233927
• 负责人: George Miller
• 金额: $ 35.17万
• 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 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9233927
• 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; Early treatment; Elements; Epithelial; Epithelial Cells; Epithelium; Fibrosis; Genes; Growth Factor; Human; Individual; Inflammation; Inflammation Mediators; Inflammatory; Insulin-Like Growth Factor II; Interleukin-6; Investigation; Investigational Therapies; Island; Lead; Ligands; Ligation; Link; MAP Kinase Gene; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mediator of activation protein; Mitogen-Activated Protein Kinases; 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; Recruitment Activity; Regulation; Risk; Role; STAT3 gene; Signal Transduction; Sterility; Stimulus; TLR4 gene; TLR7 gene; TP53 gene; Testing; Therapeutic Intervention; Toll-like receptors; Translations; Tumor Suppressor Genes; Tumorigenicity; Work; base; c-myc Genes; carcinogenesis; carcinogenicity; cell injury; cell transformation; chronic pancreatitis; cyclin B1; cytokine; experimental study; in vivo; inhibitor/antagonist; insight; macrophage; mouse model; neoplastic; notch protein; novel; pancreatic neoplasm; pancreatic tumorigenesis; prevent; public health relevance; receptor expression; therapy development; 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-κB 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(申请人提供)：胰腺癌不同于大多数上皮性癌症，因为肿瘤肿块主要由纤维炎症间质组成。胰腺肿瘤间质的作用最近已经上升，并已被证明对肿瘤生长和侵袭性都是必不可少的。因此，靶向间质是一种有吸引力的实验治疗方法；然而，间质扩张的调节因素以及炎性间质和转化的上皮间质之间的生化串扰却知之甚少。在这个方案中，我们将确定Toll样受体(TLR)连接是否是间质的主要驱动因素 胰腺癌中的炎症和上皮细胞突变，并阐明介导其作用的新的下游信号机制和炎症细胞亚群。我们发现胰腺癌肿瘤微环境中充满了可作为TLRs配体的无菌炎症副产物。这一观察结合我们的初步工作表明，TLR在浸润性人和小鼠胰腺癌的不同细胞阵列上显著上调，从而使我们假设TLR结扎推动间质进展。此外，我们认为抑制TLR可以通过消除炎性结缔组织增生来潜在地预防或治疗早期胰腺癌。在目标1中，我们将确定人类胰腺癌的临床病理特征和预后与TLR表达的关系，以及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，我们将研究TLR抑制在胰腺肿瘤发生中的作用，并确定TLR的激活除了促进瘤周纤维炎症外，是否在上皮室内具有直接的突变作用。在目标3中，我们将研究TLR激活下游肿瘤进展的特定细胞和生化介质。我们推测，肿瘤周围树突状细胞和巨噬细胞上的TLR结扎通过典型的NF-κB和MAP-Kinase通路导致强烈的炎症。我们强有力的初步数据进一步表明，TLR介导的炎症在这些细胞中提供了IL-6和其他促炎细胞因子，促进了Kras突变的上皮细胞中STAT3的磷酸化，导致上皮和间质中的Notch激活。这是对胰腺疾病中TLR-STAT3-Notch界面的首次研究。此外，在初步数据的支持下，我们认为这种相互激活的环路促进了上皮室明显的侵袭性致癌表型，其特征是许多细胞周期调节因子(p16、p21、p27、p53、Cyclin B1、Cyclin D1)和致癌基因(c-myc、Rb和SHPTP1)的表达异常。我们相信，这个方案中的实验将为调节肿瘤周围炎症和间质-上皮细胞的相互作用提供重要的洞察力。 并为将我们的工作转化为利用临床级TLR抑制剂进行有前景的临床试验提供了科学基础。