Interplay of Tumor Microenvironment and MUC4 in Pancreatic Cancer

胰腺癌中肿瘤微环境与 MUC4 的相互作用

• 批准号: 8566911
• 负责人: Surinder K. Batra
• 金额: $ 31.02万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8566911
• 关键词: Animal Model; Animals; Cancer cell line; Cell Line; Cells; Clinical; Cues; Development; Drug resistance; Ductal Epithelial Cell; Early Diagnosis; Environment; Enzymes; Event; Extracellular Matrix; Genes; Human; Immune; In Vitro; Inflammation; Inflammatory; Interferons; Interleukin-1; Interleukin-12; Knock-in Mouse; Laboratories; Lesion; Light; MUC4 mucin; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mediator of activation protein; NCOA3 gene; Neoplasm Metastasis; Pancreas; Pancreatitis; Regulation; Retinoic Acid Receptor; Sampling; Staging; Tissues; Transgenic Organisms; Tretinoin; Tumorigenicity; Up-Regulation; Validation; cancer risk; cell motility; chromatin remodeling; cytokine; in vivo; knockout animal; mouse model; mutant; neoplastic; neoplastic cell; outcome forecast; overexpression; pancreatic cancer cells; pancreatic neoplasm; response; tumor; tumor microenvironment; tumor progression

Interplay of tumor microenvironment and MUC4 in pancreatic cancer. Clinically, MUC4 mucin is aberrantly overexpressed in pancreatic cancer (PC) tissues and its expression is associated with poor prognosis (1). Studies from our laboratory have conclusively established that MUC4 is involved in enhanced motility, invasiveness and drug resistance of tumor cells in vitro and promotes tumorigenicity and metastasis in vivo (2). MUC4 upregulation is one of the early events in pancreatic cancer as indicated by its upregulation in precursor lesions (3). Our previous studies have demonstrated that MUC4 expression in pancreatic cancer cells in part is regulated by cytokines like IFN- y which are potentially secreted by cells of tumor/inflamed pancreas microenvironment. Inflammation is regarded as a precursor to cancer and in case of pancreatic cancer the increasing evidence supporting the association of pancreatitis to pancreatic cancer risk/development underscores the importance of inflammation in this lethal malignancy. It is thus not surprising that like high MUC4 levels, high levels of pro-inflammatory cytokines (IL-1 & IL-12) in tumor correlates with poor prognosis (4). Given the importance of inflammation and involvement of MUC4 in pancreatic cancer development, and regulation of MUC4 by inflammatory cytokines like IFN- y, the overall objective of this proposal is to understand the modulation of MUC4 expression by tumor microenvironment Another aspect of MUC4 and tumor microenvironment is the ability of MUC4 to interact with and possibly modulate the components of extracellular matrix via the unique domain (NIDO). However, to keep the proposal focused and avoid overlap with our ongoing studies the emphasis of the current application is on the regulation of MUC4 by tumor microenvironment (TME).

胰腺癌中肿瘤微环境和MUC 4的相互作用 临床上，MUC 4粘蛋白在胰腺癌（PC）组织中异常过表达，并且其表达在胰腺癌组织中异常表达。 与预后不良有关（1）。我们实验室的研究最终确定MUC 4是 参与增强体外肿瘤细胞的运动性、侵袭性和耐药性， 体内致瘤性和转移（2）。MUC 4上调是胰腺癌的早期事件之一， 通过其在前驱病变中的上调来指示（3）。我们以前的研究表明MUC 4 在胰腺癌细胞中的表达部分受到细胞因子如IFN-γ的调节， 由肿瘤细胞/发炎的胰腺微环境。炎症被认为是癌症的前兆， 在胰腺癌的情况下，越来越多的证据支持胰腺炎与胰腺癌之间的关联， 癌症风险/发展强调了炎症在这种致命恶性肿瘤中的重要性。因此不 令人惊讶的是，与高MUC 4水平一样，肿瘤中高水平的促炎细胞因子（IL-1和IL-12）也是如此。 与预后不良相关（4）。鉴于炎症的重要性和MUC 4的参与， 胰腺癌的发展，以及炎症细胞因子如IFN-γ对MUC 4的调节， 该建议的目的是了解肿瘤对MUC 4表达的调节， MUC 4和肿瘤微环境的另一个方面是MUC 4相互作用的能力， 与细胞外基质的成分，并可能通过独特的结构域（NIDO）调节。但要 保持提案的重点，避免与我们正在进行的研究重叠，即当前申请的重点 肿瘤微环境（TME）对MUC 4的调控。