Interplay of Tumor Microenvironment and MUC4 in Pancreatic Cancer

胰腺癌微环境与MUC4的相互作用 临床上，MUC4粘蛋白在胰腺癌(PC)组织中异常过表达，其表达 预后不良(1)。我们实验室的研究已经确凿地证明MUC4是 参与增强肿瘤细胞的体外运动性、侵袭性和耐药性，并促进 体内成瘤和转移(2)。MUC4上调是胰腺癌的早期事件之一 在前驱病变中表达上调(3)。我们之前的研究已经证明，MUC4 胰腺癌细胞的表达部分受干扰素-γ等细胞因子的调节，这些细胞因子可能会分泌 肿瘤细胞/炎性胰腺微环境。炎症被认为是癌症的先兆， 在胰腺癌的情况下，越来越多的证据支持胰腺炎与胰腺的关联 癌症的风险/发展强调了炎症在这种致命的恶性肿瘤中的重要性。因此，它不是 令人惊讶的是，与高水平的MUC4一样，肿瘤中高水平的促炎细胞因子(IL-1和IL-12) 与预后不良相关(4)。鉴于炎症和MUC4参与的重要性 胰腺癌的发生和炎性细胞因子如干扰素-γ对MUC4的调节 本研究的目的是了解肿瘤对MUC4表达的调节 微环境MUC4与肿瘤微环境的另一个方面是MUC4相互作用的能力 结合并可能通过独特的结构域(NIDO)调节细胞外基质的成分。然而，为了 保持提案的重点，避免与我们正在进行的研究重叠，这是当前应用的重点 肿瘤微环境(TME)对MUC4的调节作用。

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).