MMP-7 IN Pacreatic Cancer and Chronic Pancreatitis

描述(申请人提供)：胰腺癌是美国癌症相关死亡的第五大常见原因，部分原因是难以及早发现，部分原因是它对传统癌症治疗方法具有抵抗力。因此，项目研究组报告中提出了一项倡议：“胰腺癌：行动议程”，以鼓励对胰腺肿瘤生物学和可靠的检测和治疗方法的研究。考虑到这一点，我们已经开始探索胰腺癌的一些基本肿瘤生物学，重点是基质金属蛋白酶-7(MMP7)的功能和表达。众所周知，在慢性胰腺炎(CP)的背景下，上皮化生会使胰腺导管腺癌(PDAC)的风险增加16-50倍。基质金属蛋白酶-7在93%的慢性胰腺炎和100%的胰腺导管腺癌(PDAC)化生管样上皮细胞中表达，在98%的PDAC组织肿瘤细胞中表达。基质金属蛋白酶-7与胰腺疾病之间的这种惊人的联系导致了发现，在基质金属蛋白酶-7基因缺失的小鼠中，CP受到严重抑制，包括几乎完全消除导管化生。在这一应用中，我们建议检验总体假设，即基质金属蛋白酶-7及其调节其表达的蛋白质都是诱导胰腺导管化生的必要条件和充分条件，有助于PDAC的启动和进展。具体地说，我们将测试在体外，对于导管上皮化生，基质金属蛋白酶-7活性是否是必要的和充分的。我们还将分析在小鼠PDAC模型中，基质金属蛋白酶-7功能是否在PDAC的形成、进展和侵袭过程中是必需的。最后，我们将研究胰腺/十二指肠同源盒蛋白(PDX-1)和AP-1因子c-jun这两种可能的基质金属蛋白酶-7表达激活剂的活性，以研究它们在永生胰管细胞和人PDAC细胞系中调节基质金属蛋白酶-7和改变肿瘤细胞行为的能力。我们还将研究PDX-1在体内调节小鼠化生模型中基质金属蛋白酶-7表达的作用。总体而言，我们希望这些研究将对我们的胰腺肿瘤生物学知识做出重大贡献，并对检测和治疗产生直接影响。

DESCRIPTION (provided by applicant): Pancreatic cancer is the 5th most common cause of cancer-related death in the United States, partly due to difficulties with early detection and partly due to its resistance to conventional cancer therapies. As such, an initiative has been put forth in the Program Research Group Report: "Pancreatic Cancer: An Agenda for Action" to encourage study of pancreatic tumor biology and reliable methods for detection and treatment. With this in mind, we have begun to explore some of the fundamental tumor biology of pancreatic cancer, focusing on the function and expression of matrix metalloproteinase-7 (MMP-7). It is known that epithelial metaplasia in the context of chronic pancreatitis (CP) increases the risk for pancreatic ductal adenocarcinoma (PDAC) by 16-50 fold. Matrix metalloproteinase-7 (MMP-7) is expressed in metaplastic duct-like epithelium in 93% and 100% of chronic pancreatitis and pancreatic ductal adenocarcinoma (PDAC) samples, respectively, and in tumor cells in 98% of PDAC samples. This striking association between MMP- 7 and pancreatic disease has led to the discovery that CP is severely inhibited in MMP-7 null mice, including an almost complete abrogation of ductal metaplasia. In this application, we propose to test the overall hypothesis that MMP-7 and proteins that regulate its expression are both necessary and sufficient to induce pancreatic ductal metaplasia, contributing to PDAC initiation and progression. Specifically, we will test if MMP-7 activity is necessary and sufficient for ductal metaplasia both in vitro. We will also analyze if MMP-7 function is necessary for PDAC formation, progression and invasion in mouse PDAC models. Finally, we will study the activity of two putative activators of MMP-7 expression, the pancreatic/duodenal homeobox protein (Pdx-1) and the AP-1 factor c-Jun, to study their ability to regulate MMP-7 and alter tumor cell behavior in immortal pancreatic duct cells and in human PDAC cell lines. We will also examine the role of Pdx-1 in regulating MMP-7 expression in mouse models of metaplasia in vivo. Overall, we expect these studies to contribute significantly to our knowledge of pancreatic tumor biology with immediate implications with regards to detection and treatment.