MMP-7 IN Pacreatic Cancer and Chronic Pancreatitis

描述（由申请人提供）：胰腺癌是美国癌症相关死亡的第五大常见原因，部分原因是早期发现困难，部分原因是其对常规癌症治疗的耐药性。因此，在项目研究小组报告“胰腺癌：行动议程”中提出了一项倡议，以鼓励研究胰腺肿瘤生物学和可靠的检测和治疗方法。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，重点关注基质金属蛋白酶-7 （MMP-7）的功能和表达。众所周知，慢性胰腺炎（CP）的上皮化生使胰腺导管腺癌（PDAC）的风险增加16-50倍。基质金属蛋白酶-7 （Matrix metalloproteinase-7, MMP-7）分别在93%和100%的慢性胰腺炎和胰腺导管腺癌（pancreatic ductal adencarcinoma， PDAC）样本的化生导管样上皮和98%的PDAC样本的肿瘤细胞中表达。MMP-7与胰腺疾病之间的这种惊人关联导致发现，在MMP-7缺失的小鼠中，CP受到严重抑制，包括几乎完全消除了导管化生。在本应用中，我们建议验证MMP-7及其表达调节蛋白是诱导胰腺导管化生的必要条件和充分条件，从而促进PDAC的发生和进展。具体来说，我们将在体外测试MMP-7活性对于导管化生是否必要和充分。我们还将分析小鼠PDAC模型中MMP-7的功能是否对PDAC的形成、进展和侵袭是必要的。最后，我们将研究两种可能的MMP-7表达激活因子的活性，胰腺/十二指肠同源盒蛋白（Pdx-1）和AP-1因子c-Jun，以研究它们在永生胰管细胞和人PDAC细胞系中调节MMP-7和改变肿瘤细胞行为的能力。我们还将在小鼠体内化生模型中研究Pdx-1在调节MMP-7表达中的作用。总的来说，我们希望这些研究能够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.