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，部分原因是早期检测困难，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。已知在慢性胰腺炎（CP）背景下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（MMP-7）分别在93%和100%的慢性胰腺炎和胰腺导管腺癌（PDAC）样本中的化生导管样上皮中表达，并且在98%的PDAC样本中的肿瘤细胞中表达。MMP- 7和胰腺疾病之间的这种显著关联导致发现CP在MMP-7缺失小鼠中被严重抑制，包括几乎完全消除导管化生。在本申请中，我们建议测试MMP-7和调节其表达的蛋白质是诱导胰腺导管化生所必需的且足够的，从而有助于PDAC的启动和进展的总体假设。具体来说，我们将测试MMP-7活性是否是必要的，足够的导管化生都在体外。我们还将分析MMP-7的功能是否是PDAC形成所必需的，在小鼠PDAC模型中的进展和侵袭。最后，我们将研究MMP-7表达的两个假定的激活剂，胰腺/十二指肠同源盒蛋白（Pdx-1）和AP-1因子c-Jun的活性，以研究它们调节MMP-7和改变永生胰腺导管细胞和人PDAC细胞系中肿瘤细胞行为的能力。我们还将研究Pdx-1在体内化生小鼠模型中调节MMP-7表达的作用。总的来说，我们希望这些研究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.