Pancreatic cancer is characterized by local invasion of adjacent structures, perineural invasion, early metastases to lymph nodes and liver, and an intense desmoplastic stromal reaction. Our understanding of the highly invasive nature of this disease, however, is severely deficient. Recently, we have made the novel finding that kallikrein 7 (KLK7) is overexpressed in pancreatic ductal adenocarcinomas (PDAC). Using a series of in vitro experiments, we have further demonstrated that KLK7 may participate both directly and indirectly in processes that facilitate the ability of pancreatic tumors to invade surrounding tissues including the shedding of E-cadherin, cleavage of fibronectin, loss of adhesion to vitronectin, degradation of desmoglein-2, and activation of proMMP-9. In preliminary studies, to examine the functional significance of KLK7 expression in pancreatic tumors, we have utilized shRNA-mediated suppression of KLK7 in tumor xenografts derived from pancreatic cancer cell lines inoculated subcutaneously in immunodeficient mice. KLK7 suppression resulted in a dramatic decrease in tumor growth;thus providing compelling evidence that aberrant expression of KLK7 in the pancreas plays an important role in pancreatic tumorigenesis. Based on our published and preliminary findings, we hypothesize that KLK7 is aberrantly expressed in pancreatic adenocarcinomas due to altered promoter methylation, which results in inappropriate induction of proteolytic activity that facilitates tumor invasion and metastasis and enhances pancreatic tumor growth. We will test these hypotheses through the following specific aims: 1) Examine the effects of suppression of KLK7 expression on pancreatic tumor development, growth, and invasion using experimental models of pancreatic cancer. 2) Examine the mechanism(s) regulating KLK7 expression in pancreatic cancer. 3) Examine downstream effects of KLK7 proteolytic activity in pancreatic cancer cells. These studies will help fill the deficits in our knowledge regarding the deregulated cellular processes that develop in pancreatic cancer that produces highly aggressive tumors and extremely poor patient outcomes and may provide insights into novel therapeutic interventions that target either KLK7 expression and/or its proteolytic activity leading to new treatments for this devastating disease.

Public Health Relevance

Pancreatic cancer is a devastating disease that has the lowest survival rate for any solid cancer. Other than cigarette smoking, few risk factors have shown a strong and consistent association with the development of pancreatic cancer. The one consistent risk factor for pancreatic cancer, however, is chronic pancreatitis, which is a significant health concern in the Veterans'patient population. One of the hallmarks of pancreatic cancer is its early systemic dissemination. Unfortunately, little is known about how cancer cells detach from the primary tumor site and grow in distant organs. Based on the observation that the protease kallikrein 7 is overexpressed in pancreatic tumors, we will investigate its role in pancreatic cancer. The results of these studies, therefore, will help fill the void in our understanding of this devastating disease and may provide novel treatment strategies.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX000828-02
Application #
8318551
Study Section
Oncology A (ONCA)
Project Start
2011-07-01
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
Indirect Cost
Name
Central Arkansas Veterans Hlthcare Sys
Department
Type
DUNS #
082573742
City
North Little Rock
State
AR
Country
United States
Zip Code
72114
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Herzog, Christian; Marisiddaiah, Raju; Haun, Randy S et al. (2015) Basement membrane protein nidogen-1 is a target of meprin ? in cisplatin nephrotoxicity. Toxicol Lett 236:110-6
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Kaushal, Varsha; Herzog, Christian; Haun, Randy S et al. (2014) Caspase protocols in mice. Methods Mol Biol 1133:141-54
Herzog, Christian; Haun, Randy S; Ludwig, Andreas et al. (2014) ADAM10 is the major sheddase responsible for the release of membrane-associated meprin A. J Biol Chem 289:13308-22
Kaushal, Gur P; Haun, Randy S; Herzog, Christian et al. (2013) Meprin A metalloproteinase and its role in acute kidney injury. Am J Physiol Renal Physiol 304:F1150-8
Makawita, Shalini; Dimitromanolakis, Apostolos; Soosaipillai, Antoninus et al. (2013) Validation of four candidate pancreatic cancer serological biomarkers that improve the performance of CA19.9. BMC Cancer 13:404
Mercado, Charles P; Byrum, Stephanie; Beggs, Marjorie L et al. (2013) Impact of elevated plasma serotonin on global gene expression of murine megakaryocytes. PLoS One 8:e72580

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