Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of adult cancer mortality in the United States. In 2007, the number of new PDA cases in the United States is estimated at 37,180. Unfortunately, most will die of this disease. This type of cancer has the highest incidence in people who smoke cigarettes. Nicotine is an important component of cigarette smoke and has been shown to activate growth-promoting pathways in several cancers. However, the means through which nicotine contributes to the aggressive nature of PDA is poorly understood. There is, therefore, an urgent need to dissect the basic molecular mechanisms that are initiated by nicotine to mediate PDA progression. In this exploratory application we propose to study the signaling pathways involved in the nicotine-induced molecular and cellular changes that lead to pancreatic cancer progression. We propose to focus on the interactions of osteopontin (OPN) in pancreatic cancer cells with regard to the initiation and progression of malignancy. OPN is a secreted glycosylated protein, variably serine-phosphorylated, that binds integrins and certain CD44 variants, triggering a cascade of intracellular signaling events regulating cell motility, survival and proliferation. Our preliminary results provide novel and intriguing insights into a complex relationship among PDA, nicotine, and OPN. Addition of nicotine to pancreatic cancer cells induced a significant increase in OPN mRNA and protein expression. Moreover, rats that were exposed to cigarette smoke show a dose-dependent upregulation in pancreatic OPN mRNA and protein expression. Analysis of cancer tissue from PDA patients showed the presence of significant amounts of OPN in the pancreatic acini and in the malignant ducts. It is unknown what role, if any, OPN plays in mediating the tumorigenic effects of nicotine in pancreatic cancer. Thus, in the proposed studies we will utilize pancreatic cancer cell lines to investigate the downstream signaling pathways that are stimulated by nicotine and activated by OPN to promote carcinogenesis. We will address the involvement of OPN downstream singling pathways that involve Src, FAK, PKC, and AKT/PI 3-kinase in modulating migration and proliferation of pancreatic cancer cells. In human PDA tissue, the expression of OPN will be correlated with angiogenesis and proliferation markers and its expression levels will be compared in patients who are smokers and non-smokers in primary and metastatic sites. We hypothesize that nicotine mediates its carcinogenic effects in pancreatic cancer through enhancement of OPN expression and subsequent activation of downstream signaling events. We further propose that blocking OPN expression and/or function may represent a novel therapeutic approach to reduce pancreatic cancer cell tumorigenicity and inhibit metastasis and recurrence after surgical resection, especially in the cigarette-smoking population. Our studies will introduce novel mechanistic insights and a better understanding of the role of nicotine as a major risk factor in the development and progression of pancreatic cancer.

Public Health Relevance

In this exploratory study, we are proposing to discern the molecular and cellular processes through which nicotine-induced OPN contributes to the progression of PDA. A powerful team of researchers and clinicians will conduct the proposed studies: Drs. Charles Yeo in pancreatic cancer and surgical oncology, David Denhardt, in osteopontin signaling and cancer metastasis, and our expertise in pancreatic pathology and osteopontin signaling and regulation in the pancreas. Data from our studies are likely to lead to novel mechanistic insights and as yet, an unknown functional link between nicotine and OPN. Unraveling these mechanisms will lead to better understanding of the role of nicotine as a major risk factor in pancreatic cancer. ? ? ? ?

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Tumor Progression and Metastasis Study Section (TPM)
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Poland, Alan P
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Thomas Jefferson University
Schools of Medicine
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