CXCR2-Dependent Pancreatic Cancer Progression and Metastasis

University Of Nebraska Medical Center, Omaha NE

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Abstract

Pancreatic cancer is the fourth leading cause of cancer-related death in both men and women and it is one ofthe most lethal malignancies with a 5-year survival rate of <5% and median survival duration of less than 6 months. In recent years there have been important advances in the understanding of the molecular biology of pancreatic cancer as well as in diagnosis, staging and treatment in patients with eariy stage tumor. However, minimal progress has been made in our understanding in progression and metastasis and treatment in patients with advanced disease. Recent reports and our preliminary data suggest that inflammation, tumorigenesis, and progression to metastasis are intimately linked in pancreatic cancer. Chronic inflammation can drive tumorigenesis, and tumors are inherently pro-inflammatory with infiltrating leukocytes thought critical for tumor maintenance and progression. Thus, molecules driving tumor-associated inflammation have considerable potential as therapeutic targets, yet this area remains relatively under-explored in pancreatic cancer. Chemokines are secreted proteins that regulate cell behavior via G-protein coupled receptors. Subsets of CC and CXC chemokines orchestrate tissue inflammation by recruiting and activating leukocytes and by regulating endothelial and epithelial cells. Constitutive expression of pro-inflammatory chemokines, a hallmark of many human cancers, helps establish a supportive tumor stroma and in some cases, directly stimulates tumor proliferation and invasion via receptors on tumor cells. Evidence suggests that CXCR2 regulates leukocytes, endothelial cells (ECs), and/or tumor cells and their precursors. To our knowledge, very little is known about the role of CXCR2 in de novo pancreatic cancer progression and metastasis.