Studying the role of integrin αVβ6 in pancreatic cancer
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Pancreatic cancer is often referred to as the “silent killer“ due to the asymptomatic nature of the disease in the early stages and the extremely poor prognosis overall. The average one-year survival rate for PDAC patients is 24% (American Cancer Society, facts and figures, 2010), decreasing to 5%-6% over 5 years (WHO report, Pancreatic cancer, 2010). Only 20% of patients are suitable for surgical resection at the time of diagnosis and treatment options available to PDAC patients have not improved significantly over the past few decades. Thus novel therapeutic approaches are essential to treat this disease. Our experimental, clinical and pre-clinical data suggest integrin αvβ6 may be a suitable target. Bioinformatics studies using the Pancreatic Expression Database revealed that the β6 gene (ITGB6) was highly up regulated in pancreatic ductal carcinoma (PDAC) compared with normal pancreas. Further analysis carried out showed that there was a significant correlation between ITGB6 expression at the mRNA level and survival in a cohort of 292 PDAC patients. Immunohistochemistry analysis on two separate patient cohorts (n=118 and n=147) showed that normal pancreas lacked αvβ6 expression whereas 91% of PDAC tissues expressed αvβ6 at the protein level. There was no significant correlation between αvβ6 expression and survival at the protein level in both cohorts of patients tested. Flow cytometry and Western blotting analyses on a panel of PDAC cell lines confirmed expression of αvβ6 in PDAC cell lines. This study investigated the functional role of αvβ6 in PDAC cell lines. Antibody mediated function blockade of αvβ6 significantly inhibited proliferation in a dose dependent manner, specifically in αvβ6 positive PDAC cell lines. A significant reduction in migration and invasion was also observed in a panel of αvβ6 positive PDAC cell lines when treated with an αvβ6 function-blocking antibody. αvβ6 targeted antibody mediated therapy in combination with gemcitabine significantly inhibited tumour growth in a physiologically relevant pre-clinical subcutaneous xenograft model of PDAC. These data reaffirms that αvβ6 is a potential novel therapeutic target and an αvβ6 specific function-blocking antibody can be used as a novel agent to treat pancreatic adenocarcinoma patients.
AuthorsVallath, Sabarinath S.
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