Integrin alpha6beta4 contributions in pancreatic adenocarcinoma

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Title: Integrin alpha6beta4 contributions in pancreatic adenocarcinoma
Author: Zobeida Cruz-Monserrate
Abstract: Pancreatic adenocarcinomas are among the most lethal human cancers due to an elevated incidence of tumor cell invasion and metastasis for reasons that are currently unclear . In this dissertation , I determined how the pro -invasive integrin alpha6beta4 expression was related to pancreatic adenocarcinoma tumor progression in tumor samples and assessed in -vitro if the expression of this integrin was required for the migration and invasion of pancreatic cancer cells . In addition , I explored the mechanisms of how the alpha6beta4 integrin could contribute to an invasive and migratory phenotype . To examine if integrin alpha6beta4 expression was related to cancer progression , immunohistochemical analysis was performed in normal pancreas , pancreatic intraepithelial neoplasia (PanIN ) lesions , pancreatic adenocarcinomas , and chronic pancreatitis . In normal pancreatic ducts , integrin alpha6beta4 was noted only at the cell’s basal interface with the basement membrane . In pancreatic adenocarcinomas , 92 % (104 /113 ) demonstrated overexpression of integrin alpha6beta4 and altered localization to the cytoplasm and membranous regions . This pattern of expression was observed in all PanIN lesions as early as PanIN -1A . In contrast , 93 % (13 /14 ) of chronic pancreatitis samples resembled the staining pattern of normal pancreas . When cancer was present in areas of chronic pancreatitis , this altered expression of alpha6beta4 integrin identified the cancer . These results indicate that the early overexpression of the alpha6beta4 integrin in pancreatic adenocarcinoma progression may contribute to the malignancy of this disease . \r \nTo understand the contribution of integrin alpha6beta4 expression in cell migration and invasion , cell lines were screened for the presence of integrin alpha6beta4 by immunoblotting and fluorescence activated cell sorting and correlated with their ability to migrate towards hepatocyte growth factor (HGF ) , a known mitogenic and motility factor of pancreatic carcinomas . I found that cell surface expression positively correlated with the cell line ability to migrate and invade towards HGF . When cells expressing high levels of integrin alpha6beta4 were treated with siRNAs targeting the alpha6 or beta4 integrin subunits , I observed a reduction in HGF -induced migration and invasion . Furthermore , the activity of the small GTPase Rac -1 decreased when alpha6beta4 integrin expression was reduced . In addition , expression of the Rac -specific nucleotide exchange factor , Tiam -1 was upregulated by the integrin alpha6beta4 and required for Rac -1 activity . These results suggest that the integrin alpha6beta4 plays an important role in the migratory and invasive phenotype of pancreatic carcinoma cells and that the Tiam -1 -Rac1 pathway is an important mediator of integrin alpha6beta4 -mediated HGF -induced migration and invasion . Overall this study provided evidence that integrin alpha6beta4 is an important contributor to the migratory and invasive phenotype that characterize pancreatic adenocarcinomas .
URI: http : / /hdl .handle .net /2152 .3 /182
Date: 2007-06-11

Citation

Integrin alpha6beta4 contributions in pancreatic adenocarcinoma. Doctoral dissertation, The University of Texas Medical Branch. Available electronically from http : / /hdl .handle .net /2152 .3 /182 .

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