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Tumor-stroma interactions in pancreatic ductal adenocarcinoma
The host stromal response to an invasive epithelial carcinoma is frequently called a desmoplastic reaction (DR) and is a universal feature of pancreatic ductal adenocarcinoma (PDA). This DR is characterized by a complex interplay between the normal host epithelial cells, invading tumor cells, stroma...
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Published in: | Molecular cancer therapeutics 2007-04, Vol.6 (4), p.1186-1197 |
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Main Authors: | , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | The host stromal response to an invasive epithelial carcinoma is frequently called a desmoplastic reaction (DR) and is a universal
feature of pancreatic ductal adenocarcinoma (PDA). This DR is characterized by a complex interplay between the normal host
epithelial cells, invading tumor cells, stromal fibroblasts, inflammatory cells, proliferating endothelial cells, an altered
extracellular matrix, and growth factors activating oncogenic signaling pathways by autocrine and paracrine mechanisms. Hence,
the tumor microenvironment is a dynamic process promoting tumor growth and invasion through mechanisms likely to include anoikis
resistance, genomic instability, and drug resistance. Cell coculture models, murine models (xenograft and genetic), and gene
expression profiling studies on human PDA biopsies have identified several key molecules, such as collagen type I, fibronectin,
laminin, matrix metalloproteinases (MMP) and their inhibitors (tissue inhibitors of MMP), growth factors (transforming growth
factor β, platelet-derived growth factor, connective tissue growth factor, and hepatocyte growth factor), chemokines, and
integrins as constituents of the DR. Despite these findings, it is unclear which molecular-cellular events initiate and drive
desmoplasia in PDA. Accumulating evidence indicates that pancreatic stellate cells when activated switch to a myofibroblast
phenotype that produces components of the extracellular matrix, MMPs, and tissue inhibitors of MMPs by activating the mitogen-activated
protein kinase (extracellular signal-regulated kinase 1/2) pathway. Based on current evidence, several therapeutic strategies
are been evaluated on identified potential therapeutic targets. This review summarizes our current understanding of the mechanisms
that potentially drive the DR in PDA and future possibilities for therapeutic targeting of this critical process. [Mol Cancer
Ther 2007;6(4):1186–97] |
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ISSN: | 1535-7163 1538-8514 |
DOI: | 10.1158/1535-7163.MCT-06-0686 |