This Article Full Text Full Text (PDF) All Versions of this Article: 1535-7163.MCT-06-0686v1 6/4/1186    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mahadevan, D. Articles by Von Hoff, D. D. Search for Related Content PubMed PubMed Citation Articles by Mahadevan, D. Articles by Von Hoff, D. D. Related Collections Tumor Biology Tumor Biology: Invasion and Metastasis Therapeutics and Targets: Identification, Validation, and Markers

Review

Tumor-stroma interactions in pancreatic ductal adenocarcinoma

¹ The University of Arizona, Arizona Cancer Center, Tucson, Arizona and ² TGen, Phoenix, Arizona

Requests for reprints: Daruka Mahadevan, Hematology/Oncology, The University of Arizona Cancer Center, 1515 North Campbell Avenue, Tucson, AZ 58724. Phone: 520-626-0191; Fax: 520-626-3663. E-mail: dmahadevan{at}azcc.arizona.edu

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 ß, 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]

Received 11/16/06; revised 1/24/07; accepted 2/26/07.

This article has been cited by other articles:

				L. Jiang, T. A. Gonda, M. V. Gamble, M. Salas, V. Seshan, S. Tu, W. S. Twaddell, P. Hegyi, G. Lazar, I. Steele, et al. Global Hypomethylation of Genomic DNA in Cancer-Associated Myofibroblasts Cancer Res., December 1, 2008; 68(23): 9900 - 9908. [Abstract] [Full Text] [PDF]

				G. C. Prendergast This month in Cancer Reviews Online: Cancer risk factors, progression mechanisms, and targeted drug studies Cancer Reviews Online Content, May 1, 2007; 2007(2): 3 - 4. [Full Text] [PDF]