Tumor-stroma interactions in pancreatic ductal adenocarcinoma

Daruka Mahadevan, Daniel D. Von Hoff

Research output: Contribution to journalReview articlepeer-review

426 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1186-1197
Number of pages12
JournalMolecular cancer therapeutics
Volume6
Issue number4
DOIs
StatePublished - Apr 2007

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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