Fibrogenesis in pancreatic cancer is a dynamic process regulated by macrophage-stellate cell interaction

Chanjuan Shi, M. Kay Washington, Rupesh Chaturvedi, Yiannis Drosos, Frank L. Revetta, Connie J. Weaver, Emily Buzhardt, Fiona E. Yull, Timothy S. Blackwell, Beatriz Sosa-Pineda, Robert H. Whitehead, R. Daniel Beauchamp, Keith T. Wilson, Anna L. Means*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

Pancreatic cancer occurs in the setting of a profound fibrotic microenvironment that often dwarfs the actual tumor. Although pancreatic fibrosis has been well studied in chronic pancreatitis, its development in pancreatic cancer is much less well understood. This article describes the dynamic remodeling that occurs from pancreatic precursors (pancreatic intraepithelial neoplasias (PanINs)) to pancreatic ductal adenocarcinoma, highlighting similarities and differences between benign and malignant disease. Although collagen matrix is a commonality throughout this process, early stage PanINs are virtually free of periostin while late stage PanIN and pancreatic cancer are surrounded by an increasing abundance of this extracellular matrix protein. Myofibroblasts also become increasingly abundant during progression from PanIN to cancer. From the earliest stages of fibrogenesis, macrophages are associated with this ongoing process. In vitro co-culture indicates there is cross-regulation between macrophages and pancreatic stellate cells (PaSCs), precursors to at least some of the fibrotic cell populations. When quiescent PaSCs were co-cultured with macrophage cell lines, the stellate cells became activated and the macrophages increased cytokine production. In summary, fibrosis in pancreatic cancer involves a complex interplay of cells and matrices that regulate not only the tumor epithelium but the composition of the microenvironment itself.

Original languageEnglish (US)
Pages (from-to)409-421
Number of pages13
JournalLaboratory Investigation
Volume94
Issue number4
DOIs
StatePublished - Apr 2014

Keywords

  • chronic pancreatitis
  • collagen
  • fibrosis
  • myofibroblasts
  • pancreatic cancer
  • pancreatic stellate cells
  • periostin

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

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