Pancreatic cancer stroma: an update on therapeutic targeting strategies

Nat Rev Gastroenterol Hepatol. 2020 Aug;17(8):487-505. doi: 10.1038/s41575-020-0300-1. Epub 2020 May 11.


Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mortality in the Western world with limited therapeutic options and dismal long-term survival. The neoplastic epithelium exists within a dense stroma, which is recognized as a critical mediator of disease progression through direct effects on cancer cells and indirect effects on the tumour immune microenvironment. The three dominant entities in the PDAC stroma are extracellular matrix (ECM), vasculature and cancer-associated fibroblasts (CAFs). The ECM can function as a barrier to effective drug delivery to PDAC cancer cells, and a multitude of strategies to target the ECM have been attempted in the past decade. The tumour vasculature is a complex system and, although multiple anti-angiogenesis agents have already failed late-stage clinical trials in PDAC, other vasculature-targeting approaches aimed at vessel normalization and tumour immunosensitization have shown promise in preclinical models. Lastly, PDAC CAFs participate in active cross-talk with cancer cells within the tumour microenvironment. The existence of intratumoural CAF heterogeneity represents a paradigm shift in PDAC CAF biology, with myofibroblastic and inflammatory CAF subtypes that likely make distinct contributions to PDAC progression. In this Review, we discuss our current understanding of the three principal constituents of PDAC stroma, their effect on the prevalent immune landscape and promising therapeutic targets within this compartment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / analogs & derivatives
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / therapeutic use
  • Angiogenesis Inhibitors / therapeutic use*
  • Animals
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Benzamides / therapeutic use
  • Cancer-Associated Fibroblasts / metabolism*
  • Carcinoma, Pancreatic Ductal / blood supply
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / immunology
  • Carcinoma, Pancreatic Ductal / metabolism
  • Extracellular Fluid
  • Extracellular Matrix / metabolism*
  • Extracellular Matrix / pathology
  • Focal Adhesion Protein-Tyrosine Kinases / antagonists & inhibitors
  • Humans
  • Hyaluronic Acid / metabolism
  • Hyaluronoglucosaminidase / therapeutic use
  • Mice
  • Molecular Targeted Therapy
  • Pancreatic Neoplasms / blood supply
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / immunology
  • Pancreatic Neoplasms / metabolism
  • Permeability
  • Pressure
  • Protein Kinase Inhibitors / therapeutic use
  • Pyrazines / therapeutic use
  • Sulfonamides / therapeutic use
  • Tumor Microenvironment / immunology
  • rho-Associated Kinases / antagonists & inhibitors


  • Angiogenesis Inhibitors
  • Antineoplastic Agents
  • Benzamides
  • Protein Kinase Inhibitors
  • Pyrazines
  • Sulfonamides
  • defactinib
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
  • Hyaluronic Acid
  • Focal Adhesion Protein-Tyrosine Kinases
  • rho-Associated Kinases
  • Hyaluronoglucosaminidase
  • PEGPH20
  • fasudil