TY - JOUR
T1 - Pancreatic cancer stroma
T2 - an update on therapeutic targeting strategies
AU - Hosein, Abdel N.
AU - Brekken, Rolf A.
AU - Maitra, Anirban
N1 - Funding Information:
The authors thank D. Primm (UT Southwestern Medical Center) for help in editing this article and C. Kwak (UT MD Anderson Cancer Center) who provided images of mouse tumours. R.A.B. acknowledges funding from the following sources: NIH grants R01 (CA192381) and U54 (CA210181 Project 2), the Effie Marie Cain Fellowship and the Jean Shelby Fund for Cancer Research at Communities Foundation of Texas. A.M. acknowledges funding from the following sources: NCI U24 CA224020, NCI R01CA218004 and NCI R01CA220236.
Publisher Copyright:
© 2020, Springer Nature Limited.
PY - 2020/8/1
Y1 - 2020/8/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41575-020-0300-1
DO - 10.1038/s41575-020-0300-1
M3 - Review article
C2 - 32393771
AN - SCOPUS:85084520894
SN - 1759-5045
VL - 17
SP - 487
EP - 505
JO - Nature Reviews Gastroenterology and Hepatology
JF - Nature Reviews Gastroenterology and Hepatology
IS - 8
ER -