Pancreatic cancer stroma: an update on therapeutic targeting strategies

By A. Hosein, R. Brekken, A. Maitra. Nature reviews: Gastroenterology & hepatology, 2020

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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. The neoplastic epithelium of pancreatic cancer exists within a dense stroma that is recognized as a critical mediator of disease progression. This Review discusses our current understanding of the three principal constituents of pancreatic cancer stroma, their effect on the prevalent immune landscape and promising therapeutic targets within this compartment. The tumour microenvironment of pancreatic ductal adenocarcinoma (PDAC) is composed of extracellular matrix (ECM) proteins, tumour vasculature, fibroblasts and immune cells. ECM proteins in PDAC can increase intratumoural pressure and act as a barrier to effective drug delivery to the tumour. Clinical trials have aimed to exploit this understanding of the PDAC ECM but have so far failed to show an improvement in patient survival. Tumour-associated vasculature has been shown to be important for PDAC disease pathogenesis in preclinical models; however, clinical trials aimed at targeting the PDAC vasculature have not prolonged patient survival. Pruning PDAC vasculature (normalization) might present a strategy for improved chemotherapy delivery and host antitumour immune responses. Molecular subtypes of pancreatic cancer-associated fibroblasts (CAFs) have been described, most notably inflammatory CAFs and myofibroblastic CAFs, which have been postulated to demonstrate protumour and antitumour properties, respectively.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/ac7b7bc4053bbc510de6bafb34b07534b79a3cb1

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