The Paradoxical Web of Pancreatic Cancer Tumor Microenvironment

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is increasing in incidence and is projected to become the second leading cause of cancer death in the United States. Despite significant advances in understanding the disease, there has been minimal increase in PDAC patient survival. PDAC tumors are unique in the fact that there is significant desmoplasia. This generates a large stromal compartment composed of immune cells, inflammatory cells, growth factors, extracellular matrix, and fibroblasts, comprising the tumor microenvironment (TME), which may represent anywhere from 15% to 85% of the tumor. It has become evident that the TME, including both the stroma and extracellular component, plays an important role in tumor progression and chemoresistance of PDAC. This review will discuss the multiple components of the TME, their specific impact on tumorigenesis, and the multiple therapeutic targets.

Figure 1

A: Overview of hematoxylin and eosin section: pancreatic ductal adenocarcinoma with desmoplastic fibrous response. B: Desmoplastic environment, including acute and chronic inflammation. Circle indicates a partially invaded islet. Original magnification: ×4 (A); ×20 (B).

Figure 2

Hematoxylin and eosin (H&E) and trichrome staining of pancreatic tumors arising in two KPC mice recapitulating the dense collagen-rich stroma seen in human pancreatic adenocarcinoma tumors. Scale bars = 100 μm.

Figure 3

Depiction of the pancreatic tumor microenvironment throughout progression from pancreatic intraepithelial neoplasia (PanIN) to pancreatic ductal adenocarcinoma (PDAC). CAF, cancer-associated fibroblast; CTLA-4, cytotoxic T-lymphocyte–associated protein 4; CXCR4, chemokine receptor type 4; MDSC, myeloid-derived suppressor cell; PDGF, platelet-derived growth factor; PGF, prostaglandin F; PSC, pancreatic stellate cell; Shh, sonic hedgehog; TGF-β, transforming growth factor-β; Treg, regulatory T cell; VEGFR, vascular endothelial growth factor receptor.