The pancreas cancer microenvironment

Abstract

Pancreatic ductal adenocarcinoma (PDA) is a common and lethal malignancy resulting in more than 250,000 deaths per year worldwide. Despite extensive efforts, cytotoxic and targeted therapies have provided only limited efficacy for patients with PDA to date. One contributing factor to the failure of systemic therapies may be the abundant tumor stromal content that is the characteristic of PDA. The PDA stroma, aptly termed the tumor microenvironment, occupies the majority of the tumor mass, and consists of a dynamic assortment of extracellular matrix components and nonneoplastic cells including fibroblastic, vascular, and immune cells. Recent work has revealed that the PDA stroma supports tumor growth and promotes metastasis and simultaneously serves as a physical barrier to drug delivery. Accordingly, methods that alter stromal composition or function, for instance interference with the vasculature via Notch/Hedgehog pathway inhibition or relief of vascular compression by hyaluronidase, are under active investigation. Here, we will review our current understanding of the PDA tumor microenvironment, and highlight opportunities for further exploration that may benefit patients.

Fig.1

PDA contains an abundant stroma. A Mouse PDA tissue was stained with Picrosirius Red and imaged under polarized light to visualize collagen fibres (20x magnification). B Masson’s Trichrome staining highlights connective tissue distribution in an example of mouse PDA. Collagen fibres are staining in blue with the cytoplasm appearing in red (40x magnification). C Immunohistochemistry for SPARC on murine PDA (α-SPARC polyclonal antibody, Protein tech catalogue number: 15274-1-AP, 10x magnification). D Histochemical staining of hyaluronan (biotinylated hyaluronan binding protein, Calbiochem 385911, 10x magnification) reveals pan-stromal deposition in murine PDA.

Fig. 2

Murine PDA is characterized by hypovasularity. In this example of CD31 immunohistochemistry the dotted line denotes the boundary between tumor (T) and peritumoral diseased pancreas (PT) (20x magnification).

Fig.3

Prominent immune cell infiltration exists in mouse PDA. This immunofluorescence staining illustrates the abundance of immune cells marked by CD45 expression (red) between neoplastic glandular structures (stained for EpCam in blue) and α-SMA positive stromal fibroblasts and perivascular cells that likely represent pericytes (green) (20x magnification).

Fig.4

Schematic of the TME network, crosstalk and interdependence in PDA with a focus on therapeutic intervention points. A Activated pancreatic stellate cells lay down vast amounts of ECM, which causes a constriction/collapse of the sparse vessel network. This impedes on gemcitabine delivery. Hypoxia generates niches for slow-cycling cells that are not targeted by chemotherapeutics. Also, an immunosuppressive microenvironment further supports tumor growth. B Hedgehog pathway inhibition causes stromal depletion accompanied by reduced ECM. The ECM can also be enzymatically targeted and both interventions lead to increased vessel patency and intra-tumoral gemcitabine delivery. The immune system can be stimulated to turn against cancer cells for instance by anti-CD40 antibody treatment.