Extracellular Influences: Molecular Subclasses and the Microenvironment in Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent form of pancreatic cancer and carries the worst prognosis of all common cancers. Five-year survival rates have not surpassed 6% for some decades and this lack of improvement in outcome urges a better understanding of the PDAC-specific features which contribute to this poor result. One of the most defining features of PDAC known to contribute to its progression is the abundance of non-tumor cells and material collectively known as the stroma. It is now well recognized that the different non-cancer cell types, signalling molecules, and mechanical properties within a tumor can have both tumor-promoting as well as -inhibitory effects. However, the net effect of this intratumour heterogeneity is not well understood. Heterogeneity in the stromal makeup between patients is even less well established. Such intertumour heterogeneity is likely to be affected by the relative contributions of individual stromal constituents, but how these contributions exactly relate to existing classifications that demarcate intertumour heterogeneity in PDAC is not fully known. In this review, we give an overview of the available evidence by delineating the elements of the PDAC stroma and their contribution to tumour growth. We do so by interpreting the heterogeneity at the gene expression level in PDAC, and how stromal elements contribute to, or interconnect, with this.

Keywords: fibroblasts; gene expression; heterogeneity; immune cells; mutations; pancreatic cancer; stroma.

Figure 1

Schematic overview of all reported expression-based subtypes in PDAC. Correlated subtypes are grouped in columns. The “Other subtypes” could not be grouped. Colours are based on the colour coding used in the original publications.

Figure 2

Schematic representation of the stromal elements described in this review that contribute to, or interconnect with subtype-specific gene expression in PDAC (outer circle, Collisson [33]; middle circle, Moffitt stroma [9]; inner circle, Bailey [32]). Middle circle represents the tumor (T), surrounding the tumor is the stroma, representing the sections and subsections. Proteins described in this review were checked for expression in the subtypes as summarized in the figure. Colours are based on the colours coding used in the original publications.