Abstract
Background/objectivesThe vascular heterogeneity of pancreatic ductal adenocarcinoma (PDAC) has never been characterised. We analysed the heterogeneous vascular density of human PDAC along with its prognostic correlation. MethodsTissue Microarrays of 87 patients with different pancreatico-biliary pathologies were analysed in an automated manner (Ariol™) after CD31 staining to assess vascular density in juxta-tumoral and panstromal compartments. In vitro and ex vivo assays were carried out to assess the role of PSC. ResultsPDAC has a distinct vascular density and distribution of vessels compared to cholangiocarcinoma. The PDAC juxta-tumoral stroma was hypovascular and the normal adjacent rim was hypervascular compared to the panstromal compartment. These features adversely affected patient prognosis, suggesting a model for spatio-temporal PDAC evolution. Mice aortic rings and 3D organotypic cultures demonstrated pro- and anti-angiogenic signalling from activated PSC and cancer cells respectively. ATRA-induced quiescence suppressed the pro-angiogenic activity of PSC. ConclusionHuman PDAC has variable vascularity at microscopic level suggesting that novel stromal directed therapies would need to be determined by pathological characteristics.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is characterised by loss of acino-lobular architecture, progressive subversion of the stromal/epithelial ratio and extracellular matrix (ECM) deposition [1]
Our recent studies have revealed a differential inflammatory infiltrate in the juxta-tumoral (
We demonstrate that the stromal subcompartment specific vascularisation is different, and is clinically relevant in human PDAC
Summary
Pancreatic ductal adenocarcinoma (PDAC) is characterised by loss of acino-lobular architecture, progressive subversion of the stromal/epithelial ratio and extracellular matrix (ECM) deposition [1]. The hypovascular nature and diffuse fibrosis is noted at histological examination [4]. This aspect has been highlighted in experimental conditions to account for lack of therapeutic effect of chemo- and radio-therapy [4e6]. Our recent studies have revealed a differential inflammatory infiltrate in the juxta-tumoral (
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