Pancreatic stellate cells regulate blood vessel density in the stroma of pancreatic ductal adenocarcinoma.
OBJECTIVE
The 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.


METHODS
Tissue 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.


RESULTS
PDAC 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.


CONCLUSIONS
Human PDAC has variable vascularity at microscopic level suggesting that novel stromal directed therapies would need to be determined by pathological characteristics.
Centre for Tumour Biology, Barts Cancer Institute - a CRUK Centre of Excellence, Queen Mary University of London, London EC1M 6BQ, UK; Barts and the London HPB Centre, The Royal London Hospital, Barts Health NHS Trust, London E1 1BB, UK.
Francesco
F
Di Maggio
Centre for Tumour Biology, Barts Cancer Institute - a CRUK Centre of Excellence, Queen Mary University of London, London EC1M 6BQ, UK; Barts and the London HPB Centre, The Royal London Hospital, Barts Health NHS Trust, London E1 1BB, UK.
Prabhu
P
Arumugam
Centre for Tumour Biology, Barts Cancer Institute - a CRUK Centre of Excellence, Queen Mary University of London, London EC1M 6BQ, UK.
Francesca R
FR
Delvecchio
Centre for Tumour Biology, Barts Cancer Institute - a CRUK Centre of Excellence, Queen Mary University of London, London EC1M 6BQ, UK.
Silvia
S
Batista
Centre for Tumour Biology, Barts Cancer Institute - a CRUK Centre of Excellence, Queen Mary University of London, London EC1M 6BQ, UK.
Tanguy
T
Lechertier
Centre for Tumour Biology, Barts Cancer Institute - a CRUK Centre of Excellence, Queen Mary University of London, London EC1M 6BQ, UK.
Kairbaan
K
Hodivala-Dilke
Centre for Tumour Biology, Barts Cancer Institute - a CRUK Centre of Excellence, Queen Mary University of London, London EC1M 6BQ, UK; Barts and the London HPB Centre, The Royal London Hospital, Barts Health NHS Trust, London E1 1BB, UK. Electronic address: h.kocher@qmul.ac.uk.
Hemant M
HM
Kocher
D000230:Adenocarcinoma / Q000473:pathology*; D000818:Animals; D001808:Blood Vessels / Q000473:pathology*; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology*; D002478:Cells, Cultured; D018281:Cholangiocarcinoma / Q000473:pathology; D006801:Humans; D051379:Mice; D046228:Microarray Analysis; D008833:Microcirculation / Q000187:drug effects; D009389:Neovascularization, Pathologic / Q000473:pathology; D009924:Organ Culture Techniques; D058954:Pancreatic Stellate Cells / Q000473:pathology*; D011379:Prognosis; D016019:Survival Analysis; D014212:Tretinoin / Q000627:therapeutic use; D059016:Tumor Microenvironment
D014212:Tretinoin
Angiogenesis; Juxta-tumoral; Micro-environment; Pancreatic stellate cells; Panstromal