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Identification of novel vascular projections with cellular trafficking abilities on the microvasculature of pancreatic ductal adenocarcinoma.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a nearly lethal neoplasm. It is a remarkably stroma-rich, vascular-poor and hypo-perfused tumour, which prevents efficient drug delivery. Paradoxically, the neoplastic cells have robust glucose uptake, suggesting that the microvasculature has adopted an alternative method for nutrient uptake and cellular trafficking. Using adapted thick tumour section immunostaining and three-dimensional (3D) construction imaging in human tissue samples, we identified an undiscovered feature of the mature microvasculature in advanced PDAC tumours; long, hair-like projections on the basal surface of microvessels that we refer to as 'basal microvilli'. Functionally, these basal microvilli have an actin-rich cytoskeleton and endocytic and exocytic properties, and contain glucose transporter-1 (GLUT-1)-positive vesicles. Clinically, as demonstrated by PET-CT, the tumour microvasculature with the longest and most abundant basal microvilli correlated with high glucose uptake of the PDAC tumour itself. In addition, these basal microvilli were found in regions of the tumour with low GLUT-1 expression, suggesting that their presence could be dependent upon the glucose concentration in the tumour milieu. Similar microvasculature features were also observed in a K-Ras-driven model of murine PDAC. Altogether, these basal microvilli mark a novel pathological feature of PDAC microvasculature. Because basal microvilli are pathological features with endo- and exocytic properties, they may provide a non-conventional method for cellular trafficking in PDAC tumours.

SUBMITTER: Hexige S

PROVIDER: S-EPMC5089710 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Identification of novel vascular projections with cellular trafficking abilities on the microvasculature of pancreatic ductal adenocarcinoma.

Hexige Saiyin S Ardito-Abraham Christine M CM Wu Yanhua Y Wei Youheng Y Fang Yuan Y Han Xu X Li Jianang J Zhou Ping P Yi Qing Q Maitra Anirban A Liu Jun O JO Tuveson David A DA Lou Wenhui W Yu Long L

The Journal of pathology 20150217 2

Pancreatic ductal adenocarcinoma (PDAC) is a nearly lethal neoplasm. It is a remarkably stroma-rich, vascular-poor and hypo-perfused tumour, which prevents efficient drug delivery. Paradoxically, the neoplastic cells have robust glucose uptake, suggesting that the microvasculature has adopted an alternative method for nutrient uptake and cellular trafficking. Using adapted thick tumour section immunostaining and three-dimensional (3D) construction imaging in human tissue samples, we identified a ...[more]

PMID: 25561062

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Project description:A disintegrin and a metalloprotease (ADAM)-9 is a metzincin cell-surface protease with strongly elevated expression in solid tumors, including pancreatic ductal adenocarcinoma (PDAC). In this study, we performed immunohistochemistry (IHC) of a tissue microarray (TMA) to examine the expression of ADAM9 in a cohort of >100 clinically annotated PDAC cases. We report that ADAM9 is prominently expressed by PDAC tumor cells, and increased ADAM9 expression levels correlate with poor tumor grading (P = 0.027) and the presence of vasculature invasion (P = 0.017). We employed gene expression silencing to generate a loss-of-function system for ADAM9 in two established PDAC cell lines. In vitro analysis showed that loss of ADAM9 does not impede cellular proliferation and invasiveness in basement membrane. However, ADAM9 plays a crucial role in mediating cell migration and adhesion to extracellular matrix substrates such as fibronectin, tenascin, and vitronectin. This effect appears to depend on its catalytic activity. In addition, ADAM9 facilitates anchorage-independent growth. In AsPC1 cells, but not in MiaPaCa-2 cells, we noted a pronounced yet heterogeneous impact of ADAM9 on the abundance of various integrins, a process that we characterized as post-translational regulation. Sprout formation of human umbilical vein endothelial cells (HUVECs) is promoted by ADAM9, as examined by transfer of cancer cell conditioned medium; this finding further supports a pro-angiogenic role of ADAM9 expressed by PDAC cancer cells. Immunoblotting analysis of cancer cell conditioned medium highlighted that ADAM9 regulates the levels of angiogenic factors, including shed heparin-binding EGF-like growth factor (HB-EGF). Finally, we carried out orthotopic seeding of either wild-type AsPC-1 cells or AsPC-1 cells with silenced ADAM9 expression into murine pancreas. In this in vivo setting, ADAM9 was also found to foster angiogenesis without an impact on tumor cell proliferation. In summary, our results characterize ADAM9 as an important regulator in PDAC tumor biology with a strong pro-angiogenic impact.

Dataset Information

Identification of novel vascular projections with cellular trafficking abilities on the microvasculature of pancreatic ductal adenocarcinoma.

Publications

Identification of novel vascular projections with cellular trafficking abilities on the microvasculature of pancreatic ductal adenocarcinoma.

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