Assessment of Hypoxia in the Stroma of Patient-Derived Pancreatic Tumor Xenografts

Ines Lohse,Ming-Sound Tsao,Corey Lourenco,David Hedley,Melania Pintilie,Emin Ibrahimov

doi:10.3390/cancers6010459

Abstract

The unusually dense stroma of pancreatic cancers is thought to play an important role in their biological aggression. The presence of hypoxia is also considered an adverse prognostic factor. Although it is usually assumed that this is the result of effects of hypoxia on the epithelial component, it is possible that hypoxia exerts indirect effects via the tumor stroma. We therefore measured hypoxia in the stroma of a series of primary pancreatic cancer xenografts. Nine patient-derived pancreatic xenografts representing a range of oxygenation levels were labeled by immunohistochemistry for EF5 and analyzed using semi-automated pattern recognition software. Hypoxia in the tumor and stroma was correlated with tumor growth and metastatic potential. The extent of hypoxia varied from 1%–39% between the different models. EF5 labeling in the stroma ranged from 0–20% between models, and was correlated with the level of hypoxia in the tumor cell area, but not microvessel density. Tumor hypoxia correlated with spontaneous metastasis formation with the exception of one hypoxic model that showed disproportionately low levels of hypoxia in the stroma and was non-metastatic. Our results demonstrate that hypoxia exists in the stroma of primary pancreatic cancer xenografts and suggest that stromal hypoxia impacts the metastatic potential.

Highlights

A characteristic feature of pancreatic cancer is the dense desmoplastic reaction that can account for up to 80% of the total tumor mass [1,2]
Primary xenografts were established from pancreatectomy samples that were superfluous to diagnostic needs by implantation into the flank or to the surface of the pancreas of NOD/SCID mice
The primary patient-derived xenografts used for this study displayed a wide range of tumor hypoxia

Summary

Introduction

A characteristic feature of pancreatic cancer is the dense desmoplastic reaction that can account for up to 80% of the total tumor mass [1,2]. The interactions between tumor cells and their microenvironment are complex, but the unusually dense stromal reaction seen in pancreatic cancers is thought to play an important role promoting their high lethality [3,4,5,6]. Hypoxia and its associated metabolic changes are considered to be an additional component of the tumor microenvironment, and it has long been associated with poor patient outcome [10,11,12,13,14,15,16]. There is some evidence that hypoxia favors the maintenance of a stem cell-like phenotype [17,18,19]

Results

Discussion

Conclusion