Improved Functionality of the Vasculature during Conventionally Fractionated Radiation Therapy of Prostate Cancer

Vincent A Potiron,François Paris,Thibauld Oullier,Karen Clément-Colmou,Séverine Marionneau-Lambot,Stéphane Supiot,Rym Abderrahmani,Zhaozhong Han

doi:10.1371/journal.pone.0084076

Abstract

Although endothelial cell apoptosis participates in the tumor shrinkage after single high-dose radiotherapy, little is known regarding the vascular response after conventionally fractionated radiation therapy. Therefore, we evaluated hypoxia, perfusion and vascular microenvironment changes in an orthotopic prostate cancer model of conventionally fractionated radiation therapy at clinically relevant doses (2 Gy fractions, 5 fractions/week). First, conventionally fractionated radiation therapy decreased tumor cell proliferation and increased cell death with kinetics comparable to human prostate cancer radiotherapy. Secondly, the injection of Hoechst 33342 or fluorescent-dextrans showed an increased tumor perfusion within 14 days in irradiated tumors, which was correlated with a clear reduction of hypoxia. Improved perfusion and decreased hypoxia were not explained by increased blood vessel density, size or network morphology. However, a tumor vascular maturation defined by perivascular desmin+/SMA+ cells coverage was clearly observed along with an increase in endothelial, zonula occludens (ZO)-1 positive, intercellular junctions. Our results show that, in addition to tumor cell killing, vascular maturation plays an uncovered role in tumor reoxygenation during fractionated radiation therapy.

Highlights

The sensitivity of tumors to radiation therapy (RT) is largely dependent on the intrinsic radioresistance of cancer stem cells [1], other data suggest that the sensitivity of the endothelium plays an important role [2]
Two weeks after cells were injected, tumor-bearing animals received a daily dose of 2 Gy irradiation centered on the lower abdomen, each day of the week for two weeks
We used an orthotopic model of prostate cancer with a clinically-relevant fractionation scheme, inducing modest cell death, increasing proliferation arrest with dose and differential effect between normal/tumor cells

Summary

Introduction

The sensitivity of tumors to radiation therapy (RT) is largely dependent on the intrinsic radioresistance of cancer stem cells [1], other data suggest that the sensitivity of the endothelium plays an important role [2]. An incomplete maturation of the capillaries is noted with absent or detached perivascular cells, absent or too thick basement membrane and lack of endothelial cells junction This abnormal vasculature causes hypoxia that further impacts the efficacy of irradiation because 1) lack of oxygen reduces the amount of reactive oxygen species induced by irradiation and 2) hypoxia selects radioresistant mutant cells [3]. Because of reduced oxygen consumption by damaged cells, improved perfusion, and reduced cell density, hypoxic tumor cells may gain an easier access to oxygenation, and become more sensitive to the subsequent fraction of irradiation. This process of reoxygenation is believed to confer a therapeutic advantage to CFRT through a progressive decrease of normoxic tumor cells and easier access of hypoxic cells to oxygen [3]

Methods

Results

Conclusion