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

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.

Low dose angiostatic treatment counteracts radiotherapy-induced tumor perfusion and enhances the anti-tumor effect

“…By applying DCE-MRI as a non-invasive method to monitor the tumor vascular function we found that RTx FR enhanced tumor perfusion. This is in line with observations in patients [25-27, 35-37] and in different preclinical tumor models [30, 31, 38]. In the current study, we measured perfusion during the course of RTx FR revealing that the induction of tumor perfusion became apparent after 2 weeks of treatment.…”

A voxel‐based multiscale model to simulate the radiation response of hypoxic tumors

“…In the latter, most of the in vivo studies indicate a minor role of radiation-induced vascular damage in tumors as a determinant of response for the endpoint of permanent local control. [42][43][44] Moreover, the underlying mechanisms are highly complex and most likely different at different dose levels. 45 Although the radiosensitivity of capillary cells could in principle be implemented in a similar way as for tumor cells, the underlying biological mechanisms remain still rather unclear.…”

Optimizing radiotherapy protocols using computer automata to model tumour cell death as a function of oxygen diffusion processes

“…Because the dependence of tumour cell death as a function of oxygen level is well understood and was reported previously by our group 5 , such information was easily integrated and validated in our model. Clonogenic survival and HRF measured in vitro were also included in the model, assuming the majority of radiation-induced cell death was through mitotic catastrophe.…”

“…As in the previous section, O2 levels saturate at 5% so any O2 value above 5% is capped at 5%.

Figure 3Modeling the impact of oxygen on radiotherapy. ( A ) Previously published model of O2 “leakage” 5 derived from a Monte Carlo approach with a probability of “hitting” a vessel after a given dose defined by the corresponding cell death probability of endothelial cells measured in vitro . If there is a “hit” to a blood cell, a multiplicative factor Lf is applied to the profile.

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“…As a first step for proof-of-principle, we develop a model which models a well described in-vivo situation in mouse, where orthotopic transplants of human prostate tumours are treated with radiation 5 .…”