Influence of Radiotherapy Fractionation Schedule on the Tumor Vascular Microenvironment in Prostate and Lung Cancer Models.

Karen Clément-Colmou,Grégory Delpon,Maëva Guillonneau,Vincent Potiron,François Paris,Manon Pietri,Emmanuel Jouglar,Stéphane Supiot,Sophie Chiavassa

doi:10.3390/cancers12010121

Abstract

Background. The tumor vasculature acts as an interface for the primary tumor. It regulates oxygenation, nutrient delivery, and treatment efficacy including radiotherapy. The response of the tumor vasculature to different radiation doses has been disparately reported. Whereas high single doses can induce endothelial cell death, improved vascular functionality has also been described in a various dose range, and few attempts have been made to reconcile these findings. Therefore, we aimed at comparing the effects of different radiation fractionation regimens on the tumor vascular microenvironment. Methods: Lewis lung and prostate PC3 carcinoma-derived tumors were irradiated with regimens of 10 × 2 Gy, 6 × 4 Gy, 3 × 8 Gy or 2 × 12 Gy fractions. The tumor vasculature phenotype and function was evaluated by immunohistochemistry for endothelial cells (CD31), pericytes (desmin, α-SMA), hypoxia (pimonidazole) and perfusion (Hoechst 33342). Results: Radiotherapy increased vascular coverage similarly in all fractionation regimens in both models. Vessel density appeared unaffected. In PC3 tumors, hypoxia was decreased and perfusion was enhanced in proportion with the dose per fraction. In LLC tumors, no functional changes were observed at t = 15 days, but increased perfusion was noticed earlier (t = 9–11 days). Conclusion: The vascular microenvironment response of prostate and lung cancers to radiotherapy consists of both tumor/dose-independent vascular maturation and tumor-dependent functional parameters.

Highlights

Of the intrinsic nature of cancer cells, the tumor microenvironment influences tumor growth, progression, and response to treatments [1]
RT significantly prolonged survival in all fractionation schedules compared to non-irradiated controls (Figure 1B,C; Supplementary Figure S1)
Tumor perfusion inversely correlated with tumor cell density (Supplementary Figure S3A,C) but not these results indicate that RT regulates perfusion/hypoxia effects of the dose‐per‐fraction, but with desmoplasia

Summary

Introduction

Of the intrinsic nature of cancer cells, the tumor microenvironment influences tumor growth, progression, and response to treatments [1]. In this regard, special emphasis has been placed. We and others have shown that fractionated radiotherapy (RT) induces normalization of the tumor vasculature, characterized by enhanced pericyte coverage, blood perfusion, and reduction of intra-tumoral hypoxia [6,7,8,9]. Results: Radiotherapy increased vascular coverage in all fractionation regimens in both models. Conclusion: The vascular microenvironment response of prostate and lung cancers to radiotherapy consists of both tumor/dose-independent vascular maturation and tumor-dependent functional parameters

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Conclusion