Hypoxia in Solid Tumors: How Low Oxygenation Impacts the "Six Rs" of Radiotherapy.

Andria Rakotomalala,Alessandro Furlan,Alexandre Escande,Samuel Meignan,Eric Lartigau

doi:10.3389/fendo.2021.742215

Abstract

Radiotherapy is an important component of cancer treatment, with approximately 50% of all cancer patients receiving radiation therapy during their course of illness. Nevertheless, solid tumors frequently exhibit hypoxic areas, which can hinder therapies efficacy, especially radiotherapy one. Indeed, hypoxia impacts the six parameters governing the radiotherapy response, called the « six Rs of radiation biology » (for Radiosensitivity, Repair, Repopulation, Redistribution, Reoxygenation, and Reactivation of anti-tumor immune response), by inducing pleiotropic cellular adaptions, such as cell metabolism rewiring, epigenetic landscape remodeling, and cell death weakening, with significant clinical repercussions. In this review, according to the six Rs, we detail how hypoxia, and associated mechanisms and pathways, impact the radiotherapy response of solid tumors and the resulting clinical implications. We finally illustrate it in hypoxic endocrine cancers through a focus on anaplastic thyroid carcinomas.

Highlights

Because of its high cytotoxic potential in solid tumors, radiation therapy is a standard of care in many solid tumors [1, 2]
This review proposes to outline how low oxygen levels and hypoxia-associated tumor cell adaptions affect the six Rs of radiation therapy and thereby its efficiency in solid tumors treatment
This glycolytic flux leads to an increased lactate production which correlates with a poor prognosis in HNSCC and uterine cervix cancers treated by radiotherapy [25, 26]

Summary

INTRODUCTION

Because of its high cytotoxic potential in solid tumors, radiation therapy is a standard of care in many solid tumors [1, 2]. HIF-1 and HIF-2 modulate their own set of target genes and appear differentially regulated according to the hypoxia level and duration [15] By their role in hypoxia adaption, both HIF factors have a pleiotropic impact on the cell response to irradiation. RADIOSENSITIVITY: HOW THE LOW OXYGEN LEVEL INTRINSICALLY PRIMES CANCER CELLS FOR IRRADIATION RESISTANCE “Radiosensitivity” defines the intrinsic sensitivity of tumor cells to radiation therapy. This property appears very heterogeneous within solid tumors and is impacted at two levels by hypoxia. Hypoxia promotes additional pleiotropic cellular adaptions through hypoxia-associated signaling pathways, which can prime cancer cells for radiotherapy resistance These include cell metabolism rewiring, ROS detoxification, autophagy, and resistance to cell death (Figure 3)

Cell Metabolism

ROS Homeostasis

Findings

Cell Death Resistance