Radiation-induced Bystander Effect (RIBE) alters mitochondrial metabolism using a human rectal cancer ex vivo explant model

Aisling B Heeran,Helen P Berrigan,Croí E Buckley,Heleena Moni Bottu,Orla Prendiville,Amy M Buckley,Niamh Clarke,Noel E Donlon,Timothy S Nugent,Michael Durand,Cara Dunne,John O Larkin,Brian Mehigan,Paul Mccormick,Lorraine Brennan,Niamh Lynam-Lennon,Jacintha O'Sullivan

doi:10.1016/j.tranon.2020.100882

Aisling B Heeran, Helen P Berrigan + Show 15 more

Open Access

https://doi.org/10.1016/j.tranon.2020.100882

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Abstract

Locally advanced rectal cancer is treated with neoadjuvant-chemoradiotherapy, however only 22% of patients achieve a complete response. Resistance mechanisms are poorly understood. Radiation-induced Bystander Effect (RIBE) describes the effect of radiation on neighbouring unirradiated cells. We investigated the effects of ex vivo RIBE-induction from normal and rectal cancer tissue on bystander cell metabolism, mitochondrial function and metabolomic profiling. We correlated bystander events to patient clinical characteristics.Ex vivo RIBE-induction caused metabolic alterations in bystander cells, specifically reductions in OXPHOS following RIBE-induction in normal (p = 0.01) and cancer tissue (p = 0.03) and reduced glycolysis following RIBE-induction in cancer tissue (p = 0.01). Visceral fat area correlated with glycolysis (p = 0.02) and ATP production (p = 0.03) following exposure of cells to TCM from irradiated cancer biopsies. Leucine levels were reduced in the irradiated cancer compared to the irradiated normal secretome (p = 0.04). ROS levels were higher in cells exposed to the cancer compared to the normal secretome (p = 0.04).RIBE-induction ex vivo causes alterations in the metabolome in normal and malignant rectal tissue along with metabolic alterations in bystander cellular metabolism. This may offer greater understanding of the effects of RIBE on metabolism, mitochondrial function and the secreted metabolome.

Highlights

Colorectal cancer (CRC) is the 3rd most commonly diagnosed cancer globally and the 2nd leading cause of cancer death [1]
Using a novel human ex vivo explant model of rectal cancer and normal rectal tissue, we have shown for the first time that Radiation-induced Bystander Effect (RIBE) induction ex vivo causes significant alterations in bystander cellular energy metabolism
We have demonstrated that metabolite profiles, leucine concentrations, differed in the secretome between irradiated rectal cancer tissue and irradiated normal rectal tissue, with leucine levels being reduced in the irradiated cancer secretome compared to the irradiated normal secretome

Summary

Introduction

Colorectal cancer (CRC) is the 3rd most commonly diagnosed cancer globally and the 2nd leading cause of cancer death [1]. Within the European Union, rectal cancer accounts for approximately 35% of all cases of CRC [2]. Radioresistance is a considerable problem in rectal cancer with only 22% of patients achieving a complete pathological response (pCR) to neoadjuvant chemoradiation (neo-CRT) [5], which is the best predictor of long-term patient outcome [6]. The mechanisms underlying this resistance are poorly understood and the effect of radiation on bystander cells adjacent to the irradiated volume is largely unknown

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