Heeran Aisling B, Berrigan Helen P, Buckley Croí E, Bottu Heleena Moni, Prendiville Orla, Buckley Amy M, Clarke Niamh, Donlon Noel E, Nugent Timothy S, Durand Michael, Dunne Cara, Larkin John O, Mehigan Brian, McCormick Paul, Brennan Lorraine, Lynam-Lennon Niamh, O'Sullivan Jacintha
Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin 8, Ireland.
Institute of Food and Health and Conway Institute, UCD School of Agriculture and Food Science, UCD, Belfield, Dublin 4, Ireland.
Transl Oncol. 2021 Jan;14(1):100882. doi: 10.1016/j.tranon.2020.100882. Epub 2020 Oct 23.
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.
局部晚期直肠癌采用新辅助放化疗进行治疗，然而只有22%的患者实现完全缓解。耐药机制尚不清楚。辐射诱导旁效应（RIBE）描述了辐射对邻近未受辐射细胞的影响。我们研究了从正常和直肠癌组织进行体外RIBE诱导对旁观者细胞代谢、线粒体功能和代谢组学分析的影响。我们将旁观者事件与患者临床特征相关联。体外RIBE诱导导致旁观者细胞发生代谢改变，具体表现为在正常组织（p = 0.01）和癌组织（p = 0.03）中RIBE诱导后氧化磷酸化减少，以及在癌组织中RIBE诱导后糖酵解减少（p = 0.01）。在细胞暴露于来自受辐射癌组织活检的中药后，内脏脂肪面积与糖酵解（p = 0.02）和ATP产生（p = 0.03）相关。与受辐射正常分泌组相比，受辐射癌组织中的亮氨酸水平降低（p = 0.04）。与正常分泌组相比，暴露于癌组织的细胞中ROS水平更高（p = 0.04）。体外RIBE诱导导致正常和恶性直肠组织的代谢组发生改变，同时旁观者细胞代谢也发生代谢改变。这可能有助于更深入了解RIBE对代谢、线粒体功能和分泌代谢组的影响。
