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 (pâ¯=â¯0.01) and cancer tissue (pâ¯=â¯0.03) and reduced glycolysis following RIBE-induction in cancer tissue (pâ¯=â¯0.01). Visceral fat area correlated with glycolysis (pâ¯=â¯0.02) and ATP production (pâ¯=â¯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 (pâ¯=â¯0.04). ROS levels were higher in cells exposed to the cancer compared to the normal secretome (pâ¯=â¯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.
ABSTRACT
Radiation therapy is one of the pillars of cancer treatment, with approximately one half of all cancer patients receiving it as part of their standard of care. Emerging evidence indicates that the biological effects of radiation are not limited to targeted cells. The radiation-induced bystander effect (RIBE) refers to the plethora of biological phenomena occurring in nonirradiated cells as a result of signal transmission from an irradiated cell. Experimental evidence has linked RIBE to numerous hallmarks of cancer including resisting cell death, tumor immune evasion, genomic instability, deregulated cellular energetics, tumor-promoting inflammation and sustained proliferative signaling as well as enhanced radioresistance, thus highlighting the potential role of RIBE events in patient treatment response. The mechanisms underlying RIBE events in vivo are poorly understood. However, elucidating the molecular mechanisms involved in their manifestation may reveal novel therapeutic targets to improve radiation response in cancer patients.
