Abstract
Even though bystander effects pertaining to radiation risk assessment has been extensively studied, the molecular players of radiation induced bystander effect (RIBE) in the context of cancer radiotherapy are poorly known. In this regard, the present study is aimed to investigate the effect of irradiated tumor cells on the bystander counterparts in mouse fibrosarcoma (WEHI 164 cells) tumor model. Mice co-implanted with WEHI 164 cells γ-irradiated with a lethal dose of 15 Gy and unirradiated (bystander) WEHI 164 cells showed inhibited tumor growth, which was measured in terms of tumor volume and Luc+WEHI 164 cells based bioluminescence in vivo imaging. Histopathological analysis and other assays revealed decreased mitotic index, increased apoptosis and senescence in these tumor tissues. In addition, poor angiogenesis was observed in these tumor tissues, which was further confirmed by fluorescence imaging of tumor vascularisation and CD31 expression by immuno-histochemistry. Interestingly, the growth inhibitory bystander effect was exerted more prominently by soluble factors obtained from the irradiated tumor cells than the cellular fraction. Cytokine profiling of the supernatants obtained from the irradiated tumor cells showed increased levels of VEGF, Rantes, PDGF, GMCSF and IL-2 and decreased levels of IL-6 and SCF. Comparative proteomic analysis of the supernatants from the irradiated tumor cells showed differential expression of total 24 protein spots (21 up- and 3 down-regulated) when compared with the supernatant from the unirradiated control cells. The proteins which showed substantially higher level in the supernatant from the irradiated cells included diphosphate kinase B, heat shock cognate, annexin A1, angiopoietin-2, actin (cytoplasmic 1/2) and stress induced phosphoprotein 1. However, the levels of proteins like annexin A2, protein S100 A4 and cofilin was found to be lower in this supernatant. In conclusion, our results provided deeper insight about the damaging RIBE in an in vivo tumor model, which may have significant implication in improvement of cancer radiotherapy.
Highlights
Radiotherapy is one of the common modalities for the treatment of cancer patients
Such interaction known as radiation induced bystander effect (RIBE) may significantly contribute towards clinical outcome of cancer radiotherapy depending on the nature and magnitude of the effect [1,2,3]
Effect of irradiated cells on the tumor growth of bystander tumor cells To study the effect of irradiated tumor cells on the growth of bystander tumor cells under in vivo conditions, mice were implanted with irradiated tumor cells mixed with bystander tumor cells and the tumor growth was monitored
Summary
There are issues such as radio-resistance, recurrence, side effects associated with radiotherapy which pose serious challenge before the clinicians. These issues can be better addressed through deeper insight of radiobiological processes (like bystander effect, genomic instability) under clinical conditions. There are ample situations arise during cancer radiotherapy in which irradiated tumor cells interact with bystander tumor cells. Such interaction known as radiation induced bystander effect (RIBE) may significantly contribute towards clinical outcome of cancer radiotherapy depending on the nature and magnitude of the effect [1,2,3]. Molecular understanding of RIBE in relevance to cancer radiotherapy is poorly known
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