title: Molecular Understanding of Growth Inhibitory Effect from Irradiated to Bystander Tumor Cells in Mouse Fibrosarcoma Tumor Model.
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.
authors: Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, Maharashtra, India.|Homi Bhabha National Institute, Mumbai, Maharashtra, India.
authors: Sejal
authors: S
authors: Desai
authors: Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, Maharashtra, India.
authors: Nishad
authors: N
authors: Srambikkal
authors: Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, Maharashtra, India.
authors: Hansa D
authors: HD
authors: Yadav
authors: Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, Maharashtra, India.
authors: Neena
authors: N
authors: Shetake
authors: Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, Maharashtra, India.
authors: Murali M S
authors: MM
authors: Balla
authors: Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, Maharashtra, India.|Homi Bhabha National Institute, Mumbai, Maharashtra, India.
authors: Amit
authors: A
authors: Kumar
authors: Advanced Centre for Training, Research and Education of Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India.|Homi Bhabha National Institute, Mumbai, Maharashtra, India.
authors: Pritha
authors: P
authors: Ray
authors: Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, Maharashtra, India.|Homi Bhabha National Institute, Mumbai, Maharashtra, India.
authors: Anu
authors: A
authors: Ghosh
authors: Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, Maharashtra, India.|Homi Bhabha National Institute, Mumbai, Maharashtra, India.
authors: B N
authors: http://orcid.org/0000-0001-6862-4424
authors: BN
authors: Pandey
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D024201:Bystander Effect / Q000528:radiation effects*; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000532:radiotherapy*; D005720:Gamma Rays; D051379:Mice; D008807:Mice, Inbred BALB C; D008940:Mitotic Index; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D040901:Proteomics; D011829:Radiation Dosage; D011878:Radiotherapy; D015398:Signal Transduction