High Energy Particle Radiation-associated Oncogenic Transformation in Normal Mice: Insight into the Connection between Activation of Oncotargets and Oncogene Addiction

Abstract

Concerns on high-energy particle radiation-induced tumorigenic transformation of normal tissue in astronauts, and in cancer patients undergoing radiotherapy, emphasizes the significance of elucidating the mechanisms involved in radiogenic transformation processes. Mostly used genetically modified or tumor-prone models are less reliable in determining human health risk in space or protracted post-treatment normal tissue toxicity. Here, in wild type C57BL/6 mice, we related the deregulation of distinctive set of tissue-specific oncotargets in major organs upon 56Fe (600 MeV/amu; 0.5 Gy/min; 0.8 Gy) particle radiation and compared the response with low LET γ-radiation (137Cs; 0.5 Gy/min; 2 Gy). One of the novel findings is the ‘tissue-independent’ activation of TAL2 upon high-energy radiation, and thus qualifies TAL2 as a potential biomarker for particle and other qualities of radiation. Heightened expression of TAL2 gene transcript, which sustained over four weeks post-irradiation foster the concept of oncogene addiction signaling in radiogenic transformation. The positive/negative expression of other selected oncotargets that expresses tissue-dependent manner indicated their role as a secondary driving force that addresses the diversity of tissue-dependent characteristics of tumorigenesis. This study, while reporting novel findings on radiogenic transformation of normal tissue when exposed to particle radiation, it also provides a platform for further investigation into different radiation quality, LET and dose/dose rate effect in healthy organs.

The Oncogene Addiction Switch from NOTCH to PI3K Requires Simultaneous Targeting of NOTCH and PI3K Pathway Inhibition in Glioblastoma

“…“Oncogene addiction” refers to the need that tumor cells have for sustained abundant oncogene signaling, which maintains their viability [24,25,26], and explains the requirement for continuous NOTCH signaling in GICs with mutations in NOTCH [27,28]. Our data indicate that loss of function with PTEN in GICs may result in resistance to NOTCH inhibition by GSI treatment.…”

Down-Regulation of the Proteoglycan Decorin Fills in the Tumor-Promoting Phenotype of Ionizing Radiation-Induced Senescent Human Breast Stromal Fibroblasts

“…The reduced expression of decorin was demonstrated to be a long-term effect, since it seemed to augment along with the number of subcultures post-irradiation, while no change in decorin transcriptional levels was observed within the first 24 h after exposure of the cells to ionizing radiation. In favor of our findings, exposure of mice to acute low γ-irradiation doses induced significant down-regulation of decorin protein levels in the neonatal mouse heart seven months later [ 87 ], while decorin was suppressed in healthy mouse tissues 30 days post-exposure to high linear energy transfer radiation [ 88 ].…”

LIF Inhibits Proliferation of Esophageal Squamous Carcinoma Cells by Radiation Mediated Through JAK-STAT Signaling Pathway

“…Proteomics provides a powerful means of understanding cancer pathophysiology and identifying new therapeutic targets. Carbon ion radiation has been shown to induce transcription and translation of VEGF-alpha in cancer cells 21 . Based on these previous studies, further in-depth proteomic profiling analyses protein expression in ECA109 cells irradiated with 2 Gy carbon ions.…”