Stereotactic Body Radiation Therapy (SBRT) for prostate cancer: Preliminary results of toxicity

To the Editor, Prostate cancer is the second most common cancer in men in Morocco after lung cancer. External radiotherapy (RTE) is a curative therapeutic option for localized prostate cancer, However the conventional RTE remains a long treatment (7- 8 weeks, 5 days a week) which is demanding for patients and make difficult to manage the waiting lists. The development of imaging and irradiation techniques over the last decades has allowed a high precision in the delivery of the dose to the target organ and a better protection of the organs at risk (OAR), which has encouraged the hypo fractionated irradiation of localized prostate cancer, especially after the results of radiobiology studies that suggested a low report a/b for the prostate.

Changes in the Cortex Neurons in Single and Fractional Gamma Radiation

Purpose: Comparative assessment of radiation-induced changes in neurons of the cerebral cortex after a single and fractionated exposure to ionizing radiation in doses of 0.1 – 1.0 Gy. Material and methods. The study was carried out in compliance with the rules of bioethics on 180 white outbred male rats at the age of 4 months. by the beginning of the experiment, exposed to a single or fractionated exposure to γ-quanta of 60Co in total doses of 0.1; 0.2; 0.5 and 1.0 Gy. Neuromorphological and histochemical methods were used to assess morphometric and tinctorial parameters of nerve cells, as well as changes in the content of protein and nucleic acids in neurons in the early and late periods of the post-radiation period. Using one-way analysis of variance, a comparative assessment of neuromorphological indicators under various modes of radiation exposure is given. Results: In the control and irradiated animals throughout their life, undulating changes in the indicators of the state of the neurons of the brain occur with a gradual decrease by the end of the experiment. Despite a number of features of the dynamics of neuromorphological parameters, these irradiation regimes do not cause functionally significant changes in the neurons of the cortex. However, in some periods of the post-radiation period, the changes under the studied irradiation regimes were multidirectional and did not always correspond to age control. Significant differences in the response of neurons to these modes of radiation exposure in the sensory and motor areas of the cerebral cortex have not been established. Conclusion: No functionally significant radiation-induced changes in neurons were found either with single or fractionated irradiation. At the same time, different modes of irradiation in general caused the same type of changes in neurons. However, in some periods of observation, changes in neuromorphological parameters under the studied irradiation regimes were not unidirectional and differed from age control, which indicates a possible risk of disturbances in the functioning of the nervous system against the background of other harmful and dangerous factors.

Low-Dose Fractionated Irradiation Selectivly Regulate CSPGs and PNNs, Promote Serotonergic Axonal Regeneration

Chondroitin sulphate proteoglycans (CSPGs) are major components to impeding axonal regeneration, condense in the extracellular-matrix to form perineuronal nets (PNNs) which interdigitate with axonal contacts. Each CSPG comprises a core protein with covalently attached chondroitin-sulfate glycosaminoglycan side chains (CS moieties). In the past, the representative treatment for CSPGs were chondroitinase-ABC which destroys all CS moieties. However, recent rodents researches found some CS moieties promote axon regeneration rather than inhibit axon regeneration. Using a canine model of spinal cord injury (SCI), which is a superior translational model for progressing rodent data into clinical practice, we showed that specific sulfation patterns of CS moieties play different role in modulation of axon re-growth. Upregulated CS-A expression occurred at 1-day post-SCI, earlier than CS-C expression which was increased at 14-days post-SCI. CS-A was mainly colocalized with astrocytes but CS-C was upregulated in both astrocytes and neurons/axons. Treatment with low-dose fractionated irradiation (LDI) significantly inhibited the expressions of astrocyte-associated CS-A and CS-A-enriched PNNs, but no inhibitory effect on CS-C and CS-C-enriched PNNs. There was a positive correlation between a reduction of CS-A-enriched PNNs and an increase of serotonergic (5-hydroxytryptamine, 5-HT) axonal sprouting. Increased serotonergic axon sprouting proximal to the lesion accompanied 5HT receptor up regulation following LDI treatment. Furthermore, LDI treatment promoted hindlimb motor function recovery following SCI. Taken together, our findings show that specific sulfation patterns of CS moieties and CSPG-enriched PNNs involved in carrying instructions for regulating axonal regeneration and that LDI treatment may be an efficacious strategy for treating SCI.

Interferon- and STING-independent induction of type I interferon stimulated genes during fractionated irradiation

Background Improvement of radiotherapy efficacy requires better insight in the dynamic responses that occur during irradiation. Here, we aimed to identify the molecular responses that are triggered during clinically applied fractionated irradiation. Methods Gene expression analysis was performed by RNAseq or microarray analysis of cancer cells or xenograft tumors, respectively, subjected to 3–5 weeks of 5 × 2 Gy/week. Validation of altered gene expression was performed by qPCR and/or ELISA in multiple cancer cell lines as well as in pre- and on-treatment biopsies from esophageal cancer patients (NCT02072720). Targeted protein inhibition and CRISPR/Cas-induced gene knockout was used to analyze the role of type I interferons and cGAS/STING signaling pathway in the molecular and cellular response to fractionated irradiation. Results Gene expression analysis identified type I interferon signaling as the most significantly enriched biological process induced during fractionated irradiation. The commonality of this response was confirmed in all irradiated cell lines, the xenograft tumors and in biopsies from esophageal cancer patients. Time-course analyses demonstrated a peak in interferon-stimulated gene (ISG) expression within 2–3 weeks of treatment. The response was accompanied by a variable induction of predominantly interferon-beta and/or -lambda, but blocking these interferons did not affect ISG expression induction. The same was true for targeted inhibition of the upstream regulatory STING protein while knockout of STING expression only delayed the ISG expression induction. Conclusions Collectively, the presented data show that clinically applied fractionated low-dose irradiation can induce a delayed type I interferon response that occurs independently of interferon expression or STING signaling. These findings have implications for current efforts that aim to target the type I interferon response for cancer treatment.

Repeated Irradiation with γ-Ray Induces Cancer Stemness through TGF-β-DLX2 Signaling in the A549 Human Lung Cancer Cell Line

Cancer stem cells (CSCs) play an important role in cancer recurrence and metastasis. It is suggested that the CSC properties in heterogeneous cancer cells can be induced by ionizing radiation (IR). This study investigated the role of DLX2 in the radioresistance and CSC properties induced by IR in NSCLC cancer cells. Here, A549 cells were exposed to fractionated irradiation at a cumulative dose of 52 Gy (4 Gy × 13 times) for a generation of radioresistant cells. After fractionated irradiation, surviving A549 cells exhibited resistance to IR and enhanced expression of various cancer stem cell markers. They also showed upregulation of mesenchymal molecular markers and downregulation of epithelial molecular markers, correlating with an increase in the migration and invasion. Fractionated irradiation triggered the secretion of TGF-β1 and DLX2 expression. Interestingly, the increased DLX2 following fractionated irradiation seemed to induce the expression of the gene for the EGFR-ligand betacellulin via Smad2/3 signaling. To contrast, DLX2 knockdown dramatically decreased the expression of CSC markers, migration, and proliferation. Moreover, A549 cells expressing DLX2 shRNA formed tumors with a significantly smaller volume compared to those expressing control shDNA in a mouse xenograft assay. These results suggest that DLX2 overexpression in surviving NSCLC cancer cells after fractionated IR exposure is involved in the cancer stemness, radioresistance, EMT, tumor survival, and tumorigenic capability.