Biological Effects of Low Dose Radiation (LDR) on Peri-Tumoral and Tumoral Areas with Squamous Cell Skin Cancer

Abstract

<h3>Purpose/Objective(s)</h3> Low dose radiation (LDR) may have paradoxically beneficial effects via an adaptive response. We aimed to assess the adaptive response of healthy and malignant skin tissue to low doses of radiation and explore the molecular details behind the induced adaptive response. <h3>Materials/Methods</h3> We conducted a prospective, randomized pilot study (N=8) to ascertain the biological effects of integrating 0.1 Gy of LDR into standard radiotherapy sessions (2.0 Gy fractions) over the first two weeks of radiotherapy for patients 18-80 years of age (both sexes) diagnosed with squamous cell carcinoma of skin (lesions of 1 – 10 cm). Radiation treatment was done with a linear accelerator. The patients received definitive radiation for the tumor as determined by the treating physician using 2.0 Gy fractions. In addition, 0.1 Gy of LDR was integrated into the standard radiotherapy course on day 0 and day 6 over the first two weeks of treatment. Radiation delivery to healthy tissue was with a 1.5 cm margin around the tumor using a mask over the tumor. We obtained partial thickness skin biopsy samples of the tumor and peri-tumoral normal tissue before treatment from four patients (for control). An additional four patients (actively treated) were biopsied before and 24 hours after 0.1 Gy of LDR (day 0, 1 and day 6, 7). RNA was obtained from skin biopsies and processed for genetic expression (138K genes). <h3>Results</h3> The change in gene expression in healthy peri-tumoral tissues due to LDR exposure was relatively low (only 325 genes: 170 upregulated, 155 downregulated). The <i>senescence and autophagy in cancer</i> and <i>genotoxicity pathway</i> genes showed the most significant downregulation in peritumoral healthy tissue comparing days 0 and 1. The biological pathways in peritumoral healthy tissue comparing days 6 and 7 showed predominantly downregulation of genes with most pronounced downregulation seen in <i>electron transport chain in mitochondria</i> and genes involved in <i>non-alcoholic fatty liver disease</i>. In contrast to normal peritumoral tissue, the difference in gene expression in tumor tissue due to LDR exposure was significantly more pronounced (5,651 genes: 2,896 upregulated, 2,755 downregulated) The <i>allograft rejection</i> genes and <i>nuclear receptor meta-pathway</i> were the most upregulated in the tumoral tissues comparing days 0 and 1. The nuclear receptor meta-pathway were the most upregulated in the tumoral tissues on days 6 and 7. The <i>Allograft rejection pathway in skin cancer</i> was among those upregulated. <h3>Conclusion</h3> LDR had a modest effect on miRNA expression when applied to healthy peritumoral skin. Downregulated pathways predominate, and DNA repair mechanisms are stimulated by the first dose in healthy tissue. In contrast, a more pronounced effect on gene expression (as measured by miRNA profiles), including upregulation of several key relevant pathways, was induced by LDR to malignant tissue.