Double strand break induction and kinetics indicate preserved hypersensitivity in keratinocytes to subtherapeutic doses for 7weeks of radiotherapy

UV-Radiation Response Proteins Reveal Undifferentiated Cutaneous Interfollicular Melanocytes with Hyperradiosensitivity to Differentiation at 0.05 Gy Radiotherapy Dose Fractions

“…We suggest that the hypersensitivity response toward melanocyte differentiation reflects incomplete phosphorylation of ATM in keratinocytes over the low-dose range (56) and corresponding incomplete dose-dependent paracrine signaling from keratinocytes. It has been previously established that skin keratinocytes exhibit hypersensitivity below 0.3 Gy for DNA DSBs, growth arrest, mitosis, apoptosis and overall cell loss (2)(3)(4).…”

“…These radiotherapy techniques have increased the interest in understanding the DNA damage response and cellular outcome after irradiation at sub-therapeutic doses, particularly for cell types that respond with hypersensitivity to very low doses of ionizing radiation. In previously published clinical studies of the effects of radiation on skin samples, particularly keratinocytes, low-dose hypersensitivity was established using doses below 0.3 Gy for the following cellular end points (1)(2)(3)(4): induction of DNA double-strand breaks (DSBs), growth arrest, apoptosis and rate of keratinocyte loss in the basal cell layer. The low-dose hypersensitivity, which was followed by induced radioresistance, persisted in epidermal keratinocytes for all measured effects over a radiotherapy course of 7 weeks, given daily dose fractions of 0.05-1.1 Gy.…”

Exposure of Human Skin Organoids to Low Genotoxic Stress Can Promote Epithelial-to-Mesenchymal Transition in Regenerating Keratinocyte Precursor Cells

“…High radiation doses such as those delivered during radiation therapy (RT) produce pathological changes in mesenchymal tissues with long-term alterations of fibroblast phenotypic and functional characteristics that may impair the quality of life of treated cancer patients [16,26,27], whereas the pathophysiology of epithelial complications of RT has been investigated less [17]. Furthermore, the effects of very low doses of genotoxic stress are poorly documented [19,28], although dysplasia has been reported in the skin of radiotherapy patients [18]. We have here addressed the question of possible adverse reactions subsequent to the exposition of keratinocyte stem and progenitor cells to low radiation doses.…”

“…Skin is of particular concern regarding RT adverse reactions, as this organ can develop different types of short-and long-term radio-pathologies [16]. Our group and I. Turesson's group in Sweden have shown that human skin, and notably the epidermis, can develop different types of complications after exposure to high [17] or low [18,19] radiation doses, complications such as erythema, epidermitis, dysplasia, as well as acanthosis and carcinoma in the long-term. However, the contributions of specific target cell populations in these pathophysiological processes still require in-depth studies.…”

Radiation Biomarkers in Large Scale Human Health Effects Studies

“…Considerable progress has been made recently in the development, standardisation and validation of exposure biomarkers, e.g., through the European Union (EU) projects MULTIBIODOSE (Multi-disciplinary biodosimetric tools to manage high scale radiological casualties; https://cordis.europa.eu/project/id/241536) and RENEB (Realizing the European Network of Biodosimetry; http://cordis.europa.eu/project/id/295513). Progress in the area of predictive markers of individual response to radiation exposure has been much more limited, although a number of small scale studies (7-10 patients plus matched controls) and recently larger studies (42->1000 patients) have also suggested an association of DNA double-strand break-related markers or apoptosis with clinical radiosensitivity in non-syndromic patients [8][9][10][11][12][13].…”