When DNA Mutations Interplay with Cellular Proliferation: A Narrative History of Theories of Carcinogenesis.

While cancer is one of the most documented diseases, how normal cells become cancerous is still debated. To address this question, in the first part of this review, we investigated the long succession of theories of carcinogenesis since antiquity. Initiated by Hippocrates, Aristotle, and Galen, the humoral theory interpreted cancer as an excess of acid, the black bile. The discovery of the circulation of blood by Harvey in 1628 destroyed the basis of the humoral theory but revived the spontaneous generation hypothesis which was also promoted by Aristotle. In 1859, the theory of microbes promoted by Pasteur demonstrated the irrelevance of this last theory and contributed to the emergence of the germ cancer theory, opposed to the cellular theory of cancer, in which cancer was supposed to be caused by microbes or transformed cells, respectively. These theories were progressively refined by the notions of initiation, promotion, and progression thanks to advances in mutagenesis and cellular proliferation. In the second part of this review, recent discoveries and paradigms in carcinogenesis, notably the role of the protein ATM, a major actor of the stress response involved in both mutagenesis and cellular proliferation, were discussed to better understand the current state of the art of carcinogenesis.

Seventy Years of Dose-response Models: From the Target Theory to the Use of Big Databases Involving Cell Survival and DNA Repair.

Radiobiological data, whether obtained at the clinical, biological or molecular level has significantly contributed to a better description and prediction of the individual dose-response to ionizing radiation and a better estimation of the radiation-induced risks. Particularly, over the last seventy years, the amount of radiobiological data has considerably increased, and permitted the mathematical formulas describing dose-response to become less empirical. A better understanding of the basic radiobiological mechanisms has also contributed to establish quantitative inter-correlations between clinical, biological and molecular biomarkers, refining again the mathematical models of description. Today, big data approaches and, more recently, artificial intelligence may finally complete and secure this long process of thinking from the multi-scale description of radiation-induced events to their prediction. Here, we reviewed the major dose-response models applied in radiobiology for quantifying molecular and cellular radiosensitivity and aimed to explain their evolution: Specifically, we highlighted the advances concerning the target theory with the cell survival models and the progressive introduction of the DNA repair process in the mathematical models. Furthermore, we described how the technological advances have changed the description of DNA double-strand break (DSB) repair kinetics by introducing the important notion of DSB recognition, independent of that of DSB repair. Initially developed separately, target theory on one hand and, DSB recognition and repair, on the other hand may be now fused into a unified model involving the cascade of phosphorylations mediated by the ATM kinase in response to any genotoxic stress.

Neurologic Changes Induced by Whole-Brain Synchrotron Microbeam Irradiation: 10-Month Behavioral and Veterinary Follow-Up.

PURPOSE: Novel radiation therapy approaches have increased the therapeutic efficacy for malignant brain tumors over the past decades, but the balance between therapeutic gain and radiotoxicity remains a medical hardship. Synchrotron microbeam radiation therapy, an innovative technique, deposes extremely high (peak) doses in micron-wide, parallel microbeam paths, whereas the diffusing interbeam (valley) doses lie in the range of conventional radiation therapy doses. In this study, we evaluated normal tissue toxicity of whole-brain microbeam irradiation (MBI) versus that of a conventional hospital broad beam (hBB). METHODS AND MATERIALS: Normal Fischer rats (n = 6-7/group) were irradiated with one of the two modalities, exposing the entire brain to MBI valley/peak doses of 0/0, 5/200, 10/400, 13/520, 17/680, or 25/1000 Gy or to hBB doses of 7, 10, 13, 17, or 25 Gy. Two additional groups of rats received an MBI valley dose of 10 Gy coupled with an hBB dose of 7 or 15 Gy (groups MBI17* and MBI25*). Behavioral parameters were evaluated for 10 months after irradiation combined with veterinary observations. RESULTS: MBI peak doses of ≥680 Gy caused acute toxicity and death. Animals exposed to hBB or MBI dose-dependently gained less weight than controls; rats in the hBB25 and MBI25* groups died within 6 months after irradiation. Increasing doses of MBI caused hyperactivity but no other detectable behavioral alterations in our tests. Importantly, no health concerns were seen up to an MBI valley dose of 17 Gy. CONCLUSIONS: While acute toxicity of microbeam exposures depends on very high peak doses, late toxicity mainly relates to delivery of high MBI valley doses. MBI seems to have a low impact on normal rat behavior, but further tests are warranted to fully explore this hypothesis. However, high peak and valley doses are well tolerated from a veterinary point of view. This normal tissue tolerance to whole-brain, high-dose MBI reveals a promising avenue for microbeam radiation therapy, that is, therapeutic applications of microbeams that are poised for translation to a clinical environment.

Microbeam Radiation Therapy Opens a Several Days' Vessel Permeability Window for Small Molecules in Brain Tumor Vessels.

PURPOSE: Synchrotron microbeam radiation therapy (MRT), based on an inhomogeneous geometric and microscopic irradiation pattern of the tissues with high-dose and high-dose-rate x-rays, enhances the permeability of brain tumor vessels. This study attempted to determine the time and size range of the permeability window induced by MRT in the blood-brain (tumor) barrier. METHODS AND MATERIALS: Rats-bearing 9L gliomas were exposed to MRT, either unidirectional (tumor dose, 406 Gy) or bidirectional (crossfired) (2 × 203 Gy). We measured vessel permeability to molecules of 3 sizes (Gd-DOTA, Dotarem, 0.56 kDa; gadolinium-labeled albumin, ∼74 kDa; and gadolinium-labeled IgG, 160 kDa) by daily in vivo magnetic resonance imaging, from 1 day before to 10 days after irradiation. RESULTS: An equivalent tumor dose of bidirectional MRT delivered from 2 orthogonal directions increased tumor vessel permeability for the smallest molecule tested more effectively than unidirectional MRT. Bidirectional MRT also affected the permeability of normal contralateral vessels to a different extent than unidirectional MRT. Conversely, bidirectional MRT did not modify the permeability of normal or tumor vessels for both larger molecules (74 and 160 kDa). CONCLUSIONS: High-dose bidirectional (cross-fired) MRT induced a significant increase in tumor vessel permeability for small molecules between the first and the seventh day after irradiation, whereas permeability of vessels in normal brain tissue remained stable. Such a permeability window could facilitate an efficient and safe delivery of intravenous small molecules (≤0.56 kDa) to tumoral tissues. A permeability window was not achieved by molecules larger than gado-grafted albumin (74 kDa). Vascular permeability for molecules between these 2 sizes has not been determined.