Carbon Ion Radiobiology

Radiotherapy using accelerated charged particles is rapidly growing worldwide. About 85% of the cancer patients receiving particle therapy are irradiated with protons, which have physical advantages compared to X-rays but a similar biological response. In addition to the ballistic advantages, heavy ions present specific radiobiological features that can make them attractive for treating radioresistant, hypoxic tumors. An ideal heavy ion should have lower toxicity in the entrance channel (normal tissue) and be exquisitely effective in the target region (tumor). Carbon ions have been chosen because they represent the best combination in this direction. Normal tissue toxicities and second cancer risk are similar to those observed in conventional radiotherapy. In the target region, they have increased relative biological effectiveness and a reduced oxygen enhancement ratio compared to X-rays. Some radiobiological properties of densely ionizing carbon ions are so distinct from X-rays and protons that they can be considered as a different “drug” in oncology, and may elicit favorable responses such as an increased immune response and reduced angiogenesis and metastatic potential. The radiobiological properties of carbon ions should guide patient selection and treatment protocols to achieve optimal clinical results

The role of hypoxia and radiation in developing a CTCs-like phenotype in murine osteosarcoma cells

Introduction: Cancer treatment has evolved significantly, yet concerns about tumor recurrence and metastasis persist. Within the dynamic tumor microenvironment, a subpopulation of mesenchymal tumor cells, known as Circulating Cancer Stem Cells (CCSCs), express markers like CD133, TrkB, and CD47, making them radioresistant and pivotal to metastasis. Hypoxia intensifies their stemness, complicating their identification in the bloodstream. This study investigates the interplay of acute and chronic hypoxia and radiation exposure in selecting and characterizing cells with a CCSC-like phenotype. Methods: LM8 murine osteosarcoma cells were cultured and subjected to normoxic (21% O2) and hypoxic (1% O2) conditions. We employed Sphere Formation and Migration Assays, Western Blot analysis, CD133 Cell Sorting, and CD133+ Fluorescent Activated Cell Sorting (FACS) analysis with a focus on TrkB antibody to assess the effects of acute and chronic hypoxia, along with radiation exposure. Results: Our findings demonstrate that the combination of radiation and acute hypoxia enhances stemness, while chronic hypoxia imparts a cancer stem-like phenotype in murine osteosarcoma cells, marked by increased migration and upregulation of CCSC markers, particularly TrkB and CD47. These insights offer a comprehensive understanding of the interactions between radiation, hypoxia, and cellular responses in the context of cancer treatment. Discussion: This study elucidates the complex interplay among radiation, hypoxia, and cellular responses, offering valuable insights into the intricacies and potential advancements in cancer treatment

The role of hypoxia and radiation in developing a CTCs-like phenotype in murine osteosarcoma cells

Introduction: Cancer treatment has evolved significantly, yet concerns about tumor recurrence and metastasis persist. Within the dynamic tumor microenvironment, a subpopulation of mesenchymal tumor cells, known as Circulating Cancer Stem Cells (CCSCs), express markers like CD133, TrkB, and CD47, making them radioresistant and pivotal to metastasis. Hypoxia intensifies their stemness, complicating their identification in the bloodstream. This study investigates the interplay of acute and chronic hypoxia and radiation exposure in selecting and characterizing cells with a CCSC-like phenotype.Methods: LM8 murine osteosarcoma cells were cultured and subjected to normoxic (21% O2) and hypoxic (1% O2) conditions. We employed Sphere Formation and Migration Assays, Western Blot analysis, CD133 Cell Sorting, and CD133+ Fluorescent Activated Cell Sorting (FACS) analysis with a focus on TrkB antibody to assess the effects of acute and chronic hypoxia, along with radiation exposure.Results: Our findings demonstrate that the combination of radiation and acute hypoxia enhances stemness, while chronic hypoxia imparts a cancer stem-like phenotype in murine osteosarcoma cells, marked by increased migration and upregulation of CCSC markers, particularly TrkB and CD47. These insights offer a comprehensive understanding of the interactions between radiation, hypoxia, and cellular responses in the context of cancer treatment.Discussion: This study elucidates the complex interplay among radiation, hypoxia, and cellular responses, offering valuable insights into the intricacies and potential advancements in cancer treatment

Towards sustainable human space exploration—priorities for radiation research to quantify and mitigate radiation risks

Human spaceflight is entering a new era of sustainable human space exploration. By 2030 humans will regularly fly to the Moon’s orbit, return to the Moon’s surface and preparations for crewed Mars missions will intensify. In planning these undertakings, several challenges will need to be addressed in order to ensure the safety of astronauts during their space travels. One of the important challenges to overcome, that could be a major showstopper of the space endeavor, is the exposure to the space radiation environment. There is an urgent need for quantifying, managing and limiting the detrimental health risks and electronics damage induced by space radiation exposure. Such risks raise key priority topics for space research programs. Risk limitation involves obtaining a better understanding of space weather phenomena and the complex radiation environment in spaceflight, as well as developing and applying accurate dosimetric instruments, understanding related short- and long-term health risks, and strategies for effective countermeasures to minimize both exposure to space radiation and the remaining effects post exposure. The ESA/SciSpacE Space Radiation White Paper identifies those topics and underlines priorities for future research and development, to enable safe human and robotic exploration of space beyond Low Earth Orbit

Helium ions for radiotherapy? Physical and biological verifications of a novel treatment modality

Purpose: Modern facilities for actively scanned ion beam radiotherapy allow in principle the use of helium beams, which could present specific advantages, especially for pediatric tumors. In order to assess the potential use of these beams for radiotherapy, i.e., to create realistic treatment plans, the authors set up a dedicated He-4 beam model, providing base data for their treatment planning system TRiP98, and they have reported that in this work together with its physical and biological validations. Methods: A semiempirical beam model for the physical depth dose deposition and the production of nuclear fragments was developed and introduced in TRiP98. For the biological effect calculations the last version of the local effect model was used. The model predictions were experimentally verified at the HIT facility. The primary beam attenuation and the characteristics of secondary charged particles at various depth in water were investigated using He-4 ion beams of 200 MeV/u. The nuclear charge of secondary fragments was identified using a Delta E/E telescope. 3D absorbed dose distributions were measured with pin point ionization chambers and the biological dosimetry experiments were realized irradiating a Chinese hamster ovary cells stack arranged in an extended target. Results: The few experimental data available on basic physical processes are reproduced by their beam model. The experimental verification of absorbed dose distributions in extended target volumes yields an overall agreement, with a slight underestimation of the lateral spread. Cell survival along a 4 cm extended target is reproduced with remarkable accuracy. Conclusions: The authors presented a simple simulation model for therapeutical He-4 beams which they introduced in TRiP98, and which is validated experimentally by means of physical and biological dosimetries. Thus, it is now possible to perform detailed treatment planning studies with He-4 beams, either exclusively or in combination with other ion modalities. (C) 2016 Author(s)

Carbon Ion Radiobiology

Radiotherapy using accelerated charged particles is rapidly growing worldwide. About 85% of the cancer patients receiving particle therapy are irradiated with protons, which have physical advantages compared to X-rays but a similar biological response. In addition to the ballistic advantages, heavy ions present specific radiobiological features that can make them attractive for treating radioresistant, hypoxic tumors. An ideal heavy ion should have lower toxicity in the entrance channel (normal tissue) and be exquisitely effective in the target region (tumor). Carbon ions have been chosen because they represent the best combination in this direction. Normal tissue toxicities and second cancer risk are similar to those observed in conventional radiotherapy. In the target region, they have increased relative biological effectiveness and a reduced oxygen enhancement ratio compared to X-rays. Some radiobiological properties of densely ionizing carbon ions are so distinct from X-rays and protons that they can be considered as a different “drug” in oncology, and may elicit favorable responses such as an increased immune response and reduced angiogenesis and metastatic potential. The radiobiological properties of carbon ions should guide patient selection and treatment protocols to achieve optimal clinical results

Influence of LET and oxygen status on cell survival and adhesion molecule expression

Hypoxia is one of the most common causes for tumor radio-resistance and metastasis. High LET irradiation is expected to reduce these problems. To measure the oxygen enhancement ratio (OER), the relative biological effectiveness (RBE) and the adhesion molecule expression, experiments with different LET, ions (carbon, nitrogen, oxygen and lithium) at different oxygen concentrations have been done. 1)To simulate different tumor conditions, CHO-K1 (Chinese Hamster Ovary) cell survival, has been measured after x-ray or carbon (100 keV/μm) irradiation under normoxic (air), hypoxic (0.5% oxygen) and anoxic (0% oxygen) conditions. The carbon irradiation gave an OER value of 1.8±0.1 in anoxia, while for photon irradiation it results in a value of 2.4±0.1. In hypoxia, the OER values decrease to 1.29±0.07 and to 1.5±0.1 for carbon and photon irradiation respectively. 2)To measure the influence of LET and atomic number on the OER, survival curves and measurement of RBE and OER with carbon ion at different LET, nitrogen and oxygen have been done. •The results showed that even if there were almost no differences in RBE in this LET range under oxic conditions, in anoxia RBE increases with increasing LET. The range of values found was from 3.1±0.2 for carbon 100 keV/μm to 4.4±0.2 for nitrogen 160 keV/μm (anoxia) and from 2.6±0.2 to 2.4±0.2 (normoxia). OER values decrease with increasing LET. Using different ions with different LET, the values found were from 1.8±0.1 for carbon 100 keV/μm to 1.30±0.04 for nitrogen 160 keV/μm. A clear influence of atomic number could not be seen in this atomic number range. 3)To measure a possible influence of the atomic numbers on the RBE for normal tissue and tumor tissue, experiments with irradiation of extended volume have been performed with nitrogen and oxygen and compared with carbon measurements. •Measurements resulting in a comparable survival on the entrance channel and exhibit the highest efficiency in the tumor for nitrogen ion. Mono-energetic lithium experiments showed RBE values close to 1 in the first centimetres of the plateau and an increase in RBE inside the Bragg peak. Results were compared to different model calculations. iv 4)As a model to better resemble the conditions in a human tumor and to study the E-cadherin expression after X-ray and carbon ion exposure, the PC3 cell line (Human prostate cancer cells) has been used. Survival curves experiment with normoxic and re-oxygenated chronic hypoxic cells have been performed. •After 72 hours in hypoxia/re-oxygenation the cells showed a decrease in radio-resistance when irradiated with X-rays but not when irradiated with carbon ions. Cell cycle synchronization due to an insufficient oxygenation could be the explanation for this. 5)To study the adhesion molecules and to understand the underlying mechanisms that give to the cells the invasive phenotype measurements of E-cadherin protein and gene expression have been performed. No difference after 24 hours anoxia in the protein expression was discovered compared to the normal oxic condition. Irradiation with X-rays produces a slight increase of E-cadherin after hypoxic treatment compared to normoxic cells. A low dose of carbon ion irradiation resulted in an over-expression of E-cadherin. For X-rays, this effect was not found. X-ray irradiation with low doses seems to reduce E-cadherin expression compared to unirradiated cells or irradiation with high doses

Tumor Hypoxia and Circulating Tumor Cells

Circulating tumor cells (CTCs) are a rare tumor cell subpopulation induced and selected by the tumor microenvironment’s extreme conditions. Under hypoxia and starvation, these aggressive and invasive cells are able to invade the lymphatic and circulatory systems. Escaping from the primary tumor, CTCs enter into the bloodstream to form metastatic deposits or re-establish themselves in cancer’s primary site. Although radiotherapy is widely used to cure solid malignancies, it can promote metastasis. Radiation can disrupt the primary tumor vasculature, increasing the dissemination of CTCs. Radiation also induces epithelial–mesenchymal transition (EMT) and eliminates suppressive signaling, causing the proliferation of existent, but previously dormant, disseminated tumor cells (DTCs). In this review, we collect the results and evidence underlying the molecular mechanisms of CTCs and DTCs and the effects of radiation and hypoxia in developing these cells