Extended investigations of low dose radiation effects

The planned 3-year project is an extension of Dr. Schöllnbergers ongoing research efforts that he has been conducting within FWF grant P18055 at the University of Salzburg. The project is also in the tradition of his earlier high-level studies in the US (participation in the DOE Low Dose Project) and the Netherlands (EU Marie Curie Individual Fellowship). One important biological endpoint that has been extensively used in the past for risk estimations is in vitro neoplastic transformation. In the planned project a novel biophysical model will be developed that allows to simulate this biological endpoint. The model is especially suited to describe protective effects of low doses of low-LET radiation as discovered 10 years ago by Dr. Azzam and his colleagues. They observed that after low dose gamma-ray exposures the risk of in vitro neoplastic transformation was reduced from the spontaneous level to a rate three- to fourfold below that level. In the planned project the different biological mechanisms that could lead to these protective effects will be studied. One possibility is bystander-induced apoptosis. Here, Dr. Schöllnbergers earlier developed model will be implemented into the new model. A mathematical extension will make the model more realistic with respect to its dose-dependence. Genomic instability will also be included into the model together with low-dose hyper- radiosensitivity and induced radioresistance. The new models will be tested on an important and representative data set of Dr. Redpaths laboratory that shows a reduction of the transformation frequency below the spontaneous frequency. This aspect of the planned project is especially innovative because it parallels experimental efforts from one of the most renowned European laboratories for the investigation of the intercellular induction of apoptosis. Dr. Schöllnbergers planned visits and collaborations with Dr. Georg Bauer, the head of this research group, will lead to a detailed biophysical model for this bystander-induced protective effect. The model will be implemented into a high-level computer language and interactive environment. Other possibilities to explain the data sets of Azzam and Redpath relate to a radiological induction of radical scavengers and error-free DNA repair that also impact on endogenously produced radicals and DNA lesions. This will also be investigated. These deterministic models will be made stochastic by Monte Carlo Simulations. The proposed new model for in vitro neoplastic transformation comprises system-biological concepts by simulating two levels of biological organization: the molecular and the cellular level. The model fits to the in vitro data will lead to certain values for the degree of induction of various cellular defence mechanisms. During the planned project these results will be implemented into Dr. Schöllnbergers existing lung cancer models to perform predictions for the lifetime probability of lung cancer after low dose exposures with gamma rays. The planned project can lead to improved and more realistic risk estimates for low doses of ionizing radiations. These risk estimates will be obtained through mechanistic multistage models at low doses and are therefore much more relevant than traditional estimates that are based on high dose data. With respect to the nuclear power stations at its borders, the planned project is especially relevant for Austrian citizens.

The main finding of FWF project P 21630-N22 of Priv.-Doz. Dr. Helmut Schöllnberger is that the carcinogenic process that leads to the formation of the first cancer cell in lung and colon tumors is dominated by the growth of mutated cells, whereas the mutation rates have less effect. This significant finding that has importance for cancer research was achieved in an international collaboration with top experts from Imperial College London, ETH Zürich, and RIVM in the Netherlands. The FWF Project of Dr. Schöllnberger, until September 2009 working at the University of Salzburg, was mainly concerned with questions related to the origin of the first cancer cell in lung and colon cancer. In a simplified way, the formation of a cancer cell can be imagined as follows: out of a pool of normal stem cells one cell receives a critical mutation leading to a mutant cell. The latter has a selective growth advantage compared to the normal cells leading to a clone of mutated cells. If one of these mutated cells receives another critical mutation, then this cell converts into a malignant cell that may subsequently grow into a clinically detectable tumor. Since decades, it is a much disputed question in cancer research what the most important process is in the formation of the first malignant cell, mutation induction or the clonal growth of mutated cells. Two different state-of-the-art mathematical cancer models were used to investigate this question. One model is an evolutionary concept of tumorigenesis, the other one is the well-know stochastic two-stage model. While both models are very different from a mathematical point of view, they share important features. Both explain the appearance of the first malignant cancer cell by accumulating mutations with a selective advantage in a cell population, and both distinguish the generation of a new (mutated) cell type from its growth (i.e. the clonal expansion of mutated cells). The dynamics of the carcinogenic process can be directly compared between the two models in terms of the time to appearance of the first malignant cell. For each of the two models a mathematical formula was developed that gives the time until 50% of a population of individuals harbour a first cancer cell which can grow into a malignant cancer. In both formulae the parameters governing the growth of clones of mutated cells that contain advantageous mutations enter the equation directly, whereas the mutation rates have a much smaller influence. Thus, in both models, the selection parameters have the strongest impact on the waiting time equations, suggesting that cell selection is the major driving force of carcinogenesis. The observed prominent role of cell selection was confirmed by numerical evaluation of the waiting time equations using best estimates from various model fits to epidemiological data and suitable values from the scientific literature. Dr. Schöllnberger and his co-investigators expect the main finding to hold also for other solid tumors. The study has been published in 2010 in Cancer Research, one of the most prestigious scientific journals in this field. The study relates to the biological mechanisms of tumor cell formation and therefore represents basic research. Possible implications for medical areas such as patient treatment are unclear.