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Induction of osteosarcoma and leukemia by bone-seeking alpha-emitting radionuclides


The metabolic pathways of alpha-emitting radionuclides, and the cell populations undergoing carcinogenic transformation after exposure to alpha-radiation.

Studies carried out by VITO have established an in vitro culture model of osteogenic differentiation from murine bone marrow precursors. The administration of Americium 241 to mice prior to analysis of marrow cell population induced a dramatic increase in the in vitro proliferation of the cells of the osteogenic lineage. The in vivo data from NRPB indicate that a significant proportion of administered Americium 241 does indeed enter the marrow cell mass. Thus the osteogenic stem cell must be considered as a potential target of osteosarcomagenic radionuclides that otherwise are deposited in bone.

In vivo data from NRPB has also established that a number of other radionuclides are able to enter the skeleton, and ultimately irradiate osteogenic and hematopoietic marrow elements. In particular Polonium 210 contamination was shown to result in some 10% of the dose reaching the marrow. Polonium 210 was administered in vitro in the VITO cell culture system, and the effects upon skeletogenic precursor cells examined. Significantly, the addition of Polonium 210 to cultures of marrow derived cells potentiated the proliferation and osteogenic differentiation. The effect was not seen directly on the putative stem cell (CFU-F) population, but on cells derived from CFU-F derived precursors.

The radionuclide distribution studies of the NRPB have concentrated upon three bone-seeking radionuclides Plutonium 239, Americium 241 and Uranium 233. The dose distribution studies show the majority of the injected radionuclide that is retained is deposited within the skeleton (85% of retained Plutonium 239, 88% of retained Americium 241 and 97% of retained Uranium 233). Differences in the skeletons ability to handle the various radionuclides were also established.

The deposition of radionuclides in the marrow may result in direct irradiation of hematogenic marrow cell elements, as well as that of the osteogenic lineage. Indeed NRPB studies have shown that the deposition of injected radionuclides Plutonium 239, Polonium 210 and Americium 241, and to a lesser extent Uranium 233, results in concentration at the marrow-bone interface.

Molecular events in alpha-particle induced radiation carcinogenesis

The role of genetic factors in determining carcinogenic risk was firmly established by the experiments of the GSF-P. In a mouse model system they have introduced gene mutations into the male germ line by chemical mutagenesis. The offspring of these mutagenised parents were shown to be at a significantly increased risk of radiation-induced osteosarcoma, with a marked shortening of the tumor latency period. Thus we can conclude the heritable factors can influence susceptibility of radiation-induced malignancy. This observation makes it possible to define future studies to identify the genes responsible for determining susceptibility.

The methods available for the analysis of gene mutations has changed dramatically during the course of the project. A range of different alternatives has been tested by the TUM and their relevance to the detection of gene alterations in radiation induced tumors evaluated, in particular the possible mutation of the p53 tumor suppressor gene locus. These studies have demonstrated that immunohistochemical study of p53 mutations is prone to generate both false-positive and false-negative results.

The p53 tumor suppressor gene is implicated in the regulation of DNA repair and genome stability. Thus, in cells subjected to DNA damage p53 mediates cell cycle transit to allow repair or to initiate cell suicide in severely damaged cells. Consequently loss of p53 function would be anticipated to have dramatic repercussions for the integrity of the genome in irradiated cells. In a collaboration between the GSF-P and the GSF-IMV it was established that p53 gene mutations were a frequent occurrence in radiation-induced osteosarcoma cell lines. The frequency of p53 mutations in these preliminary studies was close to 100%, suggesting that loss of p53 function may be a key event in radiation carcinogenesis, particularly in the skeleton. Efforts to repeat this observation in tumor tissue have met with only moderate success.

The activation of retroviral sequences, regarded as constitutive passive bystanders within the genome, may play a role in the etiology of the malignant cells generated by irradiation. Studies by the GSF-IMV and the IMB have continued to elucidate the mechanisms by which the activated retroviral genome can influence malignancy.

In vitro studies have also confirmed the importance of retroviral sequences in the oncogenic process following irradiation. Using osteogenic cells present within the murine mandibular chondyle the IMV has established that a combination of Radium 223 and infectious retrovirus can synergise in activating cell proliferation. The increased cell division is presumed to be the result of deregulated proliferative control associated with oncogenesis. Extraction of the irradiated and infected cells from the chondyle tissue confirmed that the proliferative activity was maintained in vitro during cell culture, and presumably indicates a direct interaction of irradiation and virus on the target cells. A search for the potential mediators of the enhanced cell proliferation was initiated by the IMV, and proved fruitful. Whilst the classical oncogenes c-fos, c-myc and c-jun were unaffected, the recently described T1 gene was significantly over-expressed.

The molecular mechanism(s) responsible for the carcinogenesis following irradiation are certainly transferred to progeny cells, either as active genetic alterations or by epigenetic mechanisms such as viral infection. The MRC study has revealed that radiation-induced alterations in the stability of the genome itself are transmitted during cell divisions.
Radiation-induced carcinogenesis is initiated and sustained by complex genetic and epigenetic changes to the irradiated cell. These bring about hereditable alteration of the somatic cell phenotype,leading eventually to carcinogenesis. Environmental, occupational or, historically, therapeutic human exposure to bone-seeking alpha-emitting radionuclides leads to long-term retention of the radionuclides within the bone. This internal contamination is associated with an increased risk of carcinogenesis in the bone and bone marrow, leading to osteosarcoma and leukaemia. Experimental analysis of radiation-induced carcinogenesis in the bone marrow-skeletal system is thus directly relevant to human radiation protection. These studies will also provide a tool for analysing events common to other radiation-induced tumours, and will increase the accuracy of risk estimates in the human population after exposure at low dose or low dose rate. In the current proposal, animal studies will continue to provide information on tumour induction, as well as the distribution of dose to specific cell populations within sensitive tissues. We seek to determine the exact radiation dose to those cells at risk. The distribution and tumour-induction potentials of different bone-seeking elements in vivo will be investigated. Increasingly it is recognised that prediction of effects at low doses in humans requires knowledge of the mechanisms involved in carcinogenesis at the cellular and molecular levels. This information is accessible through the application of molecular techniques, where genetic events characterising the carcinogenic change in the cellular phenotype have been recognised. Analysis and quantification of these changes in radiation-induced tumours will incorporate studies on i) the activation of endogenous retrotransposons after irradiation, and their role in inducing altered patterns of gene expression; and ii) Identifying and quantifying loss-of-function mutations resulting in permanent inactivation of tumour suppressor genes. Appropriate model systems are required for accurate analysis of the mutational events causing radiation-induced carcinogenesis. We will develop models of stem cell populations at risk in both the bone marrow and skeletal systems, as well as characterising the role of germ line mutagenesis in determining sensitivity to radiation.


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