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Background: Thus far, a well-established logical pattern of malignancy does not exist. The current approach to cancer properties is primarily descriptive with usually, for each of them, extensive analyses of the underlying associated biomolecular mechanisms. However, this remains a catalog and it would be valuable to determine the organizational chart that could account for their implementation, hierarchical links and input into tumor regulation. Hypothesis: Striking phenotypic similarities exist between trophoblast (invasive and expanding early placenta) and cancer regarding cell functions, logistics of development, means of protection and capacity to hold sway over the host organism. The concept of cancer cell trophoblastic-like transdifferentiation appears to be a rational proposal in an attempt to explain this analogy and provide a consistent insight into how cancer cells are functioning. Should this concept be validated, it could pave the way to promising research and therapeutic perspectives given that the trophoblastic properties are vital for the tumor while they are permanently epigenetically turned off in normal cells. Specifically targeting expression of the trophoblastic master genes could thereby be envisaged to jeopardize the tumor and its metastases without, in principle, inducing adverse side effects in the healthy tissues. Conclusion: A wide set of functional features of cancer tissue regulation, including some apparently paradoxical facts, was reviewed. Cancer cell misuse of physiological trophoblastic functions can clearly account for them, which identifies trophoblastic-like transdifferentiation as a likely key component of malignancy and makes it a potential relevant anticancer target.

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BACKGROUND: Cancer is mainly watched through the prism of random mutations and related corruption of signaling pathways. However, it would seem puzzling to explain the tumor organization, pugnacity and steady evolution of the tumorous disease and, moreover, a systematic ascendancy over the healthy tissues, only through stochastic genomic alterations. MALIGNANCY SPECIFIC PROPERTIES: Considering the core characteristics of cancer cells, it appears that two major sets of properties are emerging, corresponding to well-identified physiological phenotypes, i.e., (1) the trophoblastic logistical functions for cell survival, protection, expansion, migration, and host-tissue conditioning for angiogenesis and immune tolerance and (2) the sexual functions for genome maintenance. To explain the resurgence of these trophoblastic and sexual phenotypes, a particular cell reprogramming, to be called "malignant transdifferentiation" in view of its key role in the precancer-to-cancer shift, appears to be a convincing hypothesis. PERSPECTIVES: The concept of malignant transdifferentiation, in addition to oncogenic mutations, would determine a more rational approach of oncogenesis and would open so far unexplored ways of therapeutic actions. Indeed, the trophoblastic phenotype would be a good candidate for therapeutic purposes because, on the one hand, it covers numerous properties that all are vital for the tumor, and on the other hand, it can be targeted with potentially no risk of affecting the healthy tissues as it is not expressed there after birth.

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The epigenetic plasticity of cancer stem-like cells allows them to reprogram multifaceted properties. Being determined by an oncogene driving force, the reprogrammed properties are suitable for extensive, non-homeostatic clone expansion rather than controlled tissue generation. They belong to physiological phenotypes, under strict control in normal cells but illicitly expressed in malignant cells. Comparing the embryo nidation implemented by trophoblast with tumor progression, it clearly appears that trophoblastic and cancerous cells share strongly similar behavior and logistical properties, likely making the trophoblastic phenotype a core component of the malignant phenotype. By reprogramming it, malignant cells acquire a coordinated set of functions very efficient for survival, protection, expansion and migration. This phenotype seems to have not yet been experimentally studied in depth as to its contribution to oncogenesis. We suggest opening a specific field of research on malignant cells and host tissue receptivity, guided by the relationship between nidation and tumor implantation.

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Diethylene Triamine Pentaacetic Acid (DTPA) is used for decorporation of plutonium because it is known to be able to enhance its urinary excretion for several days after treatment by forming stable Pu-DTPA complexes. The decorporation prevents accumulation in organs and results in a dosimetric benefit, which is difficult to quantify from bioassay data using existing models. The development of a biokinetic model describing the mechanisms of actinide decorporation by administration of DTPA was initiated as a task in the European COordinated Network on RAdiation Dosimetry (CONRAD). The systemic biokinetic model from Leggett et al. and the biokinetic model for DTPA compounds of International Commission on Radiological Protection Publication 53 were the starting points. A new model for biokinetics of administered DTPA based on physiological interpretation of 14C-labeled DTPA studies from literature was proposed by the group. Plutonium and DTPA biokinetics were modeled separately. The systems were connected by means of a second order kinetics process describing the chelation process of plutonium atoms and DTPA molecules to Pu-DTPA complexes. It was assumed that chelation only occurs in the blood and in systemic compartment ST0 (representing rapid turnover soft tissues), and that Pu-DTPA complexes and administered forms of DTPA share the same biokinetic behavior. First applications of the CONRAD approach showed that the enhancement of plutonium urinary excretion after administration of DTPA was strongly influenced by the chelation rate constant. Setting it to a high value resulted in a good fit to the observed data. However, the model was not yet satisfactory since the effects of repeated DTPA administration in a short time period cannot be predicted in a realistic way. In order to introduce more physiological knowledge into the model several questions still have to be answered. Further detailed studies of human contamination cases and experimental data will be needed in order to address these issues. The work is now continued within the European Radiation Dosimetry Group, EURADOS.

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Calcium diethylenetriamine pentacetate (Ca-DTPA) has been used for medical treatment of plutonium and americium contaminations in the CEA and COGEMA plants from 1970 to 2003. This paper is a survey of the injections Ca-DTPA administered as a chelating molecule and it will be a part of the authorisation process for Ca-DTPA by intravenous administration. Out of 1158 injections administered to 469 persons, 548 events of possible or confirmed contamination were reported. These employees were followed by occupational physicians according to the current French regulations. These incidents took place at work, were most often minor, not requiring follow-up treatment. The authors present (1) a synthesis of the most recent findings. Due to its short biological half-time and its limited action in the blood, Ca-DTPA does not chelate with plutonium and americium as soon as these elements are deposited in the target organs. It justifies an early treatment, even in cases of suspected contamination followed by additional injections if necessary (2) data concerning these 1158 injections (route of contamination, dosage, adverse effects, etc.) The authors also investigated a study on the efficacy of the product on a group of persons having received five or more injections. These results were compared with the efficacy estimated theoretically. Dosages and therapeutic schemes were proposed based on these observations. This synthesis is the result of a collective work having mobilised the occupational medicine departments, the medical laboratories inside a working group CEA-COGEMA-SPRA.

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Cancers induced by ionizing radiation have no particular specificity nor genetic remarkable signature, excepting numerous multideletions. They should therefore be studied in the general field of cancer biology in its broad sense. A gap remains between the initial events like the rather well identified genomic damage and the subsequent emerging cellular clone with cancer characteristics. Intermediate steps are generally described as accumulation of mutations and epigenetic modifications leading at one point to the malignant phenotype. However we have no clear nor understandable model on these steps of malignant transformation till now. It is quite possible that specific causes (tobacco, alcohol, radiations, chemical toxics) which produce different initial abnormalities then lead to (or accelerate the entry in) the common and same way as that resulting of accumulations of damage due to ageing. Genomic instability is certainly an important factor involved in the cellular drift leading to malignant transformation. We postulate that only cells having both a high telomerase activity and a low apoptotic activity may become cancerous. The hypothesis is that cancer results from a genome reprogramming of these cells due to an oncogenic mitotic pressure which induces a loss of the differentiation control. We propose to name anti-apoptosis, in contrast to apoptosis which is the programmed death, the ultimate process by which a cell loses its tissue-related properties. The oncogenic activation may propagate to primordial genes of development resulting in emergence of a subnuclear with tumoral activity. Bio-molecular studies of embryonic development and of genome re-programming will probably allow us to better understand the mechanisms of cancer.

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