Um modelo multiescala para a carcinogênese.
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Data
2015-06-02
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Universidade Federal de Viçosa
Resumo
Nesta tese de doutoramento, desenvolvemos um modelo multiescala para o processo de carcinogênese. Permitido pela existência de mutações, o câncer emerge das interações entre diversas células em várias escalas de tempo e espaço. Inicialmente, desenvolvemos um modelo para a escala microscópica do câncer, ou o a seja, para o que ocorre “dentro das células”. Um sistema dinâmico booleano e a integrando as principais rotas de sinalização envolvidas no câncer foi construído. O sistema produz padrões estacionários de expressão gênica – atratores – dependendo do microambiente celular. Agrupamos os atratores da rede em distintos fenótipos celulares e determinamos mutações drivers que promovem transições fenotípicas. As mutações apontadas estão em acordo com aquelas catalogadas nos diversos censos de genes associados ao câncer. Empregamos o modelo para a avaliar o efeito de terapias molecularmente direcionadas. Descobrimos que as monoterapias são aditivas em seus efeitos e que a associa ̧ao de diversas drogas é necessária para a erradicação do câncer. No modelo multiescala, as células, representadas pelo sistema dinâmico booleano, e a interagem entre si e com um microambiente permeado por substâncias químicas (nutrientes, oxigênio, ıons H+ , e vários fatores parácrinos). A dinâmica do modelo revela que, pressionadas pela competição por recursos e por um microambiente em permanente mudança, as células selecionam mutações que as tornam progressivamente mais agressivas. No estágio final, elas são autossuficientes em fatores de crescimento, insensíveis a fatores inibidores de crescimento, evadiram da apoptose, e possuem um potencial replicativo ilimitado; caracteríısticas de células e cancerosas. Nossos resultados suportam a hipótese da aquisição de um fenótipo mutador pelo câncer. Também sugerem que as células glicolíticas permanentes surgem como consequência de mutações selecionadas por outros processos, não havendo mecanismo de seleção específico para esse fenótipo.
In this doctoral thesis, we developed a multiscale model for the process of carcino- genesis. Allowed by the existence of mutations, cancer emerges from interactions between different cells in different scales of time and space. Initially, we develo- ped a model for the microscopic scale of cancer, i.e., about what occurs “inside the cells”. A Boolean dynamical system integrating the main signaling pathways involved in cancer was constructed. This system exhibits stationary gene ex- pression patterns – attractors – dependent on the cell’s microenvironment. We grouped the network attractors into distinct cell phenotypes and determined dri- ver mutations that promote phenotypic transitions. The predicted drivers are in agreement with those pointed out by diverse census of cancer genes recen- tly performed for several human cancers. Finally, the Boolean network model was employed to evaluate the outcome of molecularly targeted cancer therapies. The major find is that monotherapies are additive in their effects and that the association of targeted drugs is necessary for cancer eradication. In the multiscale model, cells, represented by their Boolean dynamical systems, interact among them and with a microenvironment permeated by chemicals (nu- trients, oxygen, H+ ion, and several paracrine factors). The model’s dynamics shows that, pressured by competition for resources and by an ever-changing mi- croenvironment, the cells select mutations that make them progressively more aggressive. In the final stages, the cells have acquired the following capabili- ties: self-sufficiency in growth signal, insensitivity to anti-growth signals, evading apoptosis, and limitless replicative potential; characteristics shared by cancer cells. Our results support the hypothesis of a mutator phenotype in cancer. Also they suggest that permanent glycolytic cells appear as a consequence of mutations selected by other processes. Therefore, there is no selection for this phenotype.
In this doctoral thesis, we developed a multiscale model for the process of carcino- genesis. Allowed by the existence of mutations, cancer emerges from interactions between different cells in different scales of time and space. Initially, we develo- ped a model for the microscopic scale of cancer, i.e., about what occurs “inside the cells”. A Boolean dynamical system integrating the main signaling pathways involved in cancer was constructed. This system exhibits stationary gene ex- pression patterns – attractors – dependent on the cell’s microenvironment. We grouped the network attractors into distinct cell phenotypes and determined dri- ver mutations that promote phenotypic transitions. The predicted drivers are in agreement with those pointed out by diverse census of cancer genes recen- tly performed for several human cancers. Finally, the Boolean network model was employed to evaluate the outcome of molecularly targeted cancer therapies. The major find is that monotherapies are additive in their effects and that the association of targeted drugs is necessary for cancer eradication. In the multiscale model, cells, represented by their Boolean dynamical systems, interact among them and with a microenvironment permeated by chemicals (nu- trients, oxygen, H+ ion, and several paracrine factors). The model’s dynamics shows that, pressured by competition for resources and by an ever-changing mi- croenvironment, the cells select mutations that make them progressively more aggressive. In the final stages, the cells have acquired the following capabili- ties: self-sufficiency in growth signal, insensitivity to anti-growth signals, evading apoptosis, and limitless replicative potential; characteristics shared by cancer cells. Our results support the hypothesis of a mutator phenotype in cancer. Also they suggest that permanent glycolytic cells appear as a consequence of mutations selected by other processes. Therefore, there is no selection for this phenotype.
Descrição
Palavras-chave
Biofísica, Câncer, Expressão gênica, Modelos computacionais
Citação
FUMIÃ, Herman Fialho. Um modelo multiescala para a carcinogênese. 2015. 164f. Tese (Doutorado Física) - Universidade Federal de Viçosa, Viçosa. 2015.