Comunicación célula tumoral - célula normal irradiadas: ¿cómo afecta la sobrevida y la capacidad invasiva de la célula tumoral?
Radiotherapy, a key therapeutic tool in oncology, is effective but not specific. It can lead to local acute reactions, increase the risk of developing new primary tumors and, paradoxically, increase the proliferative and invasive capacity of surviving tumor cells with the consequent increased chance...
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| Formato: | Tesis de maestría acceptedVersion |
| Lenguaje: | Español |
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Facultad de Farmacia y Bioquímica
2018
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| Acceso en línea: | http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=afamaster&cl=CL1&d=HWA_2762 http://repositoriouba.sisbi.uba.ar/gsdl/collect/afamaster/index/assoc/HWA_2762.dir/2762.PDF |
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| Sumario: | Radiotherapy, a key therapeutic tool in oncology, is effective but not specific. It can lead to local acute reactions, increase the risk of developing new primary tumors and, paradoxically, increase the proliferative and invasive capacity of surviving tumor cells with the consequent increased chance of recurrences and metastasis.\nFor many years, it was accepted that biological effects of ionizing radiation occur as a direct result of damage to the DNA of irradiated cells. However, in recent years scientific evidence has indicated that intercellular communication can affect the response in irradiated cells and still cause damage in non-irradiated cells.\nThe epithelial-mesenchymal transition (EMT) is a biological process that allows epithelial cells to acquire mesenchymal characteristics. Its inappropriate activation in epithelial carcinomas contributes to invasion and metastasis, and the tumor cell/normal cell /stroma interaction plays an important role in this process.\nWhen radiotherapy is used to treat breast cancer after conservationsurgery, the irradiation field comprises an extensive portion of healthy breast tissue since approximately 50% of patients bear malignant cells spreadall through the breast.\nThe aim of this work was to studytwo aspects of communication between irradiated benign mammary epithelial cells (MCF-10A) and irradiated tumor cells (MCF-7 and MDA-MB-231):\n1) To investigate the effect of factors secreted by the irradiated benign mammary epithelial cells on biological responses related to DNA damage in irradiated mammary tumor cells.\n2) To investigate the effect of the factors secreted by the irradiated benign mammary epithelial cells on the EMT process in irradiated mammary tumor cells.\nTo accomplishour aims irradiated tumor cells were incubated with conditioned media from irradiated MCF-10A cells. Conditioned media from non-irradiated MCF-10A cells, non-conditioned media and non-irradiated tumor cells were usedas controls.\nDNA double strand breaks wereevaluated by detection of histone ?-H2AX foci and chromosomal instability by the cytoma assay.Results indicate that ionizing radiation induces in both neoplastic mammary lines the immediate appearance of histone ?-H2AX foci that disappear after 48 hours. Conditioned media from MCF-10A producedwaves of damage in the DNAbeing, irradiated and non-irradiated mammary tumor cells left with a residual damage.As regards chromosomal instability,our results showed in the MDA-MB-231 tumor line a basal frequency of micronuclei, internuclear bridges and nuclear buds superior to thatfound in the neoplastic line MCF-7. In both irradiated tumor cell lines, we observed an increase in the frequency of the markers studied. Incubation with conditioned media also produced an increase in markers of chromosomal instability in both irradiated and non-irradiated tumor cells.The effect of the conditioned media from irradiated MCF-10A was greater than the effect of the conditioned media from non irradiated cells.\nWe also demonstrated that factors secreted by the benign mammary cells (irradiated or not) affect the proliferation of tumor cells (irradiated and non-irradiated) and favor the TEM process. We observed changes in cell morphology (cells with irregular shape, fusiform and dispersed), changes in subcellular localization of E-cadherin (membrane to cytoplasm) and ?-catenin (membrane to cytoplasm and nucleus), risein the expression of the mesenchymal marker vimentin and in nuclear localization of the transcription factor Slug, increase in gelatinolytic activity and in cell migration. The acquisition or enhancement of mesenchymal features in tumor cells was mediated at least in part by the activation of type I receptor TGF-? (through TGF-?1 secreted by the benign cells or by a tumor autocrine circuit) and by a signaling pathway that includes the activation/phosphorylation of Src.\nOur results expose the relevance of the tumor-host interaction in tumor behavior and in the response to radiotherapy. |
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