Estudi del paper del TGF-β en la carciogènesi causada per la deficiència de PTEN
Universitat de Lleida. Departament de Ciències Mèdiques Bàsiques
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The TGF-β and the PI3K/Akt/mTROC1 pathways are two important regulators of the homeostasis of endometrial cellular cells. Alterations in the elements of these two pathways have been associated with endometrial carcinogenesis. On the one hand, the PI3K/Akt pathway is one of the main regulators of cell proliferation in the endometrium, this pathway is altered in a large number of endometrial tumors, both due to gain of function alterations and also because a loss of its main inhibitor, Pten. On the other hand, the TGF-/Smad pathway is also capable of regulating cell proliferation in a large number of tissues. Its role in cell regulation is controversial cause it can act as a tumor suppressor or as a powerful inducer of EMT and metastasis, depending on the cellular context on which it acts. That is why this thesis analyzes the effect of TGF- in the same cell type (endometrial epithelial cells) but in two different contexts, one in a well-polarized three-dimensional culture and another in a two-dimensional culture with poor cellular polarization. In recent times, many interaction mechanisms have been described between these two pathways that attempt to explain the coordinated effects which occurs between the PI3K/Akt and the TGF-β pathway that regulate processes such as proliferation and cell survival. In this thesis, the effects of cellular polarity and alterations in the PI3K/Akt and the TGF-/Smad pathways have been studied in terms of proliferation and survival on endometrial epithelial cells, as well as its role in the development and progression of endometrial cancer. To achieve these objectives, genetically modified murine models and three-dimensional endometrial cell cultures have been used. In the case of three-dimensional cultures of normal endometrial cells, TGF- is capable to induce apoptotic cell death. However, in Smad3 or Pten deficient cultures, there is a total inhibition of the apoptotic cell death induced by TGF-β and a marked increase in cell proliferation. These results support a tumor suppressor role of TGF-β when acting on endometrial cells, and that molecular alterations that affect its signaling can result in the acquisition of resistance to apoptosis and an increased cell proliferation, two of the fundamental characteristics of oncogenic processes. At a molecular level, the possible interactions between PTEN and Smads have been studied. In this terms, the results show that Smad3 directly regulates Pten transcription and, on the other hand, that PTEN regulates the activation of the Smads, establishing a regulation loop between these two pathways that control cell proliferation and tumor suppressor functions in the endometrium. In the second part of this thesis, the effects of the presence of extracellular matrix and the establishment of correct cellular polarity in relation to TGF-β effects on endometrial cells have been studied. Unlike the effects observed in three-dimensional cultures, the lack of extracellular matrix and the consequent loss of cellular polarity causes a completely different response to TGF-β addition to these cells changing the apoptotic cell response to an induction of the epithelial-mesenchymal transition leading a brake in cell proliferation. At a molecular level, the absence of the extracellular matrix has been shown to cause an over-activation of the PI3K/Akt and the ERK/MAPK pathways, resistance to apoptosis induced by TGF-β and a promotion of the epithelial to mesenchymal transition. These results show that the correct establishment of cellular polarity due to the presence of cell matrix can act as an important tumor suppressor.
European research projects
- Tesis Doctorals 
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