Señales de nicho que regulan la autorrenovación de células madre y células madre tumorales
- Autores: Paula A. Castro García
- Directores de la Tesis: M. Carmen Ramirez Castillejo (dir. tes.)
- Lectura: En la Universidad de Castilla-La Mancha ( España ) en 2011
- Idioma: español
- Tribunal Calificador de la Tesis: Luis Antón Aparicio (presid.), Francisco Sánchez Sánchez (secret.), Helena Mira Aparicio (voc.), Ana Isabel Ferrer Pérez (voc.), Luz Irene Pascual (voc.)
- Materias:
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- Resumen
The main target of numerous investigations is the comprehension of the biology of stem cells in order to use their regenerative capacity. Currently, it has been also a target for being considered the tumoral origin of several types of cancer.
The hypothesis of the tumor like stem cells or cancer stem cells postulates the existence of tumor cells with characteristics of stem cells, and therefore, capacity of self renewal, cycles of slow division and greater resistance to chemotherapy. This similarity with the normal stem cells, could confer an innate defense to them forehead to the conventional therapies, so that these cells could be the origin of the relapse in patients with neoplasic disease. It is as well as it arose the model based on the tumor like stem cell who implies that only one small subpopulation of the tumor is the one in charge to initiate the development and maintenance of the cancer and, as the healthy stem cell, the cancer stem cells would have properties of self renewal, relative quiescence, and chemoresistance through drug transporting protein expression as BCRRP1. Also de cancer stem cells will be dependent of the surrounding environment or cellular niche for the maintenance of the tumor and its metastasis capacity.
In this work, first we have studied the deficiencies in stem cells related to the acceleration of the senescence appearance. It is interested how a molecule that acts on the stem cells self renewal, can modify the pattern of premature aging. The effect of PEDF protein has been described as a fundamental factor in the processes of self renewal of the neural stem cells. In this work we analyzed the functionality of PEDF as an essential factor for the activation of the neurogenic niche in the model of mouse with accelerated senescencia SAMP8. Where the balance between quiescencia and self renewal of the neural stem cells population is affected. The treatment with PEDF made a possible recovery of the stem cells lost in the model.
Our second objective was to study these same effects in self renewal, this time in tumor like stem cells. We considered to determine the population of cancer stem cells in neoplasic model, and to analyze the characteristics of slow cycles cells and resistance to chemotherapy. In addition, we have studied the implication that macro-molecules such as PEDF protein and its carboxyl terminal part could have in the regulation of the cancer stem cells self-renewal.
Interestingly has been described also that PEDF carboxyl terminal end has an effect in opposition to the complete molecule, reason why we decided to use it like a posible inhibitor of self renewal of cancer stem cells subpopulation. We identified this population through their slow cell cycle and several markers have been related with this populations, as the membrane protein CD133 related to self renewal and BCRP1 related to drug resistance. We have verified that PEDF carboxyl terminal part end reduces the drugs resistant capacity in the C6 glioma line and in line derived of a breast metastasic ascitis Pa00. The treatment with PEDF protein in this subpopulation increases the drugs resistance, and the number of BCRP1+ and CD133+ cells with slow cell cycle, in vitro and in xenograft transplant. Therefore the proteins BCRP1, CD133, and the markers of slow cellular cycle as DDFDA can be used jointly to delimit the presence of a population of cancer stem like cells. And the self renewal processes can be modified with the carboxy terminal end of the PEDF protein.
In our opinion, PEDF activity is important in the normal stem cells but also in cancer stem cells as they have an extensive proliferative potential and a great capacity to produce new tumors. This suggests that tumors like stem cells undergo processes that are analogous to those of the stem cells, and to study the differences will be an important goal for the future
