It is now well established that within a tumor mass there is a hierarchical organization, stemming from a cell subpopulation retaining the highest tumorigenic potential, referred as cancer stem cells (CSCs), responsible for tumor initiation and progression. Although recent advances in stem cell biology led to the acquisition of new view of thyroid carcinoma as a stem cell disease, the cellular origin of thyroid CSCs remains unknown. In Chapter 1 it is critically discussed the potential role of thyroid stem cells (TSCs) in light of the available information on the oncogenic role of genetic alterations underlying the thyroid carcinogenesis. Understanding the key events that regulate thyroid transformation may be fundamental for clinical intervention in terms of prevention, diagnosis and therapy. Although stem cells (SCs), with their unique self-renewal potential, are considered the favored candidates for sequential accumulation of genetic alterations in tumor transformation, any cell with proliferative capacity, within the hierarchy in a normal tissues, could be considered a cell of origin able to initiate a tumor. In the second chapter of this thesis (Chapter 2), we describe how the in vitro differentiation of human embryonic stem cells (hESCs) represents a reliable experimental approach to obtain an unlimited source of derived thyroid cells at different stages of differentiation. Understanding the cellular hierarchy of normal thyroid tissue could allow the identification of cells-of-origin and tumor-related driven mutations underlying the thyroid carcinogenesis. It is widely assumed that estrogens play an important role in the initiation and progression of different malignancies through their interaction with SC compartment. Based on this scenario, direct effects of estrogens in growth and function of normal and malignant thyroid cells are closely described in Chapter 3. A growing body of evidence suggested that CSCs could be considered a source of primary mediators of chemo-radiation resistance leading to failure in cancer therapy. A better understanding of molecular mechanisms underlying CSCs resistance may improve the efficacy of current cancer therapies. In the fourth chapter of this thesis (Chapter 4), we suggest that targeting CSCs metabolism is a potential alternative strategy to cancer therapy.
|Titolo:||THE TUMOR CELL IDENTITY: A GATEWAY TO THE MOLECULAR BASIS OF MALIGNANT TRANSFORMATION|
|Citazione:||Scavo, E.THE TUMOR CELL IDENTITY: A GATEWAY TO THE MOLECULAR BASIS OF MALIGNANT TRANSFORMATION.|
|Appare nelle tipologie:||4.2 Tesi di dottorato|