INTEGRIN ALPHAVBETA3 AS THERAPEUTIC TARGET AND IMAGING BIOMARKER FOR VASCULAR ENDOTHELIAL CELLS AND CANCER EPITHELIAL CELLS
Tesi di Dottorato
Data di Pubblicazione:
2010
Citazione:
INTEGRIN ALPHAVBETA3 AS THERAPEUTIC TARGET AND IMAGING BIOMARKER FOR VASCULAR ENDOTHELIAL CELLS AND CANCER EPITHELIAL CELLS / E.m.v. Araldi ; tutor: Battaglia Cristina ; direttore della scuola: Maria Luisa Villa. Universita' degli Studi di Milano, 2010 Dec 09. 23. ciclo, Anno Accademico 2010. [10.13130/araldi-elena-maria-vittoria_phd2010-12-09].
Abstract:
Integrins are heterodimeric transmembrane proteins belonging to a family of cell adhesion receptors evolutionary old and that play pivotal roles in physiological and pathological processes, such as neo-angiogenesis and cancer spreading. Integrins are composed by an extracellular domain, a single transmembrane region and a short cytoplasmic tail. In particular, the cytoplasmic domain is crucial for the regulation of integrin activity and function. It controls the integrin affinity state and its ECM ligand-binding activity, but it also promotes cellular responses upon extracellular ligand binding. Integrins are in fact activated upon binding with their extracellular ligands (inside-out signalling) and may change different conformations according to individual variations. This leads to the so-called outside-in signalling, which activates complex and cell-specific signalling events depending on the other molecular partners involved. Given that integrins lack of intrinsic kinase activity, ligated integrins cluster with few signalling and adaptor proteins from the cytoplasm, including growth factor receptors, cytokine receptors and trafficking molecules. This clustering gives rise to dynamic macromolecular protein structures globally termed adhesion complexes. Integrin ligation finally promotes signalling events leading to cell spreading, migration, survival and proliferation. The concomitant engagement of integrins and growth factor receptors optimizes the global yield of the activation through the integration of different signalling patways. Again, this cooperative signalling plays a pivotal role in the regulation of tumor cell adhesion, migration, invasion, survival and in the homeostasis of the angiogenic endothelium. The cross-talk between integrins and growth factors or cytokines receptors plays an important role also in the biology of several host cell types, with a particular focus on endothelial cell migration, proliferation and survival.
Therefore, integrins act as molecular bridges between the extracellular matrix and the cytoskeleton, displaying mechanical functions and affecting cell biology by means of complex intracellular signalling pathways. Integrins are able to mediate cell adhesion to immune cells, depending upon specific short peptide sequences recognized by integrins on their ligands. To this regard, it is noteworthy that the same ligand may be bound by different integrins because of their redundancy. As previously underlined, integrins play pivotal roles in traction for cell motility and invasion, in remodelling of the ECM by means of localization of proteases, in cell growth through adhesion-dependent control of proliferation, in cell signalling thanks to the cross-talk with growth factors and cytokine receptors.
Few data confirm that some endothelial integrins, such as the RGD sequence recognizing integrins αvβ3, αv5 and α5β1, are very important in the regulation of cell growth, survival and migration during angiogenesis and lymphangiogenesis. In particular, the αv integrins have key roles in embryonic development of blood vessels in placenta and brain, whereas fibronectin-binding integrins are essential for developmental angiogenesis. In addition, it has been demonstrated that a number of integrins is highly expressed in human metastatic cancers. Integrins are able to promote migration, survival and invasion because of their ability to degrade basement membrane by interacting with proteolytic enzymes (e.g. metalloproteases). Integrins may either enhance cell survival or initiate apoptosis depending on environmental cues. Integrin αvβ3 drive cancer cell invasion, proliferation, survival and also the EMT. Integrin αvβ3 cross-talks with VEGFR in melanoma, glioblastoma and angiogenic endothelial cel
Tipologia IRIS:
Tesi di dottorato
Keywords:
integrins ; angiogenesis ; cancer ; peptidomimetics ; RGD
Elenco autori:
E.M.V. Araldi
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