EphB1 and Notch4: transmembrane receptors as novel pharmacological targets for glioblastoma and therapeutic angiogenesis

Pezzini, Stefano (2022) EphB1 and Notch4: transmembrane receptors as novel pharmacological targets for glioblastoma and therapeutic angiogenesis, [Dissertation thesis], Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Scienze biotecnologiche, biocomputazionali, farmaceutiche e farmacologiche, 34 Ciclo.
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The Eph receptor family of tyrosine kinases and its ligands, ephrins, are membrane-anchored molecules that regulate cell-cell interactions. They are expressed in most cells and tissue types. Eph/ephrin signaling is involved in tumorigenesis, metastasis and angiogenesis. In glioblastoma EphB1 downregulation is correlated with aggressive cancer phenotypes, as this receptor may act as tumor suppressor. Starting from these evidences, we aimed at characterizing the role played by EphB1 receptor in glioblastoma by investigating its expression and modulation in U87 human glioblastoma cells. The loss of EphB1 receptor expression and its subsequent reduced activity are relevant pro-tumoral events in glioblastoma cells. Consistently, treating U87 cells with the EphB1 receptor agonist or antagonist further reduces or increases cancer cell aggressiveness, respectively. Other different peptides, designed starting from the antagonist already available, affected U87 cell migration. The Eph/ephrin signaling pathway is also involved in angiogenesis. Therapeutic angiogenesis is an attractive strategy for CAD and PAD patients. VEGF is the master regulator of vascular growth and it represents the major molecular target for therapeutic angiogenesis. Previous studies in the host group show that the induction of normal or aberrant angiogenesis by VEGF depends strictly on the amount secreted in the microenvironment around each producing cell, and not on the total dose delivered. Therefore, here I investigated the Notch4 signaling pathway as a target for therapeutic angiogenesis. We found that Notch4 inhibition: 1) did not impair normal angiogenesis by low and safe levels of VEGF; 2) did not impair the initial formation of vascular enlargements; and 3) normalized aberrant angiogenesis by high VEGF levels of expression by limiting the degree of initial vascular enlargement induced by VEGF.

Tipologia del documento
Tesi di dottorato
Pezzini, Stefano
Dottorato di ricerca
Settore disciplinare
Settore concorsuale
Parole chiave
EphB1, ephrins, glioblastoma, Notch4, VEGF, therapeutic angiogenesis
Data di discussione
18 Marzo 2022

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