Investigations into the molecular mechanisms of angiogenesis based on gene expression data in a murine model, and its application in breast cancer prognosis

Author(s)

Jhonatas Sirino Monteiro

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Matemática e Estatística (IME/SBI)
• Defense date: 2022-09-27

Examining board members

João Carlos Setubal; David Corrêa Martins Junior; Eduardo Moraes Rego Reis; Israel Tojal da Silva

• Advisor: João Carlos Setubal; Ricardo José Giordano

Abstract

Angiogenesis is the process of forming new blood vessels from pre-existing vessels. Physiological angiogenesis is quite restricted during adulthood, and it occurs under the delicate control of gene expression. Angiogenesis-dependent diseases, such as retinopathies and cancer, induce factors capable of altering the expression of these genes, promoting a disordered development of new blood vessels, this process being characterized as pathological angiogenesis. Vascular endothelial growth factor (VEGF) is known to be one of the main components that orchestrate angiogenesis and therefore this factor has become a therapeutic target for the treatment of angiogenesis-dependent diseases. These therapies are effective, but a significant fraction of patients is refractory or resistant to anti-VEGF therapy. Another difficulty is the adverse effects since VEGF is also important for the survival of endothelial cells. Therefore, more efficient alternative therapies with fewer side effects are needed. In recent decades, with advances in genomic technologies, it was found that non-coding RNAs (ncRNAs) play a central role in gene regulation, including angiogenesis. The present work sought to identify ncRNAs important in angiogenesis to produce an integrated network of pathological angiogenesis mRNAs and ncRNAs. Two gene regulatory networks were produced, each representing a phase of neovascularization: (1) the initial response to hypoxia and (2) the consequent proliferation, migration, and differentiation of endothelial cells during the process of neovascularization. Precision medicine is an area that seeks to develop targeted therapies for each patient. For example, which patient responds or does not respond to a particular drug. Using the genes identified in the two networks, we developed 3 angiogenesis gene signatures with prognostic value for patients with breast cancer, another angiogenesis-dependent disease. In parallel, 60 differentially expressed isoforms were identified and, therefore, possible selective therapeutic targets of pathological angiogenesis. Collectively, the results of these studies demonstrate the potential of the gene networks produced for the development of new therapies or diagnostic methods for angiogenesis-dependent diseases. (AU)

• FAPESP's process: 19/05287-2 - Determination and analysis of gene regulation network of angiogenesis in a murine model
• Grantee: Jhonatas Sirino Monteiro
• Support Opportunities: Scholarships in Brazil - Doctorate