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Evaluation of the anti-tumour and angiogenic activity of the Aspergillus fumigatus secretome

Abstract

Invasive aspergillosis (IA) is major cause of morbidity and mortality in profoundly immunocompromised patients. Although many species of Aspergillus have been isolated in nature, A. fumigatus is the primary causative agent of human infections. Once the conidia reach the alveoli, they germinate and produce hyphae that invade the pulmonary tissue. These hyphae have a tropism for blood vessels, characterizing the angioinvasion. This infection triggers thrombosis, hypoxia, and proinflammatory cytokine release, all of which are stimuli for angiogenesis. The fungi produce a wide variety of secondary metabolites and molecules of biotechnological and pharmaceutical interests. In this perspective, the search for modulators of angiogenesis with therapeutic potential is our main interest in this project. The aim of this study is investigate the A. fumigatus secretome on the modulatory activity of angiogenesis and cancer. Moreover, the the anti-angiogenic potential of the main antifungals used in the clinical practice will be evaluated. The angiogenesis modulation by molecules isolated from the A. fumigatus secretome and/or antifungal drugs will be evaluated in vitro using endothelial cell cultures by capillary-like tube formation assay, proliferation and viability assays. The selected molecules with angiogenic activity will be tested in vivo in mouse models of matrigel plug assay. In addition, the investigation of anti-tumoral activity of these molecules will be performed by using A549 lung adenocarcinoma cell line oncytotoxicity, cell death, proliferation and invasion assays. This study presents an innovative nature and aims to identify anti-angiogenic and anti-cancer molecules Furthermore, this work intend to better understand the dynamics of angiogenesis established through the pathogenesis and the treatment of invasive fungal infections. The knowledge generated from this research may help to improve the treatment of invasive aspergillosis as well as to shed light on the mechanism of IA pathogenesis. (AU)