Monocarboxylate transporters as angiogenic mediators: role on endothelial-tumor cell crosstalk
Year: 2013
Type: dissertation
Abstract: During the hyperplasic growth of tumors, there is an impairment in both nutrient and oxygen supply to the neoplastic cells located far away from blood vessels, which would influence tumor progression. Thus, tumors have acquired the ability to assemble their own vasculature, mainly through the pre-existing vessels – tumor angiogenesis. However, tumor blood vessels exhibit structural and functional abnormalities, leading to the development of hypoxic regions, which are responsible for the metabolic reprogramming towards glycolysis, regardless of oxygen availability – “Warburg effect”. The end-product of the pathway, lactic acid, is readily released to the tumor milieu through MCTs, contributing to malignant progression. Thus, the aims of the current work are to investigate 1) the role of MCTs on endothelial cell response to hypoxia and 2) the role of MCTs on the angiogenic stimulation by tumor cells. Hence, our experiments demonstrated that MCT1 and MCT4 isoforms, their molecular chaperones, CD147 and CD44, as well as other key metabolic markers are expressed in human brain endothelial cells, mainly under hypoxia, contributing to the increased glycolytic phenotype. Further inhibition of MCT activity, using CHC, as well as MCT downregulation impaired endothelial cell viability and the development of capillary-like structures, which seems to be independent on lactate transport activity, under hypoxic environments. Upon endothelial cell growth in glioma cells’ conditioned media (CM), metabolic adaptations in HBMEC cells were observed, which may contribute to the maintenance of endothelial cell survival, in spite of a decrease in endothelial cell proliferation and, consequently in the development of capillary-like structures that were observed in vitro. In vivo experiments showed a similar phenotypic alteration in chick chorioallantoic membrane vascularization, after exposure to MCT4- and MCT1/4- silenced glioma cells’ CM from both normoxia and hypoxia, relatively to scramble groups. Thus, besides its role in tumor cells, our data point out the importance of MCT1 and, to a lower extent MCT4, on the maintenance of endothelial cell function, under normoxia. Under hypoxia, the absence of these both isoforms seems to be counterbalanced, which may be due to the overexpression of other transporters at the plasma membrane of endothelial cells. In addition, MCTs seem to be players in tumor microenvironment, acting as essential mediators in tumor-endothelial cell interplay.
Author: Carla Filipa Pereira Bezerra
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2616703011