Year: 2010
Type: dissertation
Abstract: Most solid tumours rely on glycolysis for energy production, even in conditions of high oxygen tension (‘‘aerobic glycolysis’’, also known as the Warburg effect), giving rise to enhanced lactate production. This lactate production is responsible for extracellular acidification, which, conditioning the tumour environment, favours tumour invasion and suppresses anticancer immune response. Transport of lactate across the plasma membrane is mediated by a family of protoncoupled monocarboxylate transporters (MCTs), which comprises 14 members. The isoforms MCT1-MCT4 are proton symporters that exhibit different affinities for lactate, leading to different levels of tissue expression. Since some MCT isoforms (especially MCT1 and MCT4) play a role in the intracellular pH homeostasis, by exporting the accumulating lactic acid, they are upregulated in glycolytic tumours, where high levels of lactate are produced, such as high grade gliomas, colorectal carcinomas and lung cancer. However, the role of MCTs in tumours is far from being well understood and their potential as therapeutic targets is poorly explored, being the main aim of this work to further elucidate the significance of MCT expression in solid tumours. Thus, MCTs expression and their clinic-pathological value were evaluated in human series of colorectal, cervical, gastric and breast carcinomas. Also, MCT regulation by chaperones was further investigated by analysing CD147 in cervical, gastric and breast carcinomas series, as well as performing a screening in colorectal, breast, lung and ovary tumour samples, where CD44 expression was evaluated, as a putative MCT chaperone, in addition to CD147. Finally, some in vitro studies were performed, to determine the contribution of MCTs to cancer cell metabolic profile and viability. Importantly, up-regulation of MCTs, in particular MCT1, was found in colorectal, cervical and breast carcinomas, but not in gastric carcinomas, which, in fact, showed a decrease of MCT4 along towards malignancy. Also, MCT1 was associated with poor prognosis, especially in breast carcinomas, as well as in gastric carcinoma where MCT1/CD147 co-expression was associated with poorer patient prognostic. Also, as anticipated, CD147 was found to be co-expressed with both MCT1 and MCT4 in the large series studied (cervical, gastric and breast carcinomas). In the tumour screening, CD44 was only associated with MCT1 in lung cancer, however, series were very small and some results warrant further attention. Finally, the in vitro studies showed a CHCinduced inhibition of cell proliferation in human breast cancer cell lines that was, in some cases, accompanied by metabolic alterations. In conclusion, the results presented in this thesis have an important impact on the comprehension of MCT contribution to malignant phenotype and pave the way for further studies aiming to the development of cancer therapies directed to MCTs.
Author: Céline Pinheiro
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W17051995