Os transportadores de monocarboxilatos como mediadores na angiogénese: O seu papel nas interações tumor-endotélio

Dissertação de Mestrado em Ciências da SaúdeDuring 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.Durante o crescimento hiperplásico dos tumores, há um défice no transporte de nutrientes e de oxigénio para as células distantes dos vasos sanguíneos, comprometendo o desenvolvimento do tumor. Assim, as células tumorais desenvolveram a capacidade de construir a sua própria rede vascular, recorrendo à do tecido - angiogénese tumoral. Todavia, a vasculatura tumoral possui anomalias que promovem o desenvolvimento de regiões de hipóxia. Consequentemente, as células neoplásicas são capazes de reprogramar o seu metabolismo, favorecendo a glicólise, independentemente da disponibilidade de oxigénio – “efeito de Warburg”. O ácido lático resultante é libertado para o microambiente tumoral, via MCTs, promovendo a progressão maligna. Assim, pretende-se avaliar 1) o papel dos MCTs na resposta das células endoteliais à hipóxia, bem como 2) o seu papel na estimulação da angiogénese. Foi demonstrado que MCT1 e MCT4, as suas proteínas auxiliares, bem como marcadores importantes na via glicolítica são expressos em células endoteliais cerebrais, nomeadamente em hipóxia, contribuindo para o aumento do fenótipo glicolítico. A inibição da atividade dos MCTs, bem como a inibição da sua expressão, diminuiu a viabilidade celular e o desenvolvimento de estruturas do tipo capilar que, sob hipóxia, parece ser independente do transporte de lactato. O crescimento de células endoteliais em meio condicionado proveniente de células tumorais, cuja expressão dos MCTs foi inibida, induziu adaptações metabólicas em células endoteliais, contribuindo para a manutenção da viabilidade celular, apesar da diminuição da proliferação celular e do número de estruturas do tipo capilar desenvolvidas. Estudos in vivo demonstraram alterações fenotípicas na vascularização na membrana corioalantóide do embrião de galinha após a adição de meios condicionados, produzidos em normoxia e hipóxia após silenciamento individual do MCT4 ou em combinação com o MCT1. Em suma, além do seu papel em células tumorais, os nossos resultados sugerem a importância do MCT1, e em menor extensão do MCT4, na manutenção da função endotelial, em normoxia. Em hipóxia, a inibição do MCT1 e do MCT4 parece ser compensada, pela sobre expressão de outros transportadores na membrana plasmática de células endoteliais, sob condições de hipóxia. Além disso, os MCTs parecem também desempenhar um papel importante no microambiente tumoral, atuando como proteínas essenciais nas interações tumorendotélio

Global variation in postoperative mortality and complications after cancer surgery: a multicentre, prospective cohort study in 82 countries

© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 licenseBackground: 80% of individuals with cancer will require a surgical procedure, yet little comparative data exist on early outcomes in low-income and middle-income countries (LMICs). We compared postoperative outcomes in breast, colorectal, and gastric cancer surgery in hospitals worldwide, focusing on the effect of disease stage and complications on postoperative mortality. Methods: This was a multicentre, international prospective cohort study of consecutive adult patients undergoing surgery for primary breast, colorectal, or gastric cancer requiring a skin incision done under general or neuraxial anaesthesia. The primary outcome was death or major complication within 30 days of surgery. Multilevel logistic regression determined relationships within three-level nested models of patients within hospitals and countries. Hospital-level infrastructure effects were explored with three-way mediation analyses. This study was registered with ClinicalTrials.gov, NCT03471494. Findings: Between April 1, 2018, and Jan 31, 2019, we enrolled 15 958 patients from 428 hospitals in 82 countries (high income 9106 patients, 31 countries; upper-middle income 2721 patients, 23 countries; or lower-middle income 4131 patients, 28 countries). Patients in LMICs presented with more advanced disease compared with patients in high-income countries. 30-day mortality was higher for gastric cancer in low-income or lower-middle-income countries (adjusted odds ratio 3·72, 95% CI 1·70–8·16) and for colorectal cancer in low-income or lower-middle-income countries (4·59, 2·39–8·80) and upper-middle-income countries (2·06, 1·11–3·83). No difference in 30-day mortality was seen in breast cancer. The proportion of patients who died after a major complication was greatest in low-income or lower-middle-income countries (6·15, 3·26–11·59) and upper-middle-income countries (3·89, 2·08–7·29). Postoperative death after complications was partly explained by patient factors (60%) and partly by hospital or country (40%). The absence of consistently available postoperative care facilities was associated with seven to 10 more deaths per 100 major complications in LMICs. Cancer stage alone explained little of the early variation in mortality or postoperative complications. Interpretation: Higher levels of mortality after cancer surgery in LMICs was not fully explained by later presentation of disease. The capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention. Early death after cancer surgery might be reduced by policies focusing on strengthening perioperative care systems to detect and intervene in common complications. Funding: National Institute for Health Research Global Health Research Unit

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licenseBackground: Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide. Methods: A multimethods analysis was performed as part of the GlobalSurg 3 study—a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital. Findings: Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3·85 [95% CI 2·58–5·75]; p<0·0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63·0% vs 82·7%; OR 0·35 [0·23–0·53]; p<0·0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer. Interpretation: Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised. Funding: National Institute for Health and Care Research