Obesity and brain cancerunveiling molecular mechanisms of inflammatory and angiogenic pathways in glioma

Resumo

Gliomas represent the most common primary malignant brain tumors in adults, with an extremely poor prognosis. Despite its high morbidity, the etiology of glioma remains largely unknown. Obesity, favoured by the modern lifestyle, acquired epidemic proportions nowadays, and has been associated with various major causes of death and morbidity including malignant neoplasms. So, there might be a relationship between the increased incidence of gliomas and dysfunction of adipose tissue. The present study begins with 3T3-L1 adipocytes in culture, and its conditioned medium (adipokines-enriched medium), then it is disclosed adipocyte-released factors related with glioma growth, hormones, metabolic and angiogenic behavior by MALDI-TOF-MS and proteomic array analysis. Formerly, it is studied some modified cytokines on adipose tissue from diet-induced obese C57Bl/6J mice. To conclude, it is analysed the sphingolipid profile, namely ceramides and sphingosine-1-phosphate levels on normal and obese diet-induced mice serum, as well as liver function, lipid profile and uric acid and glucose. Adipocyte cells overexpressed several pro-inflammatory and angiogenic factors, such as IL6, IL11, LIF, TNFα, endocan, HGF, IGF1 and VEGF. Nevertheless, they underexpressed TIMP-1, SerpinE1, coagulation factor III, endostatin, PDGFA and ADAMTS1. On adipose tissue, IL6, Ob (Y-20) and TNFα were overexpressed in HFD group, while IL1β and PDGFA were underexpressed. On tumoral tissue, IL6 did not present significant variation, though IL1β and Ob tended to be overexpressed while TNFα and PDGFA disposed to be underexpressed. Sphingolipid analysis, as well as liver function, reinforces the premise that excessive dietary intake worsens metabolic syndrome in general and, more precisely, chronic low-grade inflammation. Relationship between obesity and cancer is paradoxical, however it is strengthened the idea on obesity protecting against glioma only at initiation and proliferation phases.