Circulating microRNAs in cancer: Hope or hype?

Circulating miRNAs are a novel class of stable, minimally invasive disease biomarkers that are considered to be valuable in diagnosis, prognosis and treatment response monitoring. Unlike intracellular miRNAs, circulating miRNAs are released from their producer cells and, based on their targeted functions, they may shuttle in and out of circulation. Their discovery has opened up new avenues for clinical realms and led to a quest for targeted biomarkers. Subsequently, as more cell-free miRNAs are being discovered, their expression is expected to provide precise information regarding disease progression and treatment outcomes, thereby fostering personalized therapeutic strategies. The significance of circulating miRNAs capitalizes on the fact that they are highly stable in body fluids and their expression levels can be detected by common techniques such as qPCR and microarray. However, discrepancies have started to emerge in terms of their reliability and their response under physiological and pathological conditions. Functional studies are still pending, which may determine whether circulating miRNAs play a role as a central component or just as an auxiliary tuner. Also, the distinct clinical signatures that they display have never been subjected to an extensive critical review and experimental validation. As a consequence, the applicability of circulating miRNAs remains a matter of deliberation, despite many intriguing perspectives about their competency. In this review, we highlight some ambiguous issues with the application of circulating miRNAs, which may warrant an immediate consideration. We propose that the circulating miRNA domain needs to be reevaluated to authenticate their specific role and to probe whether they actually carry any clinical weightage.

Methionine and Kynurenine Activate Oncogenic Kinases in Glioblastoma, and Methionine Deprivation Compromises Proliferation.

PURPOSE: We employed a metabolomics-based approach with the goal to better understand the molecular signatures of glioblastoma cells and tissues, with an aim toward identifying potential targetable biomarkers for developing more effective and novel therapies. EXPERIMENTAL DESIGN: We used liquid chromatography coupled with mass spectrometry (LC-MS/Q-TOF and LC-MS/QQQ) for the discovery and validation of metabolites from primary and established glioblastoma cells, glioblastoma tissues, and normal human astrocytes. RESULTS: We identified tryptophan, methionine, kynurenine, and 5-methylthioadenosine as differentially regulated metabolites (DRM) in glioblastoma cells compared with normal human astrocytes (NHAs). Unlike NHAs, glioblastoma cells depend on dietary methionine for proliferation, colony formation, survival, and to maintain a deregulated methylome (SAM:SAH ratio). In methylthioadenosine phosphorylase (MTAP)-deficient glioblastoma cells, expression of MTAP transgene did not alter methionine dependency, but compromised tumor growth in vivo We discovered that a lack of the kynurenine-metabolizing enzymes kynurenine monooxygenase and/or kynureninase promotes the accumulation of kynurenine, which triggers immune evasion in glioblastoma cells. In silico analysis of the identified DRMs mapped the activation of key oncogenic kinases that promotes tumorigenesis in glioblastoma. We validated this result by demonstrating that the exogenous addition of DRMs to glioblastoma cells in vitro results in oncogene activation as well as the simultaneous downregulation of Ser/Thr phosphatase PP2A. CONCLUSIONS: We have connected a four-metabolite signature, implicated in the methionine and kynurenine pathways, to the promotion and maintenance of glioblastoma. Together, our data suggest that these metabolites and their respective metabolic pathways serve as potential therapeutic targets for glioblastoma. Clin Cancer Res; 22(14); 3513-23. ©2016 AACR.