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Circulating Glioma Biomarkers: Agents of Detection

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High-grade gliomas represent one of the most aggressive and treatment-resistant types of human brain cancer, with a median survival rate of only 14.6 months for patients with grade IV glioma (glioblastoma) [1,2].

neural glioma High-grade gliomas represent one of the most aggressive and treatment-resistant types of human brain cancer, with a median survival rate of only 14.6 months for patients with grade IV glioma (glioblastoma) [1,2]. Using state-of-the-art proteomics technologies, researchers from the Erasmus Medical Center in The Netherlands investigated the proteomic profile from for glioblastoma patients in order to identify protein biomarkers that can discriminate glioblastoma patients from controls, as well as to increase diagnostic accuracy. In this particular study, researchers screened potential biomarker candidates from blood serum and cerebrospinal fluid (CSF) and discovered various molecular anomalies of gliomas. They identified a combined loss of chromosome arms 1p and 19q, the presence of isocitrate dehydrogrenase 1 (IDH1) mutation, amplification of epidermal growth factor receptor (EGFR), copy number aberrations of chromosomes 7 and 10, and the presence of MGMT hypermethalation promoter [3]. Researchers also analyzed the contents of exosomes obtained from circulating tumor-derived exosomes and found a valuable supply of molecules, each representative of the parental cells they originated. These proteins, nucleic acids, lipids, metabolites, and other molecules they carry are molecular signatures and powerful effectors of many diseases, including cancer [4]. Exosomes purged from diseased cells contained mutant oncoproteins and oncogenic transcripts of microRNA and DNA sequences. Additional study on the contents of exosomes can help identify their cells of origin. This presents an opportunity to identify new cancer biomarkers or possible therapeutic targets in body fluids in the treatment of gliomas [5,6]. A Glioma is a type of tumor that starts in the brain or spine. The most common site of gliomas is the brain, and is more commonly diagnosed in men than women [Wikipedia.org]. So far, various tumor-related molecules with altered expression patterns have been found in circulating exosomes of glioma patients including EGFRvII, EGFR, podoplanin (PDPN), phosphatase and tensin homolog (PTEN), 12 miR-21, and mutant IDH1 mRNA [7,8]. Exosomes may carry substantial amounts of bound antibody-recognizing tumor antigens (autoantibodies), which can be used to reveal the presence of tumor antigens; exosome-based immunotherapy is under development [9]. A non-invasive test allowing for personalized therapy would be the Holy Grail in the field of brain tumor research. Currently, the best doctors can offer patients is standard therapy surgery, radiation, and chemotherapy. Information gleaned from a simple biomarker test, however, would allow practitioners to account for specific genetic defects within a tumor that may interfere with treatment plans.

Circulating Tumor Cells

Researchers in Denmark focused their work on circulating tumor cells (CTCs) since they are an important indicator of metastatic disease or relapse, and only can be detected in the blood or urine samples of patients with advanced-stage cancer. Their presence has been linked to an anti-tumor immune response, which can help to halt progression and improve the overall survival odds in patients. CTCs may be yield valuable therapeutic strategies due to its ability to reflect the molecular heterogeneity of the tumor cell. Their use in current clinical applications involves the molecular characterization and their classification into subsets depending on their response to treatments [10]. The specificity and sensitivity of detection is still a technical challenge since only one cell per 109 cells represents a CTC in the blood of patients. Various technologies have recently emerged to assist scientists in detecting CTCs including, microchips, filtration devices, quantitative reverse-transcription PCR assays, automated microscopy systems, and telomerase promoter-based assays [11]. These imaging techniques have contributed to higher detection rates overall, but because of some overlap in marker expression between tumor cells and normal cells, there are limitations to detecting higher-order lineage cancer biomarkers.

Circulating Tumor-associated Nucleic Acids 

Circulating nucleic acids (CNAs) have been identified in blood and other bodily fluids of patients with various diseases [12]. CNAs are promising targets for development as tumor biomarkers (circulating tumor-associated nucleic acids [ctNAs]) because of the possibility to profile tumors at the genomic and transcriptomic levels. Nucleic acids appear in body fluids as a sequel of apoptotic tumor cells or tumor necrosis, but they may also be actively secreted into the circulation [13]. Levels of CNAs are influenced by many factors: the turnover of (tumor) cell populations, cell degradation rates, filtering processes present in the blood or lymphatic circulation, clearance by liver and kidney, infection, age, sex, treatment, stress on epigenetic mechanisms, diet, lifestyle, and more [14,15]. Although nucleic acids are valuable as biomarkers because they can be measured in sensitive high-throughput PCR detection assays, the identification, quantitation, and validity of ctNAs remain challenging. In order to link the presence of tumor-associated oncogenes in body fluids of cancer patients to tumor-specific molecular events, the pre-analytic conditions must be well defined and standardized [16]. In other words, you need to know what you're looking for. Rapid advances in proteomics, as well as other omics based technologies, including genomics, transcriptomics, and metabolomics, has opened the doorway of discovery to a large number of potential biomarker candidates that can improve early tumor diagnosis and medical intervention. The use of these tools may become standard procedure for clinical use for diagnosis, prognosis, and other aspects of patient care. The overall assessment of glioma biomarkers from CSF and blood serum are helping to provide clinical diagnostic value in monitoring patient treatment plans. Glioma biomarkers may also help to develop point of care technologies for patients in neurocritical care. Get your free Biomarker E-guide below:   [pardot-form id="2228" title="Biomarkers E - Guide form" height="175"]   SOURCES Image: Glioma and dendritic cells. Courtesy: American Brain Tumor Association. [1] Ohgaki H, Kleihues P, Genetic pathways to primary and secondary glioblastoma. Am J Pathol. 2007;170(5):1445-1453. [2] Ohgaki H, Kleihues P, Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol. 2005;64(6):479-489. [3,10] Kros, et al. Circulating glioma biomarkers in blood and CSF. Neuro-Oncology 2014; 0, 1-18, doi:10.1093/neuonc/nou207. [4] Al-Nedawi K, Meehan B, Rak J. Microvesicles: messengers and mediators of tumor progression. Cell Cycle.2009;8(13):2014-2018. [5] Taylor DD, Gercel-Taylor C. The origin, function, and diagnostic potential of RNA within extracellular vesicles present in human biological fluids. Front Physiol. 2013;4:142. [6,9,11] Redzic JS, Ung TH, Graner Mw. Glioblastoma extracellular vesicles: reservoirs of potential biomarkers.Pharmgenomics Pers Med. 2014;7:65-77. [7] Skog J, Wurdinger T, van Rijn S, et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nature Cell Biology. 2008;10(12):1470-1476. [8] Shao H, Chung J, Balaj L, et al. Protein typing of circulating microvesicles allows real-time monitoring of glioblastoma therapy. Nature Medicine. 2012;18(12):1835-1840. [11] Pantel K, Alix-Panabieres C. Real-time liquid biopsy in cancer patients: fact or fiction?. Cancer Res.2013;73(21):6384-6388. [12,13,14] Boisselier B, Gallego Perez-Larraya J, Rossetto M, et al. Detection of IDH1 mutation in the plasma of patients with glioma. Neurology. 2012;79(16):1693 - 1698. [15,16] Schwarzenbach H, Hoon DS, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer. 2011;11(6): 426 - 437.