Abstract
World Health Organization grade IV diffuse gliomas, known as glioblastomas, are the most common malignant brain tumors, and they show poor prognosis. Multimodal treatment of surgery followed by radiation and chemotherapy is not sufficient to increase patient survival, which is 12 to 18 months after diagnosis. Despite extensive research, patient life expectancy has not significantly improved over the last decade. Previously, we identified FREM2 and SPRY1 as genes with differential expression in glioblastoma cell lines compared to nonmalignant astrocytes. In addition, the FREM2 and SPRY1 proteins show specific localization on the surface of glioblastoma cells. In this study, we explored the roles of the FREM2 and SPRY1 genes and their proteins in glioblastoma pathology using human tissue samples. We used proteomic, transcriptomic, and bioinformatics approaches to detect changes at different molecular levels. We demonstrate increased FREM2 protein expression levels in glioblastomas compared to reference samples. At the transcriptomic level, both FREM2 and SPRY1 show increased expression in tissue samples of different glioma grades compared to nonmalignant brain tissue. To broaden our experimental findings, we analyzed The Cancer Genome Atlas glioblastoma patient datasets. We discovered higher FREM2 and SPRY1 gene expression levels in glioblastomas compared to lower grade gliomas and reference samples. In addition, we observed that low FREM2 expression was associated with progression of IDH-mutant low-grade glioma patients. Multivariate analysis showed positive association between FREM2 and favorable prognosis of IDH-wild type glioblastoma. We conclude that FREM2 has an important role in malignant progression of glioblastoma, and we suggest deeper analysis to determine its involvement in glioblastoma pathology.
Highlights
Based on their origins, primary brain tumors are broadly categorized as glial, glio-neuronal, embryonic, tumors of the meninges, mesenchymal tumors, tumors of the choroid plexus, tumors of Cancers 2019, 11, 1060; doi:10.3390/cancers11081060 www.mdpi.com/journal/cancersCancers 2019, 11, 1060 the hematopoietic system, pituitary tumors, and tumors of the sellar region [1,2]
When compared to expression levels in samples from patients whose disease did not progress, in patients who progressed during first-line temozolomide treatment their FREM2 gene expression levels were halved (p = 0.052) in isocitrate dehydrogenase (IDH)-mutant gliomas, while there was no change in gene expression levels in IDH-WT glioma samples
For the first time, we deeply examined the relationships between both the FREM2 and SPRY1 genes and their proteins in glioblastoma
Summary
Primary brain tumors are broadly categorized as glial, glio-neuronal, embryonic, tumors of the meninges, mesenchymal tumors, tumors of the choroid plexus, tumors of Cancers 2019, 11, 1060; doi:10.3390/cancers11081060 www.mdpi.com/journal/cancersCancers 2019, 11, 1060 the hematopoietic system, pituitary tumors, and tumors of the sellar region [1,2]. Gliomas are tumors that originate from the supportive glial cells—ependymal cells, astrocytes, and oligodendrocytes, and they are referred to as ependymomas, astrocytomas, and oligodendrogliomas, respectively. The most common type of glial tumors is astrocytomas. Even with multimodal clinical management (i.e., maximal safe surgical resection, chemotherapy, radiation), the majority of these patients only survive for 12 to 18 months post diagnosis [5,6,7]. High glioblastoma lethality is attributed to late diagnosis as a result of nonspecific symptoms, rapid progression, infiltration into surrounding tissues, intracranial location that complicates surgery, and development of resistance to treatment and common recurrence after initial treatment [10,11,12,13]. In cases of recurrent glioblastomas, the average life expectancy of the patient is reduced to 6 months [14,15]
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