Correction: Shao et al. AKT Axis, miR-21, and RECK Play Pivotal Roles in Dihydroartemisinin Killing Malignant Glioma Cells. Int. J. Mol. Sci. 2017, 18, 350

The authors wish to make the following corrections to this paper [...]

Pathology of Gliomas and the Role Immunotherapy Plays in Combatting Glioma Proliferation

Glioma, a type of tumor arising from the brain and/or spinal cord, is a relatively broad term, encompassing three main types of glial cell tumors: astrocytoma, ependymoma, and oligodendroglioma. A prognosis for a glioma can often be extremely poor, with an overall survival rate of 54.84%. With around 20,000 gliomas being diagnosed each year, it is imperative that effective treatments are developed for management of these tumors. A popular treatment pathway for the treatment of gliomas is surgery along with chemo-radiation therapy such as Temozolomide. This current treatment plan, though, has a moderate effect on lengthening glioma patients’ prognoses. The average survival of this plan is 3 to 6 months. New treatments in the field of immunotherapies may have promising effects for glioma patients’ prognoses. Arising developments in immunotherapy glioma treatment and management is an important field to investigate to further improve the effectivity of cancer treatment for glioma patients. Certain immunotherapies in trials have proven to make impactful improvements to glioma prognoses, one trial showing an increase of 2 months in median survival. This literature review will focus on the pathology and characteristics of the proliferation of malignant glioma cells and the role immunotherapy plays in combatting glioma proliferation

Soft threshold partial least squares predicts the survival fraction of malignant glioma cells against different concentrations of methotrexate’s derivatives

Chemotherapy appeared to be a significant advancement in cancer research, with fewer side effects. Methotrexate (MTX) is a widely used anticancer drug with strong activity but serious side effects. Several MTX derivatives have been reported, with modifications at various sites to reduce side effects and increase efficacy. The current study uses FTIR spectroscopy to predict the survival fraction of human malignant glioma U87 (MG-U87) cell lines against MTX derivatives. Together with Parent MTX several aldehydes viz. Benzaldehyde, Chlorobenzaldehyde, 2-Chlorobenzaldehyde, 3-Nitrobenzaldehyde, 5-Chloro-2-hydroxybenz-aldehyde, 2-Hydroxy-5-Nitrobenzaldehyde, 2-Thiocarboxyaldehyde, Trans-2-pentenal, and Glutaraldehyde are treated with MTX to obtain MTX derivatives. The prediction of survival fraction of malignant glioma cells is carried out by Lasso, Elastic net and Soft PLS at different concentration levels of synthesized derivatives, including 400 μM, 200 μM, 100 μM, 50 μM, 25 μM and 12.5 μM. The cross-validated prediction error is minimised to optimise spectral wavelength selection and model parameters. It appears that the RMSE computed from test data is significantly varying with the change of models (p = 0.012), with the change of concentrations levels (p $$\le 0.001$$ ≤ 0.001 ) and with the change of combination of models and concentration level (p $$\le 0.001$$ ≤ 0.001 ). StPLS outperforms in predicting survival fraction of glioma cells at the concentration level 50 μM, 100 μM and 400 μM respectively with relative RMSE = 0.1,0.14 and 0.55. Lasso outperforms at the concentration level 12.5 μM, and 200 μM respectively with relative RMSE = 0.4 and 0.14. Elastic net outperforms at the concentration level 25 μM with relative RMSE = 0.8. Consistently appeared influential wavelength identifies the influential functional compounds which best predicts the survival fraction. Hence FTIR appears potential candidate for estimating survival fraction of MTX derivatives.

Strategic Development of an Immunotoxin for the Treatment of Glioblastoma and Other Tumours Expressing the Calcitonin Receptor

New strategies aimed at treatment of glioblastoma are frequently proposed to overcome poor prognosis. Recently, research has focused on glioma stem cells (GSCs), some quiescent, which drive expansion of glioblastoma and provide the complexity and heterogeneity of the tumour hierarchy. Targeting quiescent GSCs is beyond the capability of conventional drugs such as temozolomide. Here, we discuss the proposal that the calcitonin receptor (CT Receptor), expressed in 76–86% of patient biopsies, is expressed by both malignant glioma cells and GSCs. Forty-two percent (42%) of high-grade glioma (HGG; representative of GSCs) cell lines available from one source express CT Receptor protein in cell culture. The pharmacological calcitonin (CT)-response profiles of four of the HGG cell lines were reported, suggesting mutational/splicing inactivation. Alternative splicing, commonly associated with cancer cells, could result in the predominant expression of the insert-positive isoform and explain the atypical pharmacology exhibited by CT non-responders. A role for the CT Receptor as a putative tumour suppressor and/or oncoprotein is discussed. Both CT responders and non-responders were sensitive to immunotoxins based on an anti-CT Receptor antibody conjugated to ribosomal-inactivating proteins. Sensitivity was increased by several logs with the triterpene glycoside SO1861, an endosomal escape enhancer. Under these conditions, the immunotoxins were 250–300 times more potent than an equivalent antibody conjugated with monomethyl auristatin E. Further refinements for improving the penetration of solid tumours are discussed. With this knowledge, a potential strategy for effective targeting of CSCs expressing this receptor is proposed for the treatment of GBM.

Targeting the Complement Pathway in Malignant Glioma Microenvironments

Malignant glioma is a highly fatal type of brain tumor, and its reoccurrence is largely due to the ordered interactions among the components present in the complex microenvironment. Besides its role in immune surveillance and clearance under physiological conditions, the complement system is expressed in a variety of tumor types and mediates the interactions within the tumor microenvironments. Recent studies have uncovered the broad expression spectrum of complement signaling molecules in the tumor microenvironment and various tumor cells, in particular, malignant glioma cells. Involvement of the complement system in tumor growth, immunosuppression and phenotype transition have also been elucidated. In this review, we enumerate the expression and function of complement molecules in multiple tumor types reported. Moreover, we elaborate the complement pathways in glioma cells and various components of malignant glioma microenvironments. Finally, we summarize the possibility of the complement molecules as prognostic factors and therapeutic targets in the treatment of malignant glioma. Specific targeting of the complement system maybe of great significance and value in the future treatment of multi-type tumors including malignant glioma.

EXTH-41. THE microRNA miR-138 MAY BE RESPONSIBLE FOR SOME OF THE EFFECTS OF METABOLIC KETOSIS ON MALIGNANT GLIOMA

We and others have demonstrated that altering metabolism through the use of a ketogenic diet (KD) has numerous effects in mouse models of malignant glioma including slowed growth, reduced hypoxia and angiogenesis, enhanced survival and potentiation of the effects of radiation and chemotherapy. These effects are recapitulated in vitro when the ketone β-hydroxybutyrate (BHB) is added to mouse and human malignant glioma cells grown under high glucose conditions. BHB has been demonstrated to be an epigenetic modifier, providing a potential mechanism for the pluripotent effects of ketones even in the presence of high glucose. Therefore, we have analyzed alterations in microRNA (miRNA) expression in tumors and cells treated with a KD or BHB, respectively. MicroRNAs are short, single-stranded, noncoding RNAs that posttranscriptionally control gene expression. Each miRNA can affect the expression of many genes and they are implicated in all hallmarks of cancer. We found a number of miRNAs deregulated in tumor tissue from mice fed a KD, particularly mmu-miR-138 which was increased over 30-fold relative to tumors from mice fed a standard diet. MiR-138 is involved in a variety of anti-tumor effects that correlate with our data from KD treated gliomas. We have shown that ketones radiosensitize glioma cells, potentially through a reduction in DNA damage repair. MiR-138 has been shown to reduce the expression of H2AX which plays a key role in sensing and repairing DNA damage. Hypoxia inducible factor-1α (HIF-1α) is also a target of miR-138, and we have demonstrated a reduction in hypoxia, angiogenesis and the expression of HIF-1α in tumors from mice fed a KD. Furthermore, when we genetically engineered tumor cells to express miR-138 and injected them into mice, only necrotic tumor foci were found. Thus, we suggest that miR-138 is an important regulatory mechanism for the anti-tumor actions of metabolic ketosis in glioma.