Maintenance of chromosomal telomere length is a hallmark of cancer cells and a prerequisite for stemness. In 85-90% of all human cancers, telomere length maintenance is achieved by reactivation of telomerase, whereas in the remaining 10-15% cancers, alternative lengthening of telomeres (ALT) is observed. Reactivation of telomerase occurs by various mechanisms, one of which is accumulation of point mutations in the promoter region of the gene encoding the protein subunit hTERT. There are numerous studies linking either hTERT overexpression or the presence of hTERT mutations to an aggressive phenotype of several human cancers. Recent findings demonstrate that hTERT expression is not only associated with replicative immortality, but also with cancer cell motility and stem cell phenotype. However, the mechanisms by which hTERT affects cancer cell migration, invasion, and distant metastasis on the one hand, and stemness and resistance on the other hand, are still poorly understood. Within this review, we aim to provide an overview on the functional involvement of hTERT in these cellular processes, focusing on metastasis formation and maintenance of stemness in different human cancers.
Due to poor prognosis of glioblastoma (GBM), there is an urgent need to develop new therapeutic strategies. Besides eliminating GBM tumor cells and stem cells, a novel therapeutic approach aims to target Glioma-associated microglia/macrophages (GAMs). We investigated the molecular profile of GAMs correlated with patient prognosis by exploiting M1/M2-like polarization markers in a cohort of 20 GBM patients. Using quantitative PCR (qPCR), the markers CXCL10 (M1) and CCL13 (M2) were validated in human macrophages and applied to a global analysis of GBM tissue. Furthermore, proteinase genes, known to be associated with GBM progression (ADAM8, MMP9, MMP14, ADAM10, ADAM17), were analyzed in correlation to M1/M2 markers. Notably, expression levels of ADAM10 and ADAM17 are significantly correlated with an M1-like phenotype and are positively associated to patient survival. Whilst ADAM8 mRNA expression was equally correlated with M1- and M2-like markers, genes for MMP9 and MMP14 are significantly associated with an M2-like phenotype and association to impaired prognosis in the GBM patient cohort. Thus, we provide a robust and reliable combination of qPCR markers to characterize global microglia/macrophage status and the associated proteinase profiles in GBM patients that can be used to analyze the tumor microenvironment, the patients’ prognosis and preselect those GBM patients for which targeting the microglia/macrophage population by repolarization might be beneficial.
Highlights d DDR1 and stem cell marker co-expression in GBM correlates with patient outcome d A DDR1-associated 14-3-3-Beclin-1-Akt1 complex induces prosurvival signaling d DDR1 targeting elicits autophagy-associated therapy sensitization
About 95% of patients with Glioblastoma (GBM) show tumor relapse, leaving them with limited therapeutic options as recurrent tumors are most often resistant to the first line chemotherapy standard Temozolomide (TMZ). To identify molecular pathways involved in TMZ resistance, primary GBM Stem-like Cells (GSCs) were isolated, characterized, and selected for TMZ resistance in vitro. Subsequently, RNA sequencing analysis was performed and revealed a total of 49 differentially expressed genes (|log2-fold change| > 0.5 and adjusted p-value < 0.1) in TMZ resistant stem-like cells compared to their matched DMSO control cells. Among up-regulated genes, we identified carbonic anhydrase 2 (CA2) as a candidate gene correlated with glioma malignancy and patient survival. Notably, we describe consistent up-regulation of CA2 not only in TMZ resistant GSCs on mRNA and protein level, but also in patient-matched clinical samples of first manifest and recurrent tumors. Co-treatment with the carbonic anhydrase inhibitor Acetazolamid (ACZ) sensitized cells to TMZ induced cell death. Cumulatively, our findings illustrate the potential of CA2 as a chemosensitizing target in recurrent GBM and provide a rationale for a therapy associated inhibition of CA2 to overcome TMZ induced chemoresistance.
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