Abstract
Malignant tumors of the central nervous system (CNS) are among cancers with the poorest prognosis, indicated by their association with tumors of high-level morbidity and mortality. Gliomas, the most common primary CNS tumors that arise from neuroglial stem or progenitor cells, have estimated annual incidence of 6.6 per 100,000 individuals in the USA, and 3.5 per 100,000 individuals in Taiwan. Tumor invasion and metastasis are the major contributors to the deaths in cancer patients. Therapeutic goals including cancer stem cells (CSC), phenotypic shifts, EZH2/AXL/TGF-β axis activation, miRNAs and exosomes are relevant to GBM metastasis to develop novel targeted therapeutics for GBM and other brain cancers. Herein, we highlight tumor metastasis in our understanding of gliomas, and illustrate novel exosome therapeutic approaches in glioma, thereby paving the way towards innovative therapies in neuro-oncology.
Highlights
Gliomas are primary tumors that arise from neuroglial stem or progenitor cells, which make up about 30% of all brain and central nervous system tumors, and 80% of all malignant brain tumors [1]
A variety of signaling molecules contribute to the invasion and metastasis in glioblastoma multiforme (GBM), we found notably that AXL/Enhancer of zeste homolog 2 (EZH2)/TGF-β1 might be a key regulator in tumor invasion, migration, and epithelial-tomesenchymal transition (EMT)
This review will give an overview of some of the signaling pathways that have been shown to participate in GBM invasion/metastasis, including the pivotal role of cancer stem cells (CSCs); phenotypic shifts, including (1) epithelial-mesenchymal transition (EMT) modulated by PI3 kinase (PI3K)/AKT/mTOR (PAM) signaling; (2) proneural-mesenchymal shift; (3) migration/proliferation dichotomy; (4) angiogenesis-invasion shift; (5) Glial-Mesenchymal Transition (GMT); EZH2/AXL metastasis in tumor growth factor-β
Summary
Gliomas are primary tumors that arise from neuroglial stem or progenitor cells, which make up about 30% of all brain and central nervous system tumors, and 80% of all malignant brain tumors [1]. Ligation of CD44 with HA activates the important pro-tumorigenic signals of Rho family of small GTPase [34,35], as well as PI3 kinase (PI3K) [36], which are known to affect cell motility, growth, proliferation and differentiation This is in addition to collagen IV, collagen V, fibronectin and laminin, which in GBM-associated vessels, have been found to enhance cell survival, proliferation and migration in vivo and in vitro [37,38,39,40,41]. This review will give an overview of some of the signaling pathways that have been shown to participate in GBM invasion/metastasis, including the pivotal role of cancer stem cells (CSCs); phenotypic shifts, including (1) epithelial-mesenchymal transition (EMT) modulated by PI3K/AKT/mTOR (PAM) signaling; (2) proneural-mesenchymal shift; (3) migration/proliferation dichotomy; (4) angiogenesis-invasion shift; (5) Glial-Mesenchymal Transition (GMT); EZH2/AXL metastasis in tumor growth factor-β (TGF-β activation; microRNAs (miRNA)/drugs in inhibition of invasion and metastasis; and the role of exosomes in tumorigenesis, metastasis and therapeutic potentials. This review will discuss the approaches to cancer therapies potentially altering GBM invasiveness
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