Abstract
Simple SummaryConsidering the high mortality rate and the increasing spread of brain tumors both in adulthood and in childhood, we explore the role and involvement of fibroblast growth factors receptors (FGFRs) in two specific types of brain tumors: astrocytoma and glioblastoma. Fibroblast growth factors (FGFs) and their receptors (FGFRs) regulate pivotal cellular processes during embryonal development of the CNS, and as a survival mechanism for adult neurons and astrocytes. Moreover, interactions between the neural cell adhesion molecules NCAM and N-cadherin with FGFR are important for a number of developmental events and have also been implicated in tumor progression. Thus, this review provides an overview on the biological mechanisms of FGFRs related to oncogenesis and a new point of view for future preclinical and clinical studies to develop increasingly targeted therapies.Despite pharmacological treatments and surgical practice options, the mortality rate of astrocytomas and glioblastomas remains high, thus representing a medical emergency for which it is necessary to find new therapeutic strategies. Fibroblast growth factors (FGFs) act through their associated receptors (FGFRs), a family of tyrosine kinase receptors consisting of four members (FGFR1–4), regulators of tissue development and repair. In particular, FGFRs play an important role in cell proliferation, survival, and migration, as well as angiogenesis, thus their gene alteration is certainly related to the development of the most common diseases, including cancer. FGFRs are subjected to multiple somatic aberrations such as chromosomal amplification of FGFR1; mutations and multiple dysregulations of FGFR2; and mutations, translocations, and significant amplifications of FGFR3 and FGFR4 that correlate to oncogenesis process. Therefore, the in-depth study of these receptor systems could help to understand the etiology of both astrocytoma and glioblastoma so as to achieve notable advances in more effective target therapies. Furthermore, the discovery of FGFR inhibitors revealed how these biological compounds improve the neoplastic condition by demonstrating efficacy and safety. On this basis, this review focuses on the role and involvement of FGFRs in brain tumors such as astrocytoma and glioblastoma.
Highlights
In the context of central nervous system (CNS) disorders, tumors are certainly one of the most widespread and lethal pathologies.types of cancers affect thetumorsCNS in its parts: brain, In the context of central These nervous system (CNS) disorders, areallcertainly one of thebone mostmarrow, widespread and lethal pathologies.These types of cancers affect the CNS in all its parts: brain, boneprimary and cerebellum
fibroblast growth factors receptors (FGFRs) are a family of tyrosine kinase receptors consisting of four members, FGFR1, FGFR2, FGFR3 and
There is substantial evidence that some cell adhesion molecules (CAMs) functions require the activation of specific second messenger signaling cascades in cells, for example the ability of neural cell adhesion molecule (NCAM), N-cadherin, and L1 to stimulate axonal growth is dependent on the tyrosine kinase activity of the fibroblast growth factor receptor (FGFR)
Summary
In the context of central nervous system (CNS) disorders, tumors are certainly one of the most widespread and lethal pathologies. Thanks to advances in imaging and radiotherapy it has been possible make a more localization of allowing a reduction in the volume irradiated brainhealthy tissue brain precise localization ofthe thetumor, tumor, allowing a reduction in theofvolume of healthy irradiated tissue [22]. FGFRs are a family of tyrosine kinase receptors consisting of four members, FGFR1, FGFR2, FGFR3 and FGFR4, with 22 known ligands [34,35] and encoded by four different genes: Flg, Bek, Cek-2, and Frek These factors share a core homology domain that consists of about 120 amino acid residues that assume a globular β-trefoil structure that consists of 12 β-strands arranged into three similar sets of four-stranded β-sheets. Receptor dimerization is essential for activation, as it phosphorylated cytoplasmic substrates, triggering signaling brings the two tyrosine kinase domains into closedownstream proximity, allowing cascades each otherthat to control cell growth andphosphorylate differentiation [48]. FGFR1–4 can beMolecules activated by(CAMs) their ligands, FGFs, and by cell adhesion molecules (CAMs) such
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