Transforming growth factor-beta and its implication in the malignancy of gliomas

Abstract

Malignant gliomas are the most common type of primary malignant brain tumors. They are characterized by enhanced growing capabilities, neoangiogenic proliferation, and extensive infiltration of the brain parenchyma, which make their complete surgical resection impossible. Together with transient and refractory responses to standard therapy, these aggressive neoplasms are incurable and present a median survival of 12 to 14 months. Transforming growth factor-beta (TGF-β) is a pleiotropic cytokine of which two of the three isoforms expressed in humans have been shown to be overexpressed proportionally to the histologic grade of glioma malignancy. The increase of chromosomal aberrations and genetic mutations observed in glioma cells turns TGF-β into an oncogene. For that reason, it plays critical roles in glioma progression through induction of several genes implicated in many carcinogenic processes such as proliferation, angiogenesis, and invasion. Consequently, investigators have begun developing innovative therapeutics targeting this growth factor or its signaling pathway in an attempt to hinder TGF-β's appalling effects in order to refine the treatment of malignant gliomas and improve their prognosis. In this paper, we extensively review the TGF-β-induced oncogenic pathways and discuss the diverse new molecules targeting this growth factor.

Exosomes isolated from plasma of glioma patients enrolled in a vaccination trial reflect antitumor immune activity and might predict survival

“…Spearman rank analyses demonstrated positive correlations between immunologic responses to the vaccine defined by ELISPOT and changes in exosomal mRNA coding for IL-8 and TGF-b, cytokines known to be critically important in glioma growth and metastasis. 28,29 These results suggest that the exosomal mRNA content reflects vaccine-induced changes in the patients' immune responses. In addition, negative correlations between vaccine-induced changes in exosomal mRNA expression levels for TIMP-1 with changes in IL-8 and TGF-b gene expression could be taken as further evidence that exosome content informs about ongoing cellular responses, whether they take place in the tumor or immune cells after vaccination.…”

Molecular crosstalk between tumour and brain parenchyma instructs histopathological features in glioblastoma

“…It should be noted that TGFB1 has a dual role in regulating invasion through induction of the process of epithelial to mesenchymal transition (EMT) [32, 33], but in the presence of VEGF, these two growth factors cooperate to regulate angiogenesis [34]. Several anti-TGFβ strategies are evaluated in clinical trials, including anti-sense oligonucleotides (Trabedersen) and small molecule inhibitors (galunisertib), but to our knowledge no combination therapies with anti-angiogenic agents have so far been reported [35, 36]. …”

A CREB1–TGFβ2 Self-Sustaining Loop in Glioblastoma

“…In addition, this complexity may be further exacerbated by altered expression of noncoding RNAs and intratumor heterogeneity. Although genomic alterations affecting components of the TGFβ pathway are not common in GBM, high levels of expression of TGFβ ligands have been seen in some GBMs ( 3 ). Despite its primarily tumor-suppressive role in the early stages of many cancers, TGFβ signaling can play a protumorigenic role in more advanced cancers, including GBM, where it promotes rather than inhibits proliferation ( 3,4 ).…”

“…Although genomic alterations affecting components of the TGFβ pathway are not common in GBM, high levels of expression of TGFβ ligands have been seen in some GBMs ( 3 ). Despite its primarily tumor-suppressive role in the early stages of many cancers, TGFβ signaling can play a protumorigenic role in more advanced cancers, including GBM, where it promotes rather than inhibits proliferation ( 3,4 ). TGFβ signaling can also promote the self-renewal capability of glioma-initiating cells that may lead to tumor recurrence ( 5 ).…”