Targeting TGF-β signaling in glioblastoma: therapeutic implications and novel drug development strategies

Abstract

Glioma, a prevalent primary brain tumor, arises from the supporting cells of the central nervous system (CNS) and is categorized into grades I-IV. Despite advancements in therapeutic strategies, including surgery, chemotherapy, radiotherapy, and targeted therapies, glioma remains associated with high mortality and recurrence rates, often leading to poor patient outcomes. The pathogenesis of glioma is influenced by a combination of environmental factors, genetic mutations, and lifestyle choices. Transforming growth factor-beta (TGF-beta) signaling plays a pivotal role in glioma progression by regulating cell proliferation, survival, and differentiation. TGF-beta activates Small mothers against decapentaplegic 2/3 (Smad2/3) proteins through specific receptors, forming a complex with Smad4 that translocate to the nucleus to modulate gene expression. In addition, TGF-beta-activated kinase 1 (TAK1) initiates mitogen-activated protein kinase (MAPK) cascades, further contributing to tumorigenesis. The TGF-beta/Smad pathway can be negatively regulated by inhibitory Smad6/7. Elevated expression of TGF-beta isoforms (Iota-& SHcy;) is correlated with increased glioma risk. TGF-beta promotes tumor growth by sustaining glioma stem cell self-renewal and suppressing antitumor immune responses. Preclinical studies demonstrate that TGF-beta signaling inhibitors reduce glioma viability and invasion in animal models, highlighting their potential as promising therapeutic agents for glioma treatment.