Brain-derived neurotrophic factor in solid tumor angiogenesis and neurovascular-immune interactions (Review)

Brain-derived neurotrophic factor (BDNF), a prototypical neurotrophin, together with its high-affinity receptor tropomyosin receptor kinase B (TrkB), regulates neuronal survival, synaptic plasticity and neurovascular unit homeostasis. Beyond the nervous system, BDNF and TrkB are aberrantly expressed in multiple solid tumors and have been implicated in proliferation, invasion, epithelial-mesenchymal transition, perineural invasion and resistance to therapy. Experimental evidence demonstrates direct vascular activity in selected settings: BDNF/TrkB promotes endothelial survival, migration and tube formation, mobilizes TrkB-positive progenitor cells and induces hypoxia-inducible factor-1α/vascular endothelial growth factor (VEGF)-dependent angiogenic programs in neuroblastoma, chondrosarcoma and hepatocellular carcinoma models. This direct evidence is concentrated in selected systems, whereas in other tumor types BDNF/TrkB is linked chiefly to tumor progression and neural or stromal remodeling that may secondarily shape vascular behavior. Within tumor cells, BDNF/TrkB integrates phosphoinositide 3-kinase/AKT, extracellular signal-regulated kinase, phospholipase Cγ and stress-responsive cascades to regulate angiogenic and inflammatory mediators, thereby linking malignant phenotypes to vascular and immune changes. The present review summarizes the molecular and physiological features of BDNF/TrkB, evaluates tumor-specific evidence within endothelial/progenitor, tumor-intrinsic and neurovascular-immune compartments and examines the potential value and limitations of tissue, circulating and multi-omics biomarkers. Potential intersections with VEGF-targeted therapy, Trk inhibitors and vascular normalization are discussed, together with the experimental and clinical gaps that must be addressed before BDNF/TrkB-directed strategies can be translated to patients with solid tumors.