The role of notch signaling in tumor angiogenesis in hematological malignancies

Abstract

The evolutionarily conserved Notch signaling pathway is a contact-dependent communication mechanism regulating cell fate, tissue patterning, and cellular metabolism. Beyond canonical NICD-RBPJ transcription, Notch engages in non-canonical crosstalk with networks like Wnt and NF-κB. In tumor angiogenesis, the endothelial Foxc1/2-DLL4-Notch1 axis coordinates tip/stalk cell plasticity, while restricting glycolytic flux via PFKFB3 downregulation to promote vessel maturation. Consequently, pathway inhibition triggers non-productive hypersprouting and vascular collapse, whereas Notch activation strategies offer potential for therapeutic vessel normalization. Crucially, Notch acts as a driving oncogene in B-cell malignancies, promoting survival and chemoresistance. In mantle cell lymphoma (MCL), somatic mutations truncate the C-terminal PEST domain, preventing proteasomal degradation and inducing constitutive NICD hyperactivation—defining an aggressive, microenvironment-sustained clinical subset. Similar NOTCH1/2 aberrations drive clonal progression in marginal zone and MALT lymphomas, and indicate poor prognosis in Hepatitis C Virus-positive diffuse large B-cell lymphoma (DLBCL). Routine genomic screening for Notch alterations provides critical prognostic stratification, laying the basis for personalized, selective therapies in refractory hematological diseases.