Pre-clinical and clinical evidences show how vascular normalization can represent a novel strategy to enhance the efficacy of and overcome the acquired resistance to anti-angiogenic therapies in cancer. Several mechanisms of tumor vessel normalization have been unveiled. Among them, secreted class 3 semaphorins (Sema3), which regulate axon guidance and angiogenesis, have been recently identified as novel vascular normalizing agents that halt metastatic dissemination by restoring the vascular function. Here, we discuss the different biological functions and mechanisms of action of Sema3 in the context of tumor vascular normalization and their impact on the different cellular components of the tumor microenvironment
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