Vascular endothelial growth factor and its receptors in multiple myeloma

Roberto Ria, Antonia Reale, Angelo Vacca

Research output: Chapter in Book/Report/Conference proceedingChapter (Book)Researchpeer-review


Angiogenesis, the formation of new blood vessels from pre-existing ones, takes place in various physiological and pathological conditions and is fundamental for tumor progression in the form of growth, invasion, and metastasis. Vascular endothelial growth factor (VEGF) is a major regulator of tumor-associated angiogenesis, which promotes tumor growth, invasion, and metastasis. The VEGF family includes VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and placental growth factor. VEGF gene encodes for VEGF-A isoforms (VEGF-A121-206) by alternative splicing. The heparin-binding domains help VEGF-A to anchor to the extracellular matrix (ECM), and are involved in binding to heparan sulfate and presentation to VEGF receptors (VEGFR). All the VEGF isoforms share common tyrosine kinase receptors, including VEGFR-1 or Flt-1, VEGFR-2 or KDR/Flk-1, and VEGFR-3 or Flt-4. VEGF isoforms bind with high-affinity to VEGFRs and play an essential role in angiogenesis, vasculogenesis, and lymphangiogenesis. A non-kinase receptor, neuropilin-1, initially shown to mediate guidance of neurite growth, acts as a high-affinity co-receptor that enhances the binding of VEGF-A to VEGFR-2, and is expressed on the surface of endothelial as well as tumor cells. VEGFRs relay signals via phospho-tyrosine residues, located in the carboxy-terminal region of a tyrosine kinase cascade that involvs various intracellular proteins. MAP kinases (MAPK) are the final effectors of the signal transduction to nucleus, where they modulate the expression of genes involved in several biological activities of endothelial cells. VEGF exerts autocrine and paracrine effects in multiple myeloma (MM) by stimulating motility and survival of tumor cells that express VEGFR as well as in endothelial cells and other stromal cells of the bone marrow milieu. Many antiangiogenic drugs targeting VEGF/VEGFR pathway (i.e., Bevacizumab, Thalidomide and its immunomodulatory derivatives, proteasome inhibitors, arsenic trioxide, tyrosine kinase inhibitors) are actually employed in the treatment of MM patients, and other molecules are under preclinical development.

Original languageEnglish
Title of host publicationCytokines
Subtitle of host publicationMechanisms, Functions and Abnormalities
EditorsMasoud H. Manjili
PublisherNova Science Publishers
Number of pages20
ISBN (Print)9781621009290
Publication statusPublished - Jan 2012
Externally publishedYes

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