Translational Research: the role of VEGF in tumor angiogenesis (2000)

Angiogenesis is defined as the formation of new bloodvessels from preexisting vasculature. Preclinical studieshave shown the major role of angiogenesis in tumor growthand metastasis formation, and therefore, inhibiting tumorangiogenesis may be a promising therapeutic modality [1,2]. Paracrine stimuli derived from tumor cells are the mainpromoters of angiogenesis. Once activated by these stimuli,endothelial cells begin to proliferate and migrate, subse-quently resulting in new tube formation and blood flow.This complex process involves numerous biological activi-ties. Vascular endothelial growth factor (VEGF) is one ofthe most potent and specific angiogenic factors of tumor-induced angiogenesis [3, 4]. Originally identified for itsability to induce vascular permeability and stimulateendothelial cell growth, VEGF is now recognized as a keyfactor required for growth of tumors [5]. The clinicalimportance of VEGF for tumor growth is supported by thefact that most tumors produce VEGF and that inhibition ofVEGF-induced angiogenesis significantly inhibits tumorgrowth in vivo [6-8]. In addition to decreasing the numberof vessels, antiangiogenic drugs may also decrease theinterstitial tumor pressure. This reduction in interstitialpressure may result from the ability of these agents to blockVEGF-induced permeability. VEGF expression has beenshown to correlate with microvessel density in a number ofsolid malignancies including carcinomas of the breast, andtissue concentrations of this growth factor appear to be pre-dictive of mortality associated with breast cancer [9, 10].Similar results have been obtained in studies of solid malig-nancies in various organs including the lung, prostate, andcolon [11-13]. These preclinical and clinical findings sup-port VEGF as a promising target for anticancer therapy.In patients with cancer, antiangiogenic agents, usedalone or combined with chemotherapy, may inhibit tumorgrowth, reduce metastasis formation, prolong survival, andimprove quality of life. Clinicians need to make a majorshift in their thinking if the beneficial effects of these novelagents are to be recognized. Appropriate schedules of suchcombinations need to be developed so that the mechanismof action (i.e., antiangiogenic or cytotoxic) is fully consid-ered. The concern that concomitant administration ofantiangiogenic drugs and chemotherapy will impair cyto-toxic drug delivery is precluded by evidence from animalstudies. Teicher et al.[14-16] clearly demonstrated thatcombination therapy with angiogenesis inhibitors has syn-ergistic antitumor effects in the Lewis lung carcinomaxenograft model. In these studies, addition of the antiangio-genic agents to the cytotoxic therapies reduced not only thenumber of lung metastases formed from the primary tumorbut also the number of large metastases. These results pro-vide evidence that antiangiogenic therapies can potentiatethe efficacy of standard anticancer therapies.This special issue of The Oncologistpresents a diversityof preclinical and clinical studies about anti-VEGF strategiesfor cancer treatment. McMahongives an excellent overviewof the role of VEGF tyrosine kinase receptors in tumor angio-genesis and the strategies being developed to inhibit this sig-naling pathway. Subsequently, Ellispresents preclinical datathat show the role of VEGF in the growth and metastasis ofcolon cancer. He also presents evidence that antiangiogenictherapy with VEGF receptor inhibitors SU5416 and SU6668inhibits the growth of liver metastases. The study by Vajkoczyand coworkers strongly supports the idea that regional differ-ences in Flk-1 activity in vivo may significantly affect tumor