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Frontiers of Medicine

Front Med    2012, Vol. 6 Issue (1) : 67-78     DOI: 10.1007/s11684-012-0176-8
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Progress in tumor vascular normalization for anticancer therapy: challenges and perspectives
Bingxue Shang, Zhifei Cao, Quansheng Zhou()
Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital of Soochow University, Suzhou 215123, China; Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Soochow University, Suzhou 215123, China
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Abstract

Antitumor angiogenic therapy has been shown promising in the treatment of several advanced cancers since the approval of the first antiangiogenic drug Avastin in 2004. Although the current antiangiogenic drugs reduce the density of tumor blood vessels and result in tumor shrinkage at the early stage of treatment, recent studies have shown that antiangiogenic therapy has transient and insufficient efficacy, resulting in tumor recurrence in patients after several months of treatment. Blockage of blood and oxygen supplies creates a hypoxic and acidic microenvironment in the tumor tissues, which fosters tumor cells to become more aggressive and metastatic. In 2001, Jain proposed tumor vascular normalization as an alternative approach to treating cancers based on the pioneering work on tumor blood vessels by several other researchers. At present, normalizing the disorganized tumor vasculature, rather than disrupting or blocking them, has emerged as a new option for anticancer therapy. Preclinical and clinical data have shown that tumor vascular normalization using monoclonal antibodies, proteins, peptides, small molecules, and pericytes resulted in decreased tumor size and reduced metastasis. However, current tumor vascular normalizing drugs display moderate anticancer efficacy. Accumulated data have shown that a variety of vasculogenic/angiogenic tumor cells and genes play important roles in tumor neovascularization, growth, and metastasis. Therefore, multiple-targeting of vasculogenic tumor cells and genes may improve the efficacy of tumor vascular normalization. To this end, the combination of antiangiogenic drugs with tumor vascular normalizing therapeutics, as well as the integration of Western medicine with traditional Chinese medicine, may provide a good opportunity for discovering novel tumor vascular normalizing drugs for an effective anticancer therapy.

Keywords angiogenesis      vasculogenesis      neovascularization      tumor      vasculature      normalization      traditional Chinese medicine     
Corresponding Authors: Zhou Quansheng,Email:quanshengzhou@yahoo.com   
Issue Date: 05 March 2012
 Cite this article:   
Bingxue Shang,Zhifei Cao,Quansheng Zhou. Progress in tumor vascular normalization for anticancer therapy: challenges and perspectives[J]. Front Med, 2012, 6(1): 67-78.
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http://journal.hep.com.cn/fmd/EN/Y2012/V6/I1/67
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Fig.1  Comparison of normal vasculature with tumor vasculature. (A) Normal blood vessels are organized in a hierarchy of evenly distributed arteries, capillaries, and veins. The vessels are covered by pericytes to maintain the integrity of the vessels. (B) Tumor blood vessels are heterogeneous and consist of irregular branches with arteriovenous shunts.
Fig.2  Normalization of disorganized tumor blood vessels for anticancer therapy. Malignant tumors may make their own blood vessels via a complex process of neovascularization through (1) VEGF and endothelial cell-mediated angiogenesis, (2) vessel co-option between endothelial cells and tumor cells, and (3) tumor cell-predominant vasculogenesis. The disorganized tumor blood vessels could be normalized using several options, including (1) anti-VEGF therapeutics, (2) PHD2 agonists, (3) VE-cadherin blocking agents, (4) targeting tumor-associated macrophages, (5) traditional Chinese medicinal herbal drugs, and (6) manipulation of pericytes.
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