Role of angiogenesis in tumor growth and metastasis,☆☆

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Abstract

Angiogenesis is required for invasive tumor growth and metastasis and constitutes an important point in the control of cancer progression. Its inhibition may be a valuable new approach to cancer therapy. Avascular tumors are severely restricted in their growth potential because of the lack of a blood supply. For tumors to develop in size and metastatic potential they must make an “angiogenic switch” through perturbing the local balance of proangiogenic and antiangiogenic factors. Frequently, tumors overexpress proangiogenic factors, such as vascular endothelial growth factor, allowing them to make this angiogenic switch. Two strategies used in the development of antiangiogenic agents involve the inhibition of proangiogenic factors (eg, anti-vascular endothelial growth factor monoclonal antibodies) as well as therapy with endogenous inhibitors of angiogenesis, such as endostatin and angiostatin. Therapy with endogenous angiogenic inhibitors such as endostatin and angiostatin may reverse the angiogenic switch preventing growth of tumor vasculature. Preclinical studies have shown that endostatin effectively inhibits tumor growth and shrinks existing tumor blood vessels. Phase 1 clinical trials of endostatin and angiostatin are ongoing, and preliminary results show minimal toxicities. Semin Oncol 29 (suppl 16):15-18. Copyright 2002, Elsevier Science (USA). All rights reserved.

Section snippets

The role of vasculature in cancer growth

Autopsy studies in accident victims show that the incidence of in situ tumors, particularly those of the breast, prostate, and thyroid gland, is substantially higher than the documented prevalence of cancer,3 indicating that tumor metastasis is a relatively infrequent phenomenon. It has been proposed that the low metastatic activity of in situ tumors may be related to the fact that they have not acquired an angiogenic phenotype (ability to recruit vasculature), because tumor growth and

The angiogenic switch

The change from a quiescent to an invasive phenotype is invariably accompanied by the acquisition of angiogenic properties (“angiogenic switch”) and vascularization of the tumor. In contrast to normal cells, which form a single layer around capillary blood vessels, multiple layers of tumor cells surround the microvasculature, effectively creating a capillary “cuff.” This dependence of tumor cells on endothelial cells, the target of angiogenic factors, may explain amplified arrest or killing of

Endogenous inhibitors of angiogenesis: Angiostatin and endostatin

Clinical and preclinical studies have shown that removal of primary tumors leads to rapid growth of previously dormant micrometastases,2, 16, 17 suggesting that primary tumors produce soluble factor(s) that suppress the growth of small tumors at remote sites. The first of these was identified as angiostatin, a 38-kd internal fragment of plasminogen,17 which was subsequently shown to also induce dormancy and regression of tumor xenografts.18 In preclinical studies, metastatic growth of secondary

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    Supported by an unrestricted educational grant from Genentech BioOncology.

    ☆☆

    Address reprint requests to Judah Folkman, MD, Children's Hospital, Hunnewell 103, 300 Longwood Ave, Boston, MA 02115.

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