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Vol. 53, Issue 1, 93-106, March 2001
Department of Cell Biology and Histology (S.M.S., C.J.F.v.N.) and
Department of Vascular Medicine (S.M.S.), Academic Medical Center,
University of Amsterdam, Amsterdam, The Netherlands
I. Introduction
II. Effects of Heparins on Experimental Primary Tumor Growth and
Metastasis
III. Effects of Heparins on the Various Steps in Cancer Progression
IV. Interference of Heparins with Proliferation of Cancer Cells
V. Interference of Heparins with the Immune System
VI. Interference of Heparins with Angiogenesis
A. Heparins and Angiogenic Growth Factors
B. Heparins and Other Processes Involved in Angiogenesis
VII. Interference of Heparins with Migration of Cancer and
Endothelial Cells
VIII. Interference of Heparins with Invasion of Cancer and
Endothelial Cells
IX. Interference of Heparins with Adhesion of Cancer Cells to
Vascular Endothelium
X. Conclusions
Acknowledgments
References
Patients with cancer are frequently treated with anticoagulants, including heparins, to treat or to prevent thrombosis. Recent randomized trials that compared low molecular weight heparin to unfractionated heparin for the treatment of deep vein thrombosis have indicated that heparins affect survival of patients with cancer. Experimental studies support the hypothesis that cancer progression can be influenced by heparins, but results of these studies are not conclusive. Heparins are negatively charged polysaccharides that can bind to a wide range of proteins and molecules and affect their activity. As a consequence, heparins have a wide variety of biological activities other than their anticoagulant effects, which may interfere with the malignant process. In the present systematic review, we critically evaluate experimental studies in which heparins have been tested as anti-cancer drugs. All animal studies, published between 1960 and 1999, that report effects of heparins on growth of subcutaneously implanted tumors, spontaneous metastasis or experimentally induced metastasis are reviewed. In addition, we discuss mechanisms by which heparins potentially exert their activity on various steps in cancer progression and malignancy related processes. It is shown that heparins can affect proliferation, migration, and invasion of cancer cells in various ways and that heparins can interfere with adherence of cancer cells to vascular endothelium. Moreover, heparins can affect the immune system and have both inhibitory and stimulatory effects on angiogenesis. Because of the wide variety of activities of heparins, it is concluded that the ultimate effect of heparin treatment on cancer progression is uncertain.
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