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March 12, 2001
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UCSD RESEARCH SHOWS
UCSD Cancer Center researchers have obtained evidence that the common anticoagulant drug heparin diminishes metastasis of certain cancers in mice by interfering with interactions between platelets (a type of normal blood cell) and specific molecules on tumor cell surfaces. This work also indicates that the early phase of these interactions is crucial for metastasis – a process in which tumor cells from the primary site enter the bloodstream, travel to distant tissues and establish new tumors. It is metastasis that eventually kills most patients with cancer.
The researchers, who report their work in the March 13 issue of the Proceedings of the National Academy of Sciences, say these findings make a compelling argument for initiating clinical trials of heparin in patients with newly diagnosed cancer.
"The notion of using anticoagulants to inhibit metastasis is not new," said the study’s senior author Ajit Varki, M.D.* "However, our new findings suggest that heparin therapy to prevent the spread of cancer in humans should be revisited, with a completely new paradigm in mind."
Animal studies in the ‘60s and ‘70s showed that heparin – which is delivered by injection or intravenously – inhibits metastasis. Follow-up human studies focused instead on the use of oral anticoagulants, which are easier to manage than heparin. Those attempts failed, however, and research in this area stalled. Other mechanisms for the heparin effect have since been suggested, but not proven.
The new research, led by Lubor Borsig, Ph.D., a postdoctoral fellow working in Varki’s laboratory, details heparin’s precise mechanism and explains why earlier clinical trials using oral anticoagulants failed.
"Our findings show that the anti-metastatic effect of heparin is not due to its ability to prevent blood clotting, as was previously thought, but rather its blockage of early tumor-platelet interactions in the bloodstream," said Borsig. "Oral anticoagulants work by a completely different mechanism and do not block these interactions."
When cancer cells break away from the original tumor and enter the bloodstream they attract platelets, which bind to sugarcoated molecules called mucins on the cancer cell surface, forming a cloak. This platelet cloak appears to protect the tumor cells from the body’s natural defense systems, enabling them to establish new tumors in other parts of the body. Heparin interferes with formation of the platelet cloak, apparently leaving tumor cells exposed to attack by white blood cells.
Experimental mice received a single dose of heparin, which lasted for only a few hours, yet this early exposure resulted in markedly reduced cancer cell survival and metastasis when the mice were examined several weeks later.
"This demonstrates that the early phase of platelet-tumor interaction, crucial for metastasis, can be inhibited by heparin," said Borsig.
This work involved an active collaboration with UCSD Cancer Center laboratories for Histology (directed by Nissi Varki, Ph.D.) and Digital Imaging (directed by James Feramisco, Ph.D.), and with the San Diego Supercomputer Center (David Nadeau). It was supported by a grant from the National Cancer Institute. The visualization collaboration with the Supercomputer Center is supported by the National Science Foundation through the National Partnership for Advanced Computational Infrastructure’s (NPACI) Scalable Visualization Toolkits project.
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*Varki is a member of UCSD Cancer Center, director of the UCSD Glycobiology Research and Training Center, and professor in the departments of Medicine and Cellular and Molecular Medicine at UCSD School of Medicine.
NOTE: Color movies
showing the effects of heparin are available for PNAS subscribers on the
journal web site as of March 13, or through the following UCSD links: Heparin
These novel images were made possible through an ongoing collaboration between
UCSD Cancer Center’s Digital Imaging Laboratory and the San Diego
Supercomputer Center. The Digital Imaging Lab created a three-dimensional
reconstruction of the microscopic data, which was then turned into animated
"fly-by" movies using the NPACI Scalable Visualization Toolkit
software for visualizing complex three-dimensional objects from large data
sets, ranging from cellular structures to virtual flights into the Orion
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