Blood Thinner, Heparin, Stops Cancer from Hiding from Immune System Under Platelet "Cloak"

March 12, 2001. A team in San Diego has made animated movies showing how a blood thinner, heparin, may reduce metastatic spread of some types of cancer.

For years, medical researchers have noticed that blood clots may be a prelude to cancer. At the same time, men who taking blood thinners for several months, according to a Sweish study last year, seemed to be protected against developing prostate cancer. This finding, though, has been questioned on the basis of older clinical trials.

Now the San Diego team has come up with a new theory and new evidence. They say that heparin hampers spread of cancer cells in mice by interfering with interactions between platelets (a type of normal blood cell) and specific molecules on tumor cell surfaces.

This work shows 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. Unchecked metastasis is what makes cancer a fatal disease. If metastasis could be reduced or slowed without dire side-effects, many patients might live with cancer as a "chronic" disease.

The researchers, who report their work in the March 13 issue of the Proceedings of the National Academy of Sciences, say their 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. Other mechanisms for the heparin effect have since been suggested, but not proven. Follow-up human studies focused instead on the use of oral anticoagulants, which are easier to manage than heparin. Those attempts mostly failed, although the Swedish team said last year that for patients who took a six-month course of warfarin or dicumarol, development of cancer "was strikingly lower compared to patients who took only a six-week course."

Not by Preventing Blood Clots -- Platelets

The new research, led by Lubor Borsig, Ph.D., a postdoctoral fellow working in Varki's laboratory, uncovered 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," Borsig said.

The work was done by UCSD Cancer Center laboratories for Histology (directed by Nissi Varki, Ph.D.), Digital Imaging (directed by James Feramisco, Ph.D.), and the San Diego Supercomputer Center (David Nadeau). It was supported by grants from the National Cancer Institute and the National Science Foundation's National Partnership for Advanced Computational Infrastructure's (NPACI) Scalable Visualization Toolkits project.