Proteins Inhibit Tumor Growth in Mice

The proteins are potential candidates for use in the treatment of cancer.

"Healthy humans produce fibulin proteins, which regulate cell proliferation, migration, and invasion. In the past, we have seen that they are depleted in numerous metastatic cancers, and that they inhibit the formation of new blood vessels in cell culture,” said William Schiemann, Ph.D., assistant professor of cell biology at U.S. National Jewish Medical and Research Center (Denver, CO, USA). "Our current findings show that fibulins can inhibit both tumor growth and blood-vessel formation in mice.”

Tumors require oxygen and nutrients supplied by blood vessels to grow. They also use blood vessels to spread to other areas of the body. This process, known as metastasis, is the most deadly stage of cancer and the leading cause of cancer-related death. Combating cancer by starving tumors of life-giving blood vessels has generated great interest in recent years.

In their most recent study, Dr. Schiemann and his coworkers injected a biologic substance, called Matrigel, into mice. Matrigel contains a growth factor that promotes blood-vessel growth and either a control substance or fibulin 3 or fibulin 5. After seven days, researchers discovered that the Matrigel plugs containing either fibulin 3 or 5 had about half as many blood vessels as did the control plugs.

The researchers then injected fibrosarcoma tumor cells into mice. The tumor cells were genetically modified to produce either fibulin 3 or fibulin 5. Three weeks after the cells were implanted, developing tumors that produced the fibulins were about 24-45% smaller than the control tumors. "We are thrilled that the fibulins continue to show promise as we move into animal models,” said Dr. Schiemann. "We also found evidence that the fibulins work through more than one biological pathway, which suggests a very robust effect. We further expect the mice to tolerate quite large doses of the fibulins, which makes us hopeful that toxicity will not be a problem.”

The investigators have not yet found which receptors the fibulins interact with to produce their anti-angiogenic effect. However, in this study, they report that the fibulins change the levels of extracellular proteins involved in dissolving and reforming the extracellular matrix, which can make way for blood-vessel growth.

Dr. Schiemann and coworkers are now working to isolate the portion of the fibulin molecules that actually attaches to receptors and causes their biologic effect. If they can find a small molecule capable of generating the fibulins' effects, it would be more effective as a viable therapy for cancer.

The study was published in the March 2006 issue of the journal Cancer Research.



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