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White blood cells of cancer-resistant mice overwhelm natural defenses of cancer cells

November 01, 2006

WINSTON-SALEM, N.C. - The discoverers of the unique mouse line that is resistant to cancer have begun to pin down how the process works and found that white blood cells in these mice overwhelm normal defenses of cancer cells.

In a report in Cancer Immunity, a journal of the Academy of Cancer Immunology, posted on line today, Zheng Cui, M.D., Ph.D., and Mark C. Willingham, M.D., of Wake Forest University School of Medicine and colleagues said that several types of white blood cells in the mice attack cancer cells by sensing, finding and surrounding them, forming a "rosette," and then killing them.

"Apparently, the mutation in the cancer-resistant mice renders the white blood cells capable of sensing unique diffusible and surface signals from cancer cells and responding to those signals by migration and physical contact," they said.

The researchers said that in ordinary mice, the white blood cells are suppressed by self-defensive signals coming from the cancer cells and don't attack the cancer. But the mutated gene or genes in the cancer-resistant mouse changes the white blood cells so they interpret those same signals from the cancer cells as an invitation to attack.

"Identifying the mutated gene (or genes) will likely explain this unique resistance to cancer through immunity," said Cui, associate professor of pathology.

Earlier this year, the same team reported in the Proceedings of the National Academy of Sciences that white blood cells taken from these cancer-resistant mice cured advanced cancers in ordinary mice and also protected those normal mice from what should have been lethal doses of highly aggressive new cancers.

But while pursuing the ability of these white blood cells to cure cancer in ordinary mice, and beginning to explore whether the same process could work in humans, the researchers have also continued to investigate how the original mutation works, a mutation that protects the cancer-resistant mice from a wide variety of injected cancer cells.

Cui and Willingham said the killing of the cancer cells in the cancer-resistant mouse requires three distinct steps:

- First, the white blood cells migrate to the site of cancer cells after sensing their presence.

- Second, they recognize unique properties on the surface of the cancer cells and closely surround those cells.

- Third, a lethal dose of each white-blood-cell type's cancer-killing compound is delivered to the cancer cells. The killing molecule varies with the white-cell type.

The ordinary mice lack the first two steps.

The researchers found that the anti-tumor response involved white blood cells of the so-called innate immune system, which the body ordinarily employs to fight off bacteria, but which had not been thought to be effective in fighting off cancer. Instead, in these cancer-resistant mice, three white-blood-cell types of the innate immune system - neutrophils, macrophages and natural killer cells - all infiltrate the tumor site in a multi-pronged killing response.

"Each cell type had independent killing activity against the cancer cells," the authors said, using different molecules. Macrophages, for instance, have to be in physical contact with the cancer cell before unleashing its combination of killer molecules.

White blood cells from the cancer-resistant mice apparently have the same ability to attack a range of tumors when transplanted to ordinary mice.

Cui and Willingham also want to explore how this one process can detect a wide range of cancer cells of so many different types. The dogma of cancer fighters has always postulated that there are many different cancers. "This new research in mice suggests that there may be some things that most cancers have in common," said Willingham, a pathologist and head of the Section on Tumor Biology.

Wake Forest University Baptist Medical Center