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The newspaper of The Johns Hopkins University February 4, 2008 | Vol. 37 No. 20
Stem Cells Make Bone Marrow Cancer Resistant to Treatment

By Vanessa Wasta
Johns Hopkins Medicine

Scientists at the Johns Hopkins Kimmel Cancer Center say they have evidence that cancer stem cells for multiple myeloma share many properties with normal stem cells and have multiple ways of resisting chemotherapy and other treatments.

A report on the evidence, published in the Jan. 1 issue of the journal Cancer Research, may explain why the disease is so persistent, the Johns Hopkins scientists say, and pave the way for treatments that overcome the cells' drug resistance.

Multiple myeloma, which affects bone marrow and bone tissue, is the second most common blood cancer and strikes more than 14,000 Americans each year. Close to 11,000 will die from the disease.

"Cancer stem cells that have distinct biology and drug sensitivity as compared with the bulk of a cancer may explain why multiple myeloma, like many other cancers, so often relapses even after chemotherapy puts patients into remission," said Richard J. Jones, professor and director of bone marrow transplant at Johns Hopkins' Kimmel Cancer Center and one of the scientists who authored the new report.

The existence of cancer stem cells--a topic of some controversy in cancer biology--is seen by some scientists as a useful explanation for the long history of difficulty in overcoming some cancers' persistence.

The Johns Hopkins investigators previously had uncovered a rare stem cell in myeloma, accounting for less than 1 percent of all the cancer's cells. Working with cell samples from myeloma patients, the team found that this stem cell originates from immune system B-cells and is capable of giving rise to the malignant bone marrow cells characteristic of the disease.

In the current study, the scientists isolated stem cells from the blood of four patients with multiple myeloma and transplanted them into mice. All the animals developed hind-limb paralysis and showed signs of cancer in the bone marrow. By contrast, plasma cells that were transplanted from multiple myeloma patients to mice did not engraft. The Johns Hopkins scientists say that re-creating the disease in mice provides more evidence that these cells act as cancer stem cells.

The Johns Hopkins scientists also compared the response of these special stem cells with the bulk of multiple myeloma plasma cells to four different chemotherapy medications commonly used to treat patients with the disease: dexamethasone, lenadilomide, bortezomib and 4- hydroxycyclophosphamide. While all four agents significantly inhibited the growth of the plasma cells, none inhibited the stem cells.

To their surprise, the researchers noted that the multiple myeloma stem cells resemble other types of adult stem cells and exhibit similar properties that may make them resistant to chemotherapy. They found that the stem cells contain high levels of enzymes that neutralize toxins, like cancer drugs, and expel them through miniature pumps on their cell surface. The investigators believe that these drug-fighting enzymes and pumps--also plentiful in normal stem cells--may help cancer stem cells resist treatment.

William Matsui, an assistant professor of oncology at Johns Hopkins and the study's lead investigator, said, "Nature made normal stem cells very hearty for a reason, namely to survive and help repair damaged tissues and organs after injury or illness. To us, it makes sense that the same processes that protect normal stem cells also exist in cancer stem cells to make them resistant to chemotherapy. We need to develop new ways to target the specific biology of cancer stem cells to prevent the continued production of mature tumor cells and disease relapse."

"Standard cancer therapy is like mowing the weed--it gets rid of the disease transiently, but the dandelion always grows back," Jones said. "We need to get rid of the root to cure disease and therefore need a different type of therapy; mowing won't work."

Matsui said the work also might make it possible to track the rare myeloma stem cells as a marker of how well a patient is doing during treatment.

The study was supported by the National Institutes of Health, the American Society of Clinical Oncology and the Pearse family. Additional participants in the research were Qiuju Wang, James P. Barber, Sarah Brennan, B. Douglas Smith, Ivan Borrello, Ian McNiece, Lan Lin, Richard F. Ambinder, Craig Peacock, D. Neil Watkins and Carol Ann Huff, all of Johns Hopkins.


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