November 26, 2002
Researchers 'Slug' it out with cell death
Thomas Look, MD
Cancer cells' ability to become resistant to powerful chemotherapy and radiation treatments has long frustrated, and fascinated, physicians and scientists. Now, researchers at Dana-Farber have found that certain cancer cells share an element of their "survival kit" with cells in the bone marrow — raising the possibility that it may one day be possible to protect healthy marrow cells from some chemo and radiation therapy.
The common element is a protein called Slug, which is especially abundant in cells of a rare form of childhood acute lymphoblastic leukemia (ALL). The cells have abnormally translocated chromosomes that result in a fusion gene called EZA-HLF. In the early 1990s, researchers led by Thomas Look, MD, (now of Pediatric Oncology) found that Slug helped these cells avoid the self-destruct process — or apoptosis — normally triggered by chemotherapy or radiation therapy.
Last month, Look and his colleagues at Dana-Farber reported that Slug has the same effect in normal bone marrow cells known as hematopoietic progenitors, which are not-yet-mature versions of blood-making cells.
In a study appearing in October's issue of the journal Cancer Cell, Look's team developed a strain of mice whose cells were hampered from producing Slug. When the mice were exposed to radiation, they died earlier than normal mice that had received the same radiation dose. In addition, their blood counts were lower than in the normal mice, and they showed more signs of internal bleeding as well as tiny pockets of bacterial infection.
When researchers examined the Slug-deficient mice's bone marrow, they found an unusually high number of hematopoietic progenitor cells that were in the midst of self-destruction. The clear conclusion was that Slug helps shield such cells from the ruinous effects of radiation and, possibly, chemotherapy.
"We knew from our previous work that Slug is part of a protein 'pathway' within certain leukemia cells that enables them to escape the apoptosis-causing effect of chemotherapy and radiation, and thereby survive even after these treatments have been administered," Look remarks. "But it seemed unlikely that this pathway exists only in pro-B cell acute leukemia cells. We wanted to discover which type of normal cells use the pathway for their own survival. It's exciting that those cells turned out to be bone marrow progenitor cells."
Exciting, because the discovery may make it possible for future patients to avoid some of the toxic side effects associated with cancer therapy. Because chemo and radiation treatment may damage normal bone marrow cells as well as cancer cells, the amount of therapy that patients can receive is limited by how much their bone marrow cells can withstand. If doctors were able to protect those cells from damage — perhaps by upregulating Slug expression — they might be able to use higher doses of chemo and radiation, killing larger numbers of cancer cells.
Contributing to the study were Adolfo Ferrando, MD, PhD, Shintaro Kamizono, MD, Markus Seidel, MD, and Wenshu Wu, PhD, of Pediatric Oncology, Hiromi Iwasaki, MD, and Koichi Akashi, MD, PhD, of Cancer Immunology and AIDS, and colleagues at St. Jude Children's Research Hospital and Harvard Medical School.
"We'd like to learn what other anti-cancer agents activate Slug, as well as identify the other proteins in the protective pathway," Look asserts. "It's a rewarding time in Slug research."
