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clinicAl diScuSSion New Targets in the Fight Against Ovarian Cancer thanKs to a discoVery by a group of researchers at yale school of medicine, therapies targeting oVarian cancer stem cells are a little closer to becoming reality. y ingQun huAng, M.d., ph.d. , associate professor of obstetrics, gynecology and reproductive sciences at Yale School of Medicine, and colleagues were inspired by the work of Ronald Buckanovich, M.D., Ph.D., of the University of Michigan. Dr. Buckanovich's team found that cancer-associated mesenchymal cells secrete bone morphogenetic protein 4 (BMP4), a growth factor that stimulates cancer stem cell growth. In earlier studies, Dr. Huang and her team found that Lin28, a stem cell factor, interacted with BMP4 messenger RNA (mRNA), but they didn't know why. To f i n d o u t , t h e y e m p l o y e d three methods: + The use of small interfering RNA allowed the team to knock down Lin28 to observe BMP4 expression, as well as overexpress Lin28 to find heightened production of BMP4. These tactics demonstrated what Dr. Huang calls "a positive connection" between the stem cell factor and the growth factor. + A method called immunoprecipitation and deep sequencing allowed 16 | Greater Boston MD News ■ MdneWS.coM researchers to use a Lin28-specific antibody to extract Lin28 and associated mRNAs — one of which was identified through deep sequencing as BMP4 mRNA — from cells. According to Dr. Huang, this method demonstrated that "Lin28 is physically associated with BMP4." + Using automated quantitative analysis, researchers were able to speedily pinpoint Lin28 and Oct4 (also a stem cell factor) expression levels in tumor samples from approximately 300 ovarian cancer patients. "Basically, we think there is a crosstalk between cancer stem cells and tumor environment, of which cancer-associated mesenchymal stem cells are a component," says Dr. Huang. "As cancer-associated mesenchymal stem cells secrete BMP4, Lin28 stimulates BMP4 expression. BMP4 goes to the tumor environment and enhances stem cell growth, making the situation worse." High levels of Lin28, the researchers found, adversely affected patient prognosis when high levels of Oct4 also presented. reason to hope The National Cancer Institute estimates more than 22,000 new cases of ovarian cancer will be diagnosed this year, with the disease claiming more than 14,000 lives. According to Dr. Huang, chemotherapy does not, for the most part, destroy ovarian cancer stem cells, making identification of cancer stem cells and development of therapies to target them vitally important to the fight against the disease. "There are many different surface markers for ovarian cancer stem cells, two of which are Lin28 and Oct4," Dr. Huang says. "Other laboratories have found other markers, other pieces of the puzzle. Sooner or later, one, clear picture is going to emerge, and we will know all the markers for ovarian cancer stem cells. If we can target, for example, Lin28 and Oct4 and knock them down, these markers might be diagnostic indicators of double-positive tumors. We also need to develop drugs targeting BMP4 and other important growth factors to see if we can knock them down or inhibit their secretion. My message to clinicians involved in treating ovarian cancer is this: Hope is on the way." ■

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