Cancer stem cells have recently been identified in several different malignancies. An example is our finding that the hallmark of multiple myeloma (MM), the neoplastic plasma cells (PC), have limited replicative potential;rather, the MM PC actually arise from self-renewing cancer stem cells that resemble memory B cells. Although the clinical significance of cancer stem cells remains uncertain, our preliminary data suggest that they are responsible for many of the relapses that follow anticancer therapy. Several unrelated malignancies, such as adult acute lymphocytic leukemia (ALL) and ovarian carcinoma, share the trait of high initial complete clinical response rates that are usually not durable. The dramatic initial response rates in ALL and ovarian carcinoma could represent therapeutic effectiveness against the differentiated cancer cells making up the bulk of the tumor;the high rate of relapses could represent rare, biologically distinct cancer stem cells resistant to the therapies effective against the tumor bulk. The development of treatments for the cancer stem cells has been hindered by the rarity of these cells;in fact, therapies directed against targets uniquely expressed by cancer stem cells might be prematurely abandoned if clinical activity is judged solely by standard response criteria that reflect the effects of treatment on the bulk of the cancer. Cancer stem cells appear to share a number of properties that distinguish normal tissue-specific stem cells from their differentiated progeny. These shared properties include cellular quiescence, high expression of ATP binding cassette (ABC) membrane transporters, increased levels of aldehyde dehydrogenase (ALDH) activity, and absence of glycosyl-phosphatidylinositol (GPI) anchors. In addition, several signaling pathways that are important for the generation and maintenance of normal stem cells during embryonic development [e.g, Notch, Wnt, and Hedgehog (Hh)] and/or postnatally (e.g., telomerase and growth factors) also appear to be important for the growth of many cancers. Shared stem cell properties not only likely contribute to the relative drug resistance of cancer stem cells, but can also aid in the identification and isolation of cancer stem cells, as well as serve as targets for new therapies that have potential effectiveness, across many cancers. The overall objective of this project is to better understand the biology of cancer stem cells in both ALL in ovarian carcinoma with an eye to improving therapeutic outcomes. One hypothesis to be tested is that the divergent outcomes between pediatric-type and adult-type ALL are the result of different stem cell populations;i.e. pediatric-type ALL arises from lymphoid progenitors while adult-type arises from hematopoietic stem cells. Another is that specifically targeting ALL and ovarian cancer stem cells will improve the outcome of these two diseases.

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