Cancer Stem Cells in Acute Lymphoblastic Leukemia and Ovarian Carcinoma

最近在几种不同的恶性肿瘤中发现了癌症干细胞。一个例子是我们发现 多发性骨髓瘤（MM）的标志，肿瘤性浆细胞（PC），具有有限的复制能力， 更确切地说，MM PC实际上来自类似于记忆B的自我更新癌症干细胞 细胞虽然癌症干细胞的临床意义仍然不确定，但我们的初步数据表明， 他们是导致许多癌症复发的原因。几个无关 恶性肿瘤，如成人急性淋巴细胞白血病（ALL）和卵巢癌，具有高表达的特点。 初始完全临床反应率通常不持久。急性淋巴细胞白血病的初始反应率 卵巢癌可以代表对分化癌细胞的治疗效果 占肿瘤的大部分;高复发率可能代表罕见的，生物学上独特的癌症 对有效对抗肿瘤块的疗法具有抗性的干细胞。治疗的发展， 癌症干细胞的研究一直受到这些细胞稀有性的阻碍;事实上，针对靶点的治疗 如果仅根据临床活性来判断， 通过反映治疗对大部分癌症的影响的标准反应标准。癌症干细胞 似乎有许多共同的特性，这些特性将正常组织特异性干细胞与它们的 分化后代这些共同的特性包括细胞静止，ATP结合的高表达， 盒（ABC）膜转运蛋白，增加的醛脱氢酶（ALDH）活性水平，和 不存在糖基-磷脂酰肌醇（GPI）锚。此外，一些信号通路， 对于胚胎发育过程中正常干细胞的产生和维持是重要的[例如， Notch、Wnt和Hedgehog（Hh）]和/或出生后（例如，端粒酶和生长因子）也似乎 对许多癌症的生长很重要。共享的干细胞特性不仅可能有助于相对 癌症干细胞的耐药性，而且还可以帮助识别和分离癌症干细胞， 也可以作为新疗法的靶点，这些新疗法在许多癌症中具有潜在的有效性。的 该项目的总体目标是更好地了解卵巢癌和ALL中癌症干细胞的生物学， 癌症，着眼于改善治疗结果。一个有待检验的假设是， 儿童型和成人型ALL之间的结果是不同干细胞群的结果;即 儿童型ALL由淋巴祖细胞引起，而成人型则由造血干细胞引起。 另一个是，专门针对ALL和卵巢癌干细胞将改善这些结果。 两种疾病。

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.