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。我们的发现就是一个例子 多发性骨髓瘤(MM)的标志是肿瘤浆细胞(PC)，其复制能力有限 相反，MM PC实际上起源于类似于Memory B的自我更新癌症干细胞 细胞。尽管癌症干细胞的临床意义仍不确定，但我们的初步数据表明 他们对抗癌治疗后的许多复发负有责任。几个不相关的 恶性肿瘤，如成人急性淋巴细胞性白血病(ALL)和卵巢癌，具有高 最初的完全临床应答率通常不是持久的。戏剧性的初始回复率在所有 卵巢癌可以代表对分化癌细胞的治疗效果。 构成肿瘤的大部分；高复发率可能代表罕见的、生物学上不同的癌症。 对治疗有抵抗力的干细胞对肿瘤有效。慢性阻塞性肺疾病的治疗进展 癌症干细胞一直受到这些细胞稀有性的阻碍；事实上，针对靶点的治疗 如果单独判断临床活动，癌症干细胞独有的表达可能会过早地被放弃 根据反映治疗对大部分癌症的影响的标准反应标准。肿瘤干细胞 似乎有许多共同的特性，将正常的组织特异性干细胞与它们的 分化的后代。这些共同的特性包括细胞静止，高表达的ATP结合 ABC膜转运蛋白，乙醛脱氢酶(ALDH)活性增加，以及 没有糖基磷脂酰肌醇(GPI)锚定。此外，几个信号通路是 在胚胎发育期间对正常干细胞的产生和维持很重要[例如， Noch、Wnt和Hedgehog(HH)]和/或出生后(例如端粒酶和生长因子)似乎也是 对许多癌症的生长都很重要。共享的干细胞特性不仅可能有助于 癌症干细胞的耐药性，但也可以帮助识别和分离癌症干细胞， 同时也是许多癌症潜在有效的新疗法的靶点。这个 该项目的总体目标是更好地了解卵巢肿瘤干细胞的生物学。 着眼于改善治疗结果的癌症。需要检验的一个假设是，分歧者 儿童型和成人型之间的结果都是不同干细胞群体的结果； 儿童型ALL来源于淋巴祖细胞，成年型来源于造血干细胞。 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.