Cancer Stem Cells in Acute Lymphoblastic Leukemia and Ovarian Carcinoma

急性淋巴细胞白血病和卵巢癌中的癌症干细胞

• 批准号: 7355826
• 负责人: RICHARD J JONES
• 金额: $ 33.76万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-26 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7355826
• 关键词: Acute Lymphocytic Leukemia; Adult; Adult Acute Lymphocytic Leukemia; Aldehyde dehydrogenase (NAD+); Binding; Biology; Cells; Clinical; Data; Disease; Drug resistance; Effectiveness; Embryonic Development; Erinaceidae; Eye; Generations; Glycosylphosphatidylinositols; Growth; Growth Factor; Hematopoietic stem cells; Lymphoid; Maintenance; Malignant Neoplasms; Malignant neoplasm of ovary; Membrane Transport Proteins; Memory B-Lymphocyte; Multiple Myeloma; Neoplastic Plasma Cell; Normal tissue morphology; Numbers; Outcome; Ovarian Carcinoma; Plasma Cells; Population; Property; Publications; Rate; Relapse; Relative (related person); Signal Pathway; Solid Neoplasm; Standards of Weights and Measures; Stem cells; Telomerase; Testing; Therapeutic; aldehyde dehydrogenases; cancer cell; cancer stem cell; cancer therapy; clinically significant; improved; leukemia; leukemic stem cell; notch protein; progenitor; response; therapeutic effectiveness; therapy development; therapy resistant; trait; treatment effect; tumor

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.

最近在几种不同的恶性肿瘤中发现了癌症干细胞。一个例子就是我们的发现 多发性骨髓瘤（MM），肿瘤浆细胞（PC）的标志有限 潜在的;相反，MM PC实际上是由类似于记忆b的自我更新的癌症干细胞引起的 细胞。尽管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 他们负责遵循抗癌疗法的许多复发。几个无关 恶性肿瘤，例如成人急性淋巴细胞性白血病（ALL）和卵巢癌，具有较高的特征 通常不耐用的初始完整临床应答率。所有人的初始响应率都显着 和卵巢癌可以代表针对分化癌细胞的治疗效果 组成大部分肿瘤；较高的复发率可能代表罕见的生物学上不同的癌症 干细胞可抗肿瘤大体的疗法。开发治疗 这些细胞的稀有性阻碍了癌症干细胞。实际上，针对目标的疗法 如果仅根据临床活动来判断癌症干细胞独特表达的独特表达 根据标准反应标准，反映了治疗对大部分癌症的影响。癌干细胞 似乎共享许多区分正常组织特异性干细胞和其特性的特性 分化后代。这些共享特性包括细胞静止，ATP结合的高表达 盒（ABC）膜转运蛋白，醛脱氢酶（ALDH）活性的水平升高和 缺乏糖基 - 磷脂酰肌醇（GPI）锚。另外，几种信号通路 对于胚胎发育过程中正常干细胞的产生和维持至关重要[例如， Notch，Wnt和Hedgehog（HH）]和/或产后（例如端粒酶和生长因子）似乎也是 对于许多癌症的生长很重要。共享的干细胞特性不仅有助于相对 癌症干细胞的耐药性，但也可以有助于鉴定和分离癌症干细胞， 以及作为在许多癌症中具有潜在有效性的新疗法的靶标。这 该项目的总体目的是更好地了解卵巢中所有人的癌症干细胞的生物学 癌，以改善治疗结果。一个要检验的假设是分歧 小儿型和成人型之间的结果都是干细胞群体不同的结果。 IE。 小儿型都来自淋巴祖细胞，而成年型造成造血干细胞。 另一个是专门针对所有目标和卵巢癌干细胞将改善这些结果的结果 两种疾病。