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: 8212933
• 负责人: RICHARD J JONES
• 金额: $ 31.1万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212933
• 关键词: Acute; Acute Lymphocytic Leukemia; Adult; Adult Acute Lymphocytic Leukemia; Binding; Biology; Cells; Childhood; Clinical; Data; Disease; Drug resistance; Effectiveness; Embryonic Development; Erinaceidae; Eye; Generations; Glycosylphosphatidylinositols; Growth; Growth Factor; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Lymphocyte; Lymphoid; Maintenance; Malignant Neoplasms; Malignant neoplasm of ovary; Membrane Transport Proteins; Memory B-Lymphocyte; Multiple Myeloma; Neoplastic Plasma Cell; Normal tissue morphology; Outcome; Ovarian Carcinoma; Plasma Cells; Property; Publications; Relapse; Relative (related person); Signal Pathway; Solid Neoplasm; 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; self-renewal; stem cell population; 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。我们的发现就是一个例子 多发性骨髓瘤 (MM) 的标志是肿瘤性浆细胞 (PC) 的复制能力有限 潜在的;相反，MM PC 实际上是由自我更新的癌症干细胞产生的，类似于记忆 B 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 他们是抗癌治疗后许多复发的原因。几个不相关的 恶性肿瘤，如成人急性淋巴细胞白血病（ALL）和卵巢癌，具有高发病率的特点 最初的完全临床缓解率通常不持久。 ALL 中引人注目的初始反应率 卵巢癌可能代表针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、生物学上独特的癌症 干细胞对有效对抗肿瘤体积的疗法有抵抗力。治疗方法的开发 癌症干细胞因其稀有性而受到阻碍；事实上，针对靶标的疗法 如果仅判断临床活性，癌症干细胞独特表达的可能会被过早放弃 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 似乎具有许多共同的特性，这些特性可以将正常组织特异性干细胞与其自身的干细胞区分开来。 分化的后代。这些共同特性包括细胞静止、ATP 结合的高表达 盒式 (ABC) 膜转运蛋白，乙醛脱氢酶 (ALDH) 活性水平增加，以及 缺乏糖基磷脂酰肌醇 (GPI) 锚。此外，还有一些信号通路 对于胚胎发育过程中正常干细胞的产生和维持很重要[例如， Notch、Wnt 和 Hedgehog (Hh)] 和/或出生后（例如端粒酶和生长因子）似乎也 对于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，但也可以帮助识别和分离癌症干细胞， 以及作为对许多癌症具有潜在有效性的新疗法的靶点。这 该项目的总体目标是更好地了解卵巢 ALL 中癌症干细胞的生物学特性 癌症着眼于改善治疗结果。需要检验的一个假设是发散 儿童型和成人型 ALL 之间的结果是不同干细胞群的结果； IE。 儿童型 ALL 源自淋巴祖细胞，而成人型 ALL 源自造血干细胞。 另一个观点是，专门针对 ALL 和卵巢癌干细胞将改善这些治疗的结果 两种疾病。