Farnie Gillian, Clarke Robert B
Breast Biology Group, Division of Cancer Studies, Faculty of Medicine and Human Sciences, University of Manchester, Paterson Institute for Cancer Research, Wilmslow Road, Manchester, M20 4BX, UK.
Stem Cell Rev. 2007 Jun;3(2):169-75. doi: 10.1007/s12015-007-0023-5.
Adult stem cells are found in numerous tissues of the body and play a role in tissue development, replacement and repair. Evidence shows that breast stem cells are multipotent and can self renew, which are key characteristics of stem cells, and a single cell enriched with cell surface markers has the ability to grow a fully functional mammary gland in vivo. Many groups have extrapolated the cancer stem cell hypothesis from the haematopoietic system to solid cancers, where using in vitro culture techniques and in vivo transplant models have established evidence of cancer stem cells in colon, pancreas, prostate, brain and breast cancers. In the report we describe the evidence for breast cancer stem cells; studies consistently show that stem cell like and breast cancer initiating populations can be enriched using cell surface makers CD44+/CD24- and have upregulated genes which include Notch. Notch signalling has been highlighted as a pathway involved in the development of the breast and is frequently dysregulated in invasive breast cancer. We have investigated the role of Notch in a pre-invasive breast lesion, ductal carcinoma in situ (DCIS), and have found that aberrant activation of Notch signalling is an early event in breast cancer. High expression of Notch 1 intracellular domain (NICD) in DCIS also predicted a reduced time to recurrence 5 years after surgery. Using a non-adherent sphere culture technique we have grown DCIS mammospheres from primary DCIS tissue, where self-renewal capacity, measured by the number of mammosphere initiating cells, were increased from normal breast tissue. A gamma-secretase inhibitor, DAPT, which inhibits all four Notch receptors and a Notch 4 neutralising antibody were shown to reduce DCIS mammosphere formation, indicating that Notch signalling and other stem cell self-renewal pathways may represent novel therapeutic targets to prevent recurrence of pre-invasive and invasive breast cancer.
成体干细胞存在于人体的众多组织中，在组织发育、替代和修复中发挥作用。证据表明，乳腺干细胞具有多能性且能自我更新，这是干细胞的关键特征，并且单个富含细胞表面标志物的细胞具有在体内生长出功能完整乳腺的能力。许多研究小组已将癌症干细胞假说从造血系统外推至实体癌，其中利用体外培养技术和体内移植模型已证实结肠癌、胰腺癌、前列腺癌、脑癌和乳腺癌中存在癌症干细胞。在本报告中，我们描述了乳腺癌干细胞的证据；研究一致表明，使用细胞表面标志物CD44+/CD24-可富集干细胞样和乳腺癌起始细胞群，且这些细胞群中包括Notch在内的基因表达上调。Notch信号通路已被视为参与乳腺发育的一条途径，且在浸润性乳腺癌中经常失调。我们研究了Notch在乳腺原位癌（DCIS）这一乳腺浸润前病变中的作用，发现Notch信号通路的异常激活是乳腺癌的早期事件。DCIS中Notch 1细胞内结构域（NICD）的高表达还预示着术后5年复发时间缩短。我们利用非贴壁球体培养技术从原发性DCIS组织中培养出了DCIS乳腺球，通过乳腺球起始细胞数量衡量的自我更新能力相较于正常乳腺组织有所增加。一种γ-分泌酶抑制剂DAPT（可抑制所有四种Notch受体）和一种Notch 4中和抗体可减少DCIS乳腺球的形成，这表明Notch信号通路和其他干细胞自我更新途径可能代表着预防乳腺浸润前癌和浸润性癌复发的新型治疗靶点。
