Harrop Richard, O'Neill Eric, Stern Peter L
Oxford BioMedica plc, Windrush Court, Transport Way, Oxford, OX4 6LT, UK.
Department of Oncology, University of Oxford, Oxford, UK.
Ther Adv Vaccines Immunother. 2019 Jan 25;7:2515135518821623. doi: 10.1177/2515135518821623. eCollection 2019.
Cancer stem cells (CSCs) can act as the cellular drivers of tumors harnessing stem cell properties that contribute to tumorigenesis either as founder elements or by the gain of stem cell traits by the malignant cells. Thus, CSCs can self-renew and generate the cellular heterogeneity of tumors including a hierarchical organization similar to the normal tissue. While the principle tumor growth contribution is often from the non-CSC components, it is the ability of small numbers of CSCs to avoid the effects of therapeutic strategies that can contribute to recurrence after treatment. However, identifying and characterizing CSCs for therapeutic targeting is made more challenging by their cellular potency being influenced by a particular tissue niche or by the capacity of more committed cells to regain stem cell functions. This review discusses the properties of CSCs including the limitations of the available cell surface markers, the assays that document tumor initiation and clonogenicity, the roles of epithelial mesenchymal transition and molecular pathways such as Notch, Wnt, Hippo and Hedgehog. The ability to target and eliminate CSCs is thought to be critical in the search for curative cancer treatments. The oncofetal tumor-associated antigen 5T4 (TBGP) has been linked with CSC properties in several different malignancies. 5T4 has functional attributes that are relevant to the spread of tumors including through EMT, CXCR4/CXCL12, Wnt, and Hippo pathways which may all contribute through the mobilization of CSCs. There are several different immunotherapies targeting 5T4 in development including antibody-drug conjugates, antibody-targeted bacterial super-antigens, a Modified Vaccinia Ankara-basedvaccine and 5T4-directed chimeric antigen receptor T-cells. These immune therapies would have the advantage of targeting both the bulk tumor as well as mobilized CSC populations.
癌症干细胞（CSCs）可作为肿瘤的细胞驱动因素，利用干细胞特性促进肿瘤发生，这些特性要么作为起始要素，要么通过恶性细胞获得干细胞特征来实现。因此，CSCs能够自我更新并产生肿瘤的细胞异质性，包括类似于正常组织的分层组织。虽然肿瘤生长的主要贡献通常来自非CSC成分，但少量CSCs能够避免治疗策略的影响，这可能导致治疗后复发。然而，由于CSCs的细胞潜能受特定组织微环境影响，或者更分化的细胞有恢复干细胞功能的能力，识别和表征用于治疗靶向的CSCs变得更具挑战性。本综述讨论了CSCs的特性，包括现有细胞表面标志物的局限性、记录肿瘤起始和克隆形成能力的检测方法、上皮-间质转化的作用以及Notch、Wnt、Hippo和Hedgehog等分子途径。在寻找治愈性癌症治疗方法中，靶向并消除CSCs的能力被认为至关重要。癌胚肿瘤相关抗原5T4（TBGP）已在几种不同的恶性肿瘤中与CSC特性相关联。5T4具有与肿瘤扩散相关的功能属性，包括通过EMT、CXCR4/CXCL12、Wnt和Hippo途径，这些途径可能都通过CSCs的动员发挥作用。目前有几种针对5T4的不同免疫疗法正在研发中，包括抗体-药物偶联物、抗体靶向的细菌超抗原、基于安卡拉痘苗病毒的改良疫苗以及5T4导向的嵌合抗原受体T细胞。这些免疫疗法将具有靶向大块肿瘤以及动员的CSC群体的优势。
