PDF(Pubmed)
Abstract：
Despite improvements in patient outcomes, pediatric cancer remains a leading cause of non-accidental death in children. Recent genetic analysis of patients with pediatric cancers indicates an important role for both germline genetic predisposition and cancer-specific somatic driver mutations. Increasingly, evidence demonstrates that the developmental timepoint at which the cancer cell-of-origin transforms is critical to tumor identity and therapeutic response. Therefore, future therapeutic development would be bolstered by the use of disease models that faithfully recapitulate the genetic context, cell-of-origin, and developmental window of vulnerability in pediatric cancers. Human stem cells have the potential to incorporate all of these characteristics into a pediatric cancer model, while serving as a platform for rapid genetic and pharmacological testing. In this review, we describe how human stem cells have been used to model pediatric cancers and how these models compare to other pediatric cancer model modalities.
Today, pediatric cancer is a leading cause of non-accidental death in children. In order to further improve outcomes, it is important for researchers and clinicians alike to recognize how pediatric cancers are distinct from adult cancers. Inherited risk of cancer may play a greater role in pediatric cancer risk, and subsequent tumor-specific acquired driver mutations initiate tumor formation. However, there is substantial interaction between inherited and acquired mutations, which supports consideration of both simultaneously. Recent advancements in biotechnology, have improved matching between early cells of development and pediatric cancer cells, although cell-of-origin for certain pediatric central nervous system tumors remain elusive. Increasingly, evidence, particularly in pediatric medulloblastoma, demonstrates that the developmental timepoint at which the cancer cell-of-origin transforms is critical to tumor identity and therapeutic response. Therefore, future therapeutic development would be bolstered by the use of disease models that faithfully recapitulate the genetic context, cell-of-origin, and developmental window of pediatric cancers. Human stem cells have the potential to incorporate all of these characteristics into a pediatric cancer model, while serving as a platform for rapid genetic and pharmacological testing. In this review, we describe how human stem cells have been used to model pediatric cancers, how human these models compare to other pediatric cancer model modalities, and how these models can be improved in the future.
Today, pediatric cancer is a leading cause of non-accidental death in children. In order to further improve outcomes, it is important for researchers and clinicians alike to recognize how pediatric cancers are distinct from adult cancers. Inherited risk of cancer may play a greater role in pediatric cancer risk, and subsequent tumor-specific acquired driver mutations initiate tumor formation. However, there is substantial interaction between inherited and acquired mutations, which supports consideration of both simultaneously. Recent advancements in biotechnology, have improved matching between early cells of development and pediatric cancer cells, although cell-of-origin for certain pediatric central nervous system tumors remain elusive. Increasingly, evidence, particularly in pediatric medulloblastoma, demonstrates that the developmental timepoint at which the cancer cell-of-origin transforms is critical to tumor identity and therapeutic response. Therefore, future therapeutic development would be bolstered by the use of disease models that faithfully recapitulate the genetic context, cell-of-origin, and developmental window of pediatric cancers. Human stem cells have the potential to incorporate all of these characteristics into a pediatric cancer model, while serving as a platform for rapid genetic and pharmacological testing. In this review, we describe how human stem cells have been used to model pediatric cancers, how human these models compare to other pediatric cancer model modalities, and how these models can be improved in the future.
摘要：
尽管患者预后有所改善，儿科癌症仍然是儿童非意外死亡的主要原因.最近对儿科癌症患者的遗传分析表明，种系遗传易感性和癌症特异性体细胞驱动突变都具有重要作用。越来越多,有证据表明,起源癌细胞转化的发育时间点对于肿瘤身份和治疗反应至关重要.因此,未来的治疗发展将通过使用忠实地概括遗传背景的疾病模型来支持，细胞起源，和儿童癌症的脆弱性发展窗口。人类干细胞有可能将所有这些特征整合到儿科癌症模型中，同时作为快速遗传和药理测试的平台。在这次审查中,我们描述了人类干细胞是如何用于儿科癌症模型的,以及这些模型与其他儿科癌症模型模式的比较.
今天,儿童癌症是儿童非意外死亡的主要原因.为了进一步改善结果，对于研究人员和临床医生来说，认识到小儿癌症与成人癌症的区别非常重要。遗传的癌症风险可能在儿科癌症风险中发挥更大的作用，和随后的肿瘤特异性获得性驱动突变启动肿瘤形成。然而,遗传和获得性突变之间存在实质性的相互作用，这支持同时考虑两者。生物技术的最新进展，改善了早期发育细胞和儿科癌细胞之间的匹配，尽管某些儿童中枢神经系统肿瘤的细胞来源仍然难以捉摸。越来越多,证据,特别是在小儿髓母细胞瘤中，证明了癌细胞起源转化的发育时间点对于肿瘤身份和治疗反应至关重要。因此,未来的治疗发展将通过使用忠实地概括遗传背景的疾病模型来支持，细胞起源，和儿科癌症的发育窗口。人类干细胞有可能将所有这些特征整合到儿科癌症模型中，同时作为快速遗传和药理测试的平台。在这次审查中,我们描述了如何使用人类干细胞来模拟儿科癌症，这些模型与其他儿科癌症模型相比，以及未来如何改进这些模型。
今天,儿童癌症是儿童非意外死亡的主要原因.为了进一步改善结果，对于研究人员和临床医生来说，认识到小儿癌症与成人癌症的区别非常重要。遗传的癌症风险可能在儿科癌症风险中发挥更大的作用，和随后的肿瘤特异性获得性驱动突变启动肿瘤形成。然而,遗传和获得性突变之间存在实质性的相互作用，这支持同时考虑两者。生物技术的最新进展，改善了早期发育细胞和儿科癌细胞之间的匹配，尽管某些儿童中枢神经系统肿瘤的细胞来源仍然难以捉摸。越来越多,证据,特别是在小儿髓母细胞瘤中，证明了癌细胞起源转化的发育时间点对于肿瘤身份和治疗反应至关重要。因此,未来的治疗发展将通过使用忠实地概括遗传背景的疾病模型来支持，细胞起源，和儿科癌症的发育窗口。人类干细胞有可能将所有这些特征整合到儿科癌症模型中，同时作为快速遗传和药理测试的平台。在这次审查中,我们描述了如何使用人类干细胞来模拟儿科癌症，这些模型与其他儿科癌症模型相比，以及未来如何改进这些模型。
