Lauko Adam, Lo Alice, Ahluwalia Manmeet S, Lathia Justin D
Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, United States; Medical Scientist Training Program, Case Western Reserve University School of Medicine, Cleveland, OH, United States.
Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States.
Semin Cancer Biol. 2022 Jul;82:162-175. doi: 10.1016/j.semcancer.2021.02.014. Epub 2021 Feb 25.
Brain tumors remain one of the most difficult tumors to treat and, depending on the diagnosis, have a poor prognosis. Of brain tumors, glioblastoma (GBM) is the most common malignant glioma and has a dismal prognosis, with only about 5% of patients alive five years after diagnosis. While advances in targeted therapies and immunotherapies are rapidly improving outcomes in a variety of other cancers, the standard of care for GBM has largely remained unaltered since 2005. There are many well-studied challenges that are either unique to brain tumors (i.e., blood-brain barrier and immunosuppressive environment) or amplified within GBM (i.e., tumor heterogeneity at the cellular and molecular levels, plasticity, and cancer stem cells) that make this disease particularly difficult to treat. While we touch on all these concepts, the focus of this review is to discuss the immense inter- and intra-tumoral heterogeneity and advances in our understanding of tumor cell plasticity and epigenetics in GBM. With each improvement in technology, our understanding of the complexity of tumoral heterogeneity and plasticity improves and we gain more clarity on the causes underlying previous therapeutic failures. However, these advances are unlocking new therapeutic opportunities that scientists and physicians are currently exploiting and have the potential for new breakthroughs.
脑肿瘤仍然是最难治疗的肿瘤之一，根据诊断情况，其预后较差。在脑肿瘤中，胶质母细胞瘤（GBM）是最常见的恶性胶质瘤，预后不佳，诊断后五年只有约5%的患者存活。虽然靶向治疗和免疫治疗的进展正在迅速改善其他多种癌症的治疗效果，但自2005年以来，GBM的标准治疗方法基本没有改变。脑肿瘤有许多经过充分研究的挑战，这些挑战要么是脑肿瘤所特有的（即血脑屏障和免疫抑制环境），要么在GBM中被放大（即细胞和分子水平的肿瘤异质性、可塑性和癌症干细胞），这使得这种疾病特别难以治疗。虽然我们会涉及所有这些概念，但本综述的重点是讨论肿瘤内和肿瘤间巨大的异质性，以及我们对GBM中肿瘤细胞可塑性和表观遗传学理解的进展。随着技术的每一次进步，我们对肿瘤异质性和可塑性复杂性的理解也在提高，并且我们对先前治疗失败的潜在原因有了更清晰的认识。然而，这些进展正在开启新的治疗机会，科学家和医生目前正在加以利用，并有取得新突破的潜力。
