Arbiser Jack L, Bonner Michael Y, Gilbert Linda C
Department of Dermatology, Emory University School of Medicine, Atlanta Veterans Administration Medical Center, Winship Cancer Institute, Atlanta, GA, USA.
NPJ Precis Oncol. 2017;1. doi: 10.1038/s41698-017-0026-x. Epub 2017 Jun 22.
Cancer is the second leading cause of death in the United States, and is an increasing cause of death in the developing world. While there is great heterogeneity in the anatomic site and mutations involved in human cancer, there are common features, including immortal growth, angiogenesis, apoptosis evasion, and other features, that are common to most if not all cancers. However, new features of human cancers have been found as a result of clinical use of novel "targeted therapies," angiogenesis inhibitors, and immunotherapies, including checkpoint inhibitors. These findings indicate that cancer is a moving target, which can change signaling and metabolic features based upon the therapies offered. It is well-known that there is significant heterogeneity within a tumor and it is possible that treatment might reduce the heterogeneity as a tumor adapts to therapy and, thus, a tumor might be synchronized, even if there is no major clinical response. Understanding this concept is important, as concurrent and sequential therapies might lead to improved tumor responses and cures. We posit that the repertoire of tumor responses is both predictable and limited, thus giving hope that eventually we can be more effective against solid tumors. Currently, among solid tumors, we observe a response of 1/3 of tumors to immunotherapy, perhaps less to angiogenesis inhibition, a varied response to targeted therapies, with relapse and resistance being the rule, and a large fraction being insensitive to all of these therapies, thus requiring the older therapies of chemotherapy, surgery, and radiation. Tumor phenotypes can be seen as a continuum between binary extremes, which will be discussed further. The biology of cancer is undoubtedly more complex than duality, but thinking of cancer as a duality may help scientists and oncologists discover optimal treatments that can be given either simultaneously or sequentially.
癌症是美国第二大死因，且在发展中国家，其致死率也在不断上升。虽然人类癌症在解剖部位和所涉及的突变方面存在很大的异质性，但仍有一些共同特征，包括无限增殖、血管生成、凋亡逃避等，这些特征即便不是所有癌症，也是大多数癌症所共有的。然而，由于新型“靶向疗法”、血管生成抑制剂和免疫疗法（包括检查点抑制剂）的临床应用，人们发现了人类癌症的一些新特征。这些发现表明，癌症是一个动态的靶点，会根据所提供的治疗方法改变信号传导和代谢特征。众所周知，肿瘤内部存在显著的异质性，并且在肿瘤适应治疗的过程中，治疗有可能会降低这种异质性，因此，即使没有明显的临床反应，肿瘤也可能会趋于同步。理解这一概念很重要，因为联合治疗和序贯治疗可能会提高肿瘤反应率并实现治愈。我们认为，肿瘤反应的类型是可预测且有限的，因此有望最终更有效地对抗实体瘤。目前，在实体瘤中，我们观察到三分之一的肿瘤会对免疫疗法产生反应，对血管生成抑制疗法的反应可能稍低，对靶向疗法的反应各不相同，复发和耐药是常见情况，还有很大一部分肿瘤对所有这些疗法都不敏感，因此仍需要化疗、手术和放疗等传统疗法。肿瘤表型可以看作是两个极端之间的连续体，这将在后面进一步讨论。癌症生物学无疑比二元性更为复杂，但将癌症视为二元性可能有助于科学家和肿瘤学家发现可以同时或序贯给予的最佳治疗方法。
