Uriel José
Visiting scientist: Apoptosis, Immunity and Cancer Group, Department of Biochemistry and Molecular and Cell Biology, University of Zaragoza, Zaragoza, Spain.
, 50 rue Corvisart, 75013, Paris, France.
Tumour Biol. 2015 Sep;36(10):7365-74. doi: 10.1007/s13277-015-3981-2. Epub 2015 Sep 7.
This "opinion article" is an attempt to take an overview of some significant changes that have happened in our understanding of cancer status during the last half century and its evolution under the progressive influence of molecular biology. As an active worker in cancer research and developmental biology during most of this period, I would like to comment briefly on these changes and to give my critical appreciation of their outcome as it affects our knowledge of cancer development as well as the current treatment of the disease. A recall of my own contribution to the subject is also included. Two subjects are particularly developed: cell injury and cell-killing therapies. Cell injury, whatever its origin, has acquired the status of a pivotal event for the initiation of cancer emergence. It is postulated that cell injury, a potential case of cellular death, may also be the origin of a process of stepwise cell reversion (retrodifferentiation or retroprogrammation) leading, by division, mature or stem cells to progressive immaturity. The genetic instability and mutational changes that accompanies this process of cell injury and rejuvenation put normal cells in a status favourable to neoplastic transformation or may evolve cancer cells toward clones with higher malignant potentiality. Thus, cell injury suggests lifestyle as the major upstream initiator of cancer development although this not exclude randomness as an unavoidable contributor to the disease. Cell-killing agents (mainly cytotoxic drugs and radiotherapy) are currently used to treat cancer. At the same time, it is agreed that agents with high cell injury potential (ultraviolet light, ionising radiations, tobacco, environmental pollutants, etc.) contribute to the emergence of malignant tumours. This represents a real paradox. In spite of the progress accomplished in cancer survival, one is tempted to suggest that we have very few chances of really cure cancer as long as we continue to treat malignancies with cell-killing therapies. Indeed, the absence of alternatives to such treatments justifies the pursuit of current procedures of cancer care. But, this should be, precisely, an urgent stimulus to explore other therapeutic approaches. Tumour reversion, immunotherapy, stem cell management and genomic analysis of embryo-foetal development could be, among others, appropriated candidates for future active research.
这篇“观点文章”旨在概述过去半个世纪里我们对癌症状况的理解所发生的一些重大变化，以及在分子生物学的不断影响下其演变情况。在这段时期的大部分时间里，我一直活跃于癌症研究和发育生物学领域，在此我想简要评论一下这些变化，并对其结果进行批判性评价，因为这些结果影响着我们对癌症发展的认识以及当前对该疾病的治疗。文中还回顾了我自己对该主题的贡献。特别探讨了两个主题：细胞损伤和细胞杀伤疗法。无论其起源如何，细胞损伤已成为癌症发生起始的关键事件。据推测，细胞损伤这种潜在的细胞死亡情况，也可能是细胞逐步逆转（去分化或重编程）过程的起源，通过分裂使成熟细胞或干细胞走向渐进性不成熟。伴随这种细胞损伤和年轻化过程的基因不稳定和突变变化，使正常细胞处于有利于肿瘤转化的状态，或者可能使癌细胞演变为具有更高恶性潜能的克隆。因此，细胞损伤表明生活方式是癌症发展的主要上游引发因素，尽管这并不排除随机性作为该疾病不可避免的促成因素。细胞杀伤剂（主要是细胞毒性药物和放疗）目前用于治疗癌症。与此同时，人们一致认为具有高细胞损伤潜能的因素（紫外线、电离辐射、烟草、环境污染物等）会导致恶性肿瘤的出现。这确实是一个真正的悖论。尽管在癌症存活率方面取得了进展，但有人不禁会提出，只要我们继续用细胞杀伤疗法治疗恶性肿瘤，我们真正治愈癌症的机会就微乎其微。事实上，由于缺乏此类治疗的替代方法，继续采用当前的癌症治疗程序是合理的。但是，恰恰这应该成为探索其他治疗方法的紧迫动力。肿瘤逆转、免疫疗法、干细胞管理以及胚胎 - 胎儿发育的基因组分析等，可能是未来积极研究的合适候选方向。
