Semmelweis University, Department of Medical Chemistry, Tuzolto u. 37-47, H-1094 Budapest, Hungary.
Semin Cancer Biol. 2013 Aug;23(4):262-9. doi: 10.1016/j.semcancer.2013.06.005. Epub 2013 Jun 21.
There is a widening recognition that cancer cells are products of complex developmental processes. Carcinogenesis and metastasis formation are increasingly described as systems-level, network phenomena. Here we propose that malignant transformation is a two-phase process, where an initial increase of system plasticity is followed by a decrease of plasticity at late stages of carcinogenesis as a model of cellular learning. We describe the hallmarks of increased system plasticity of early, tumor initiating cells, such as increased noise, entropy, conformational and phenotypic plasticity, physical deformability, cell heterogeneity and network rearrangements. Finally, we argue that the large structural changes of molecular networks during cancer development necessitate a rather different targeting strategy in early and late phase of carcinogenesis. Plastic networks of early phase cancer development need a central hit, while rigid networks of late stage primary tumors or established metastases should be attacked by the network influence strategy, such as by edgetic, multi-target, or allo-network drugs. Cancer stem cells need special diagnosis and targeting, since their dormant and rapidly proliferating forms may have more rigid, or more plastic networks, respectively. The extremely high ability of cancer stem cells to change the rigidity/plasticity of their networks may be their key hallmark. The application of early stage-optimized anti-cancer drugs to late-stage patients may be a reason of many failures in anti-cancer therapies. Our hypotheses presented here underlie the need for patient-specific multi-target therapies applying the correct ratio of central hits and network influences - in an optimized sequence.
人们越来越认识到，癌细胞是复杂发育过程的产物。致癌作用和转移形成越来越被描述为系统水平、网络现象。在这里，我们提出恶性转化是一个两阶段的过程，在这个过程中，系统可塑性的初始增加伴随着致癌作用后期可塑性的降低，这是细胞学习的一个模型。我们描述了早期肿瘤起始细胞系统可塑性增加的特征，如增加的噪声、熵、构象和表型可塑性、物理变形性、细胞异质性和网络重排。最后，我们认为，在癌症发展过程中，分子网络的大结构变化需要在致癌作用的早期和晚期采用一种截然不同的靶向策略。早期癌症发展的可塑性网络需要一个中心打击，而晚期原发性肿瘤或已建立的转移瘤的刚性网络应该通过网络影响策略来攻击，例如通过边缘、多靶或全网络药物。癌症干细胞需要特殊的诊断和靶向治疗，因为它们的休眠和快速增殖形式可能分别具有更刚性或更具可塑性的网络。癌症干细胞改变其网络刚性/可塑性的极高能力可能是其关键特征。将早期优化的抗癌药物应用于晚期患者可能是抗癌治疗中许多失败的原因之一。我们在这里提出的假设，是为了需要针对特定患者的多靶治疗方法，应用正确的中心打击和网络影响的比例，并以优化的顺序进行。
