University of Glasgow, UK.
Integr Biol (Camb). 2011 Jan;3(1):17-30. doi: 10.1039/c0ib00046a. Epub 2010 Oct 14.
Unless diagnosed early, many adult cancers remain incurable diseases. This is despite an intense global research effort to develop effective anticancer therapies, calling into question the use of rational drug design strategies in targeting complex disease states such as cancer. A fundamental challenge facing researchers and clinicians is that cancers are inherently robust biological systems, able to survive, adapt and proliferate despite the perturbations resulting from anticancer drugs. It is essential that the mechanisms underlying tumor robustness be formally studied and characterized, as without a thorough understanding of the principles of tumor robustness, strategies to overcome therapy resistance are unlikely to be found. Degeneracy describes the ability of structurally distinct system components (e.g. proteins, pathways, cells, organisms) to be conditionally interchangeable in their contribution to system traits and it has been broadly implicated in the robustness and evolvability of complex biological systems. Here we focus on one of the most important mechanisms underpinning tumor robustness and degeneracy, the cellular heterogeneity that is the hallmark of most solid tumors. Based on a combination of computational, experimental and clinical studies we argue that stochastic noise is an underlying cause of tumor heterogeneity and particularly degeneracy. Drawing from a number of recent data sets, we propose an integrative model for the evolution of therapy resistance, and discuss recent computational studies that propose new therapeutic strategies aimed at defeating the adaptable cancer phenotype.
除非早期诊断，否则许多成人癌症仍然是不治之症。尽管全球在研发有效抗癌疗法方面投入了大量精力，但这一事实仍令人质疑在针对癌症等复杂疾病状态时使用合理药物设计策略的合理性。研究人员和临床医生面临的一个基本挑战是，癌症是固有的健壮生物系统，即使受到抗癌药物的干扰，它们也能够生存、适应和增殖。从肿瘤健壮性的原则出发，正式研究和描述其潜在机制是至关重要的，如果没有对肿瘤健壮性原则的透彻理解，就不可能找到克服治疗耐药性的策略。简并性描述了结构不同的系统成分（例如蛋白质、途径、细胞、生物体）在对系统特性的贡献上具有条件可互换性，它广泛涉及复杂生物系统的健壮性和可进化性。在这里，我们关注的是支撑肿瘤健壮性和简并性的最重要机制之一，即大多数实体瘤的标志性特征——细胞异质性。基于计算、实验和临床研究的综合分析，我们认为随机噪声是肿瘤异质性，尤其是简并性的根本原因。我们从多个最近的数据集出发，提出了一个用于治疗耐药性进化的综合模型，并讨论了最近的计算研究，这些研究提出了旨在击败适应性癌症表型的新治疗策略。
