Vincent T L, Gatenby R A
Aerospace and Mechanical Engineering, University of Arizona, Tucson, AZ 85721-0119, USA.
Int J Oncol. 2008 Apr;32(4):729-37.
Human carcinogenesis is a multistep process in which epithelial cells progress through a series of premalignant phenotypes until an invasive cancer emerges. Extensive experimental observations in carcinogenesis have demonstrated this process can be divided into three general eras: initiation, promotion, and progression. However, this empirically derived, tissue-level explanation of carcinogenesis has not been reconciled with the step-wise genotypic and phenotypic changes encompassed in evolutionary paradigms such as the Feoron-Vogelstein diagram. Here, we analyze an evolutionary model of cellular dynamics that defines mutual interactions of cellular and subcellular events and tissue level changes in tumor growth and morphology. Results are expressed using an adaptive landscape that illustrates the evolutionary potential of cells that allow them to adapt to specific microenvironmental selection forces. It is shown that normal epithelial cells have a novel adaptive landscape that permits coexistence of normal cellular populations but also allows invasion by mutant phenotypes. Subsequent cancer evolution is possible due to a relaxation of tissue growth constraints (as mediated by cell-cell and cell-extracellular matrix interactions) and adaptations in response to perturbations in microenvironmental substrate concentrations (due to separation of evolving tumor cells from their blood supply by an intact basement membrane). Simulations, based on the dynamic model, produce three distinct stages of carcinogenesis that are consistent with the initiation, promotion, and progression stages observed experimentally. The simulations provide insight into the underlying cellular and microenvironmental dynamics that govern these empirical observations and suggest novel prevention strategies that may be tested experimentally.
人类致癌作用是一个多步骤过程，在此过程中上皮细胞经历一系列癌前表型，直至侵袭性癌症出现。致癌作用方面广泛的实验观察表明，这一过程可分为三个一般阶段：启动、促进和进展。然而，这种基于经验得出的、组织水平的致癌作用解释，尚未与诸如费隆-沃格尔斯坦图等进化范式中所包含的逐步基因型和表型变化相协调。在此，我们分析了一个细胞动力学的进化模型，该模型定义了细胞和亚细胞事件的相互作用以及肿瘤生长和形态的组织水平变化。结果用一个适应性景观来表示，该景观说明了细胞的进化潜力，使它们能够适应特定的微环境选择力。结果表明，正常上皮细胞具有一种新颖的适应性景观，它允许正常细胞群体共存，但也允许突变表型的侵袭。由于组织生长限制的放松（由细胞-细胞和细胞-细胞外基质相互作用介导）以及对微环境底物浓度扰动的适应（由于完整的基底膜将不断进化的肿瘤细胞与其血液供应分离），随后的癌症进化是可能的。基于动态模型的模拟产生了致癌作用的三个不同阶段，与实验观察到的启动、促进和进展阶段一致。这些模拟为支配这些经验观察的潜在细胞和微环境动力学提供了见解，并提出了可能通过实验进行测试的新预防策略。
