Center of Cancer Systems Biology, St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135, USA.
Biol Direct. 2010 Apr 20;5:23. doi: 10.1186/1745-6150-5-23.
Aside from the stepwise genetic alterations known to underlie cancer cell creation, the microenvironment is known to profoundly influence subsequent tumor development, morphology and metastasis. Invasive cluster formation has been assumed to be dependent on directed migration and a heterogeneous environment--a conclusion derived from complex models of tumor-environment interaction. At the same time, these models have not included the prospect, now supported by a preponderance of evidence, that only a minority of cancer cells may have stem cell capacity. This proves to weigh heavily on the microenvironmental requirements for the display of characteristic tumor growth phenotypes. We show using agent-based modeling that some defining features of tumor growth ascribed to directed migration might also be realized under random migration, and discuss broader implications for cause-and-effect determination in general.
Considering only the properties of random migration in tumors composed of stem cells and committed cells, we are able to recapitulate a characteristic clustering feature of invasive tumor growth, a property we attribute to "self-metastatic" growth. When the additional influence of directed migrations under chemotactic environments are considered, we find that tumor growth and invasive morphology are supported while the tumor is distant from the source, but are progressively discouraged as the tumor converges about that source.
We show that invasive clustering can derive from basic kinetic assumptions often neglected in more complex models. While higher-order mechanisms, e.g. directed migration upon chemotactic stimuli, may result in clustering growth morphologies, exclusive attributions of this phenotype to this or other structured microenvironments would be inappropriate, in light of our finding these features are observable in a homogeneous environment. Furthermore, directed migration will result in loss of the invasive phenotype as the tumor approaches the attractor source.
This article was reviewed by Mark Little and Glen Webb.
除了已知的逐步遗传改变是癌细胞产生的基础外，微环境也被认为会深刻影响后续肿瘤的发展、形态和转移。浸润性集落的形成被认为依赖于定向迁移和异质环境，这一结论来自于肿瘤-环境相互作用的复杂模型。与此同时，这些模型并没有包括这样一种可能性，即现在有大量证据支持的，只有少数癌细胞可能具有干细胞能力。这对展示特征性肿瘤生长表型的微环境要求产生了很大的影响。我们使用基于主体的建模方法表明，一些归因于定向迁移的肿瘤生长的特征也可能在随机迁移下实现，并讨论了更广泛的因果关系确定的影响。
仅考虑由干细胞和定向细胞组成的肿瘤中的随机迁移特性，我们能够再现侵袭性肿瘤生长的一个特征性集落特征，我们将其归因于“自我转移性”生长。当考虑到在趋化环境下定向迁移的额外影响时，我们发现，当肿瘤远离源时，肿瘤生长和侵袭形态得到支持，但随着肿瘤向源收敛，这种生长形态逐渐受到抑制。
我们表明，侵袭性集落可以源自于在更复杂的模型中经常被忽视的基本动力学假设。虽然更高阶的机制，如趋化刺激下的定向迁移，可能导致集落生长形态，但将这种表型专门归因于这种或其他结构微环境是不恰当的，因为我们发现这些特征在同质环境中是可以观察到的。此外，随着肿瘤接近吸引源，定向迁移将导致侵袭性表型的丧失。
这篇文章由 Mark Little 和 Glen Webb 审稿。
