Tumor Morphology and Phenotypic Evolution Driven by Selective Pressure from the Microenvironment

Abstract

Emergence of invasive behavior in cancer is life-threatening, yet ill-defined due to its multifactorial nature. We present a multiscale mathematical model of cancer invasion, which considers cellular and microenvironmental factors simultaneously and interactively. Unexpectedly, the model simulations predict that harsh tumor microenvironment conditions (e.g., hypoxia, heterogenous extracellular matrix) exert a dramatic selective force on the tumor, which grows as an invasive mass with fingering margins, dominated by a few clones with aggressive traits. In contrast, mild microenvironment conditions (e.g., normoxia, homogeneous matrix) allow clones with similar aggressive traits to coexist with less aggressive phenotypes in a heterogeneous tumor mass with smooth, noninvasive margins. Thus, the genetic make-up of a cancer cell may realize its invasive potential through a clonal evolution process driven by definable microenvironmental selective forces. Our mathematical model provides a theoretical/experimental framework to quantitatively characterize this selective pressure for invasion and test ways to eliminate it.

The impact of adhesion on cellular invasion processes in cancer and development

“…Direct representations of adhesion were first considered in the context of individual cell-based models (Turner & Sherratt 2002;Turner et al 2004;Grygierzec et al 2004). In recent years, this modelling approach has been developed significantly by Anderson and coworkers, in a series of sophisticated studies into the ways in which changes in cell-cell and cell-5 A c c e p t e d m a n u s c r i p t matrix adhesion interact with other aspects of the invasive phenotype (Anderson et al 2006Ramis-Conde et al 2008;Poplawski et al 2009). …”

Thrombin induces osteosarcoma growth, a function inhibited by low molecular weight heparin in vitro and in vivo

“…1 The malignant phenotype imposes morbidity and mortality as the rapidly growing tumor impedes normal physiologic processes or the tumor itself inflicts physiologic changes resulting in pathologic conditions. An increased tendency to activate the clotting cascade, referred to as a procoagulant state, is common in cancer patients and portends a poor clinical outcome.…”

A New Ghost Cell/Level Set Method for Moving Boundary Problems: Application to Tumor Growth

“…Frieboes et al [16,17] and Wise et al [53] have begun studying 3D tumor growth using a diffuse interface approach, while others have begun studying the tumor problem using multiphase mixture models (e.g., see [4,8], and [10]). Still others use discrete models, such as cellular automata and agents (e.g., see [1,5], and [9] for some recent examples).…”