The modulatory effect of cell–cell contact on the tumourigenic potential of pre-malignant epithelial cells: a computational exploration

Abstract

Malignant development cannot be attributed alone to genetic changes in a single cell, but occurs as a result of the complex interplay between the failure of cellular regulation mechanisms and the presence of a permissive microenvironment. Although E-cadherin is classified as a 'metastasis suppressor' owing to its role in intercellular adhesion, the observation that it may be downregulated at a premalignant stage is indicative of additional roles in neoplastic development. We have used an agent-based computational model to explore the emergent behaviour resulting from the interaction of single and subpopulations of E-cadherin-compromised cells with unaffected normal epithelial cells within a monolayer environment. We have extended this to investigate the importance of local tissue perturbations in the form of scratch-wounding, or ablation of randomly-dispersed normal cells, on the growth of a single cell exhibiting E-cadherin loss. Our results suggest that the microenvironment with respect to localized cell density and normal/ E-cadherin-compromised neighbours is crucial in determining whether an abnormal individual cell proliferates or remains dormant within the monolayer. These predictions raise important questions relating to the propensity for individual mutations to give rise to disease, and future experimental exploration of these will enhance our understanding of a complex, multifactorial pathological process.

Downregulation of E-cadherin expression in breast cancer by promoter hypermethylation and its relation with progression and prognosis of tumor

“…There are evidence that exists in the literature to confirm that downregulation of E-cadherin expression and/or function is a critical factor in the malignant progression of epithelial tumors. E-cadherin is classified as a 'metastasis suppressor' owing to its role in intercellular adhesion, and the observation that it may be downregulated at a premalignant stage is indicative of additional roles in neoplastic development [23]. E-cadherin is thought to act as a tumor suppressor gene in the breast although the mechanism of E-cadherin-mediated tumor suppression has not been fully elucidated [24].…”

Cooperation and competition in the dynamics of tissue architecture during homeostasis and tumorigenesis

“…Game theory could also help to consider more general types of cell-to-cell interactions in the microenvironmental niche of mutated cells [54] and evaluate the role of tissue topology and cell-to-cell interactions in the homeostatic maintenance of normal cytoarchitecture and the perturbations in it during cancer formation. This could complement the other tissues modelling approaches present in the literature [59][60][61][62][63][64][65], especially those that are focusing directly onto cell communication [66,67] and epithelial organization [68].…”

Systems approaches for synthetic biology: a pathway toward mammalian design

“…Existing libraries, such as MASON, Repast, and Swarm, allow for the construction of multi-scale agent-based models atop adaptable frameworks, facilitating their use by synthetic biologists with limited prior exposure to the technique. This methodology has been employed toward modeling brain capillary regeneration (Long et al, 2013), immunological and inflammatory responses (Bailey et al, 2007; Chandran et al, 2009; Pothen et al, 2013), and cancer progression (Wang et al, 2009; Basanta et al, 2012; Wodarz et al, 2012; Walker and Southgate, 2013), among other topics. Within synthetic biology specifically, agent-based models have also simulated tissue development, tissue formation, and microbial chemotaxis (Endler et al, 2009).…”