Stochastic model of contact inhibition and the proliferation of melanoma in situ

Mauro César Cafundó Morais,Alexandre S Queiroga,Alan U Sabino,Yuri Suhov,Willian W Lautenschlager,Izabella Stuhl,Alexandre F Ramos,Roger Chammas,Tharcisio Citrangulo Tortelli

doi:10.1038/s41598-017-07553-6

Abstract

Contact inhibition is a central feature orchestrating cell proliferation in culture experiments; its loss is associated with malignant transformation and tumorigenesis. We performed a co-culture experiment with human metastatic melanoma cell line (SKMEL- 147) and immortalized keratinocyte cells (HaCaT). After 8 days a spatial pattern was detected, characterized by the formation of clusters of melanoma cells surrounded by keratinocytes constraining their proliferation. In addition, we observed that the proportion of melanoma cells within the total population has increased. To explain our results we propose a spatial stochastic model (following a philosophy of the Widom-Rowlinson model from Statistical Physics and Molecular Chemistry) which considers cell proliferation, death, migration, and cell-to-cell interaction through contact inhibition. Our numerical simulations demonstrate that loss of contact inhibition is a sufficient mechanism, appropriate for an explanation of the increase in the proportion of tumor cells and generation of spatial patterns established in the conducted experiments.

Highlights

Despite the accumulated knowledge of experimental results on contact inhibition as an in vitro manifestation of homeostatic cell density control in normal tissues, the use of quantitative tools to understand its role in the growth of cancer in situ is only in its infancy[1, 2]
To evaluate the cell proliferation, the human metastatic melanoma (SK-MEL-147) and human immortalized keratinocytes (HaCaT) cell lines were selected for co-culture experiments
The choice of these cells allows us to mimic the interaction between the skin basal layer cells and the melanoma. Another reason for selecting these cell lines was to compare the co-culture development with patterns produced through a stochastic model dynamics. The latter involves a cell line that shows a distinctive degree of contact inhibition and another cell line that is highly tolerant, i.e., displays a loss of contact inhibition

Summary

Introduction

Despite the accumulated knowledge of experimental results on contact inhibition as an in vitro manifestation of homeostatic cell density control in normal tissues, the use of quantitative tools to understand its role in the growth of cancer in situ is only in its infancy[1, 2]. It has been demonstrated that p16 is responsible for a stronger sensitivity to contact inhibition in combination with p274 This has provided a clue about the cancer resistance of naked mole-rats as compared to human and murine fibroblasts. In this study we suggest that cells whose growth overcome contact inhbition, i.e. cells tolerating higher cellular densities, are more resistant to allelopathic effects of their neighbours, and can be called allelophylic (allelo, the other; phylia, affinity). This neccesitates the proposition of a theoretical model helping to account for different degrees of contact inhibition and quantify their role in the carcinogenesis. In this paper we present theoretical and experimental frameworks designed to investigate the modulated contact inhibition and its role in the formation of a carcinoma in situ and to demonstrate that allelophilic properties of cancer cells is a key feature for their uncontrolled proliferation

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