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

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.

A Review of Key Biological and Molecular Events Underpinning Transformation of Melanocytes to Primary and Metastatic Melanoma

“…The loss of contact inhibition has been shown to be an important event in vitro for controlling cell density and is postulated to be critical in vivo to facilitate the radial growth phase of the junctional components of melanocytic lesions, particularly early melanomas ( Figure 8A) [25,66,67]. As previously noted, normal melanocytes have dendritic handles that regulate equidistant melanocyte distribution within the basal epidermis.…”

“…Melanocytes possess dendritic processes that provide points of contact with the cell membranes of neighboring keratinocytes, by which the transfer of photoprotective melanin pigment is facilitated [24]. Normal melanocytes maintain uniform cell density relative to other melanocytes and the alteration of this density-dependent regulation is a key developmental event that allows the clustering of proliferating melanocytes in benign nevi and the radial and vertical growth phases of melanoma [25,26].…”

Uncertainty quantification on a spatial Markov-chain model for the progression of skin cancer

“…Regarding alternative computational models for skin cancer, we note the studies by Poleszczuk and Enderling (2013), Morais et al (2017), Gallinaro et al (2013) and Ciarletta et al (2001). In Poleszczuk and Enderling (2013), a cellular-automata framework for tumor growth in general has been developed.…”

“…The first study is due to Gallinaro et al (2013) and treats a model for melanoma cell migration with an elastic continuum. The second study by Morais et al (2017) treats a 2D probabilistic Widom-Rowlinson model that shares some features with the current model and with the model by Poleszczuk and Enderling (2013). The third study by Ciarletta et al (2001) entails a partial differential equations (PDE) based approach for the radial progression of melanoma.…”

Um modelo estocástico de simulação da dinâmica dos queratinócitos, melanócitos e melanomas no desenvolvimento dos tumores

“…Durante o projeto de pesquisa surgiram ainda outros caminhos que experimentamos trilhar, como aquele do modelo que desenvolvemos com acoplamento à simulação de difusão de um fármaco que agia diminuindo as probabilidades -ainda não trabalhávamos com taxas na ocasião do desenvolvimento do protótipo -de duplicação dos melanomas. Simulações foram realizadas também com mais tipos celulares, como foi o caso da inclusão das células de Merkel, também presentes na camada basal da epiderme, e dos queratinócitos "alelofílicos" aos melanomas, observados nos experimentos realizados pelo nosso grupo e relatados em artigo de Morais et al (2017) a ser submetido com nossa coautoria (fac-símile da primeira página no anexo A). Dessa forma, começamos a analisar os resultados dessa generalização para quatro tipos celulares ou mais (q ≥ 4).…”