Abstract
Invasion of the surrounding tissue is one of the recognised hallmarks of cancer (Hanahan and Weinberg in Cell 100: 57–70, 2000. https://doi.org/10.1016/S0092-8674(00)81683-9), which is accomplished through a complex heterotypic multiscale dynamics involving tissue-scale random and directed movement of the population of both cancer cells and other accompanying cells (including here, the family of tumour-associated macrophages) as well as the emerging cell-scale activity of both the matrix-degrading enzymes and the rearrangement of the cell-scale constituents of the extracellular matrix (ECM) fibres. The involved processes include not only the presence of cell proliferation and cell adhesion (to other cells and to the extracellular matrix), but also the secretion of matrix-degrading enzymes. This is as a result of cancer cells as well as macrophages, which are one of the most abundant types of immune cells in the tumour micro-environment. In large tumours, these tumour-associated macrophages (TAMs) have a tumour-promoting phenotype, contributing to tumour proliferation and spread. In this paper, we extend a previous multiscale moving-boundary mathematical model for cancer invasion, by considering also the multiscale effects of TAMs, with special focus on the influence that their directional movement exerts on the overall tumour progression. Numerical investigation of this new model shows the importance of the interactions between pro-tumour TAMs and the fibrous ECM, highlighting the impact of the fibres on the spatial structure of solid tumour.
Highlights
One of the key factors that distinguish cancer cells from normal cells is the ability of cancer cells to alter their local and non-local interactions to neighbouring cells and to the extracellular matrix (ECM), which leads eventually to invasion and metastasis (Hanahan and Weinberg 2000, 2011)
Based on biological evidence that the components of non-fibre ECM phase are degraded by several classes of matrix metalloproteinases (Stix et al 2001; Liao and Van Nostrand 2010), we extend here the context considered in Shuttleworth and Trucu (2019, 2020a, b), where this degradation was considered to be caused only by the MMPs secreted by the cancer cells
Remark 1 Since various experimental studies discuss the distribution of M2 tumourassociated macrophages (TAMs) macrophages inside tumour tissue and its prognostic value (Liu et al 2017; Sumimoto et al 2019), here we focus exclusively on the tumour–macrophage interactions on the tumour domain, rather than considering these mixed within the ECM further afield outside the tumour
Summary
One of the key factors that distinguish cancer cells from normal cells is the ability of cancer cells to alter their local and non-local interactions to neighbouring cells (that are either cancerous or of different types) and to the extracellular matrix (ECM), which leads eventually to invasion and metastasis (Hanahan and Weinberg 2000, 2011). There are many enzymes inside the solid tumours that can degrade the ECM, such as matrix metalloproteinases (MMPs) or urokinase plasminogen activator system (uPA), but the complete details of the cell types within the tumour microenvironment that are dominant in secreting these enzymes are still to be clarified (Madsen and Bugge 2015). Macrophages have been investigated in the past for their ability to degrade the various components of the ECM via the matrix metalloproteases (MMPs) that they can express (Werb et al 1980; Vérollet et al 2011; Madsen et al 2017), as well as for their plasticity and anti-tumour/pro-tumour roles. An earlier study (Madsen et al 2013) showed that the M2-like macrophages are responsible for the degradation of collagen, which is an important fibrous component of the ECM. Since in vitro and in vivo studies on macrophages– ECM–cancer interactions are still in their infancy, mathematical and computational approaches can help by generating new hypotheses about these interactions
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