共查询到20条相似文献,搜索用时 46 毫秒
1.
2.
Lu Peng Dumitru Trucu Ping Lin Alastair Thompson Mark A. J. Chaplain 《Bulletin of mathematical biology》2017,79(3):389-429
Known as one of the hallmarks of cancer (Hanahan and Weinberg in Cell 100:57–70, 2000) cancer cell invasion of human body tissue is a complicated spatio-temporal multiscale process which enables a localised solid tumour to transform into a systemic, metastatic and fatal disease. This process explores and takes advantage of the reciprocal relation that solid tumours establish with the extracellular matrix (ECM) components and other multiple distinct cell types from the surrounding microenvironment. Through the secretion of various proteolytic enzymes such as matrix metalloproteinases or the urokinase plasminogen activator (uPA), the cancer cell population alters the configuration of the surrounding ECM composition and overcomes the physical barriers to ultimately achieve local cancer spread into the surrounding tissue. The active interplay between the tissue-scale tumour dynamics and the molecular mechanics of the involved proteolytic enzymes at the cell scale underlines the biologically multiscale character of invasion and raises the challenge of modelling this process with an appropriate multiscale approach. In this paper, we present a new two-scale moving boundary model of cancer invasion that explores the tissue-scale tumour dynamics in conjunction with the molecular dynamics of the urokinase plasminogen activation system. Building on the multiscale moving boundary method proposed in Trucu et al. (Multiscale Model Simul 11(1):309–335, 2013), the modelling that we propose here allows us to study the changes in tissue-scale tumour morphology caused by the cell-scale uPA microdynamics occurring along the invasive edge of the tumour. Our computational simulation results demonstrate a range of heterogeneous dynamics which are qualitatively similar to the invasive growth patterns observed in a number of different types of cancer, such as the tumour infiltrative growth patterns discussed in Ito et al. (J Gastroenterol 47:1279–1289, 2012). 相似文献
3.
K Pham A Chauviere H Hatzikirou X Li HM Byrne V Cristini J Lowengrub 《Journal of biological dynamics》2012,6(Z1):54-71
Gliomas are very aggressive brain tumours, in which tumour cells gain the ability to penetrate the surrounding normal tissue. The invasion mechanisms of this type of tumour remain to be elucidated. Our work is motivated by the migration/proliferation dichotomy (go-or-grow) hypothesis, i.e. the antagonistic migratory and proliferating cellular behaviours in a cell population, which may play a central role in these tumours. In this paper, we formulate a simple go-or-grow model to investigate the dynamics of a population of glioma cells for which the switch from a migratory to a proliferating phenotype (and vice versa) depends on the local cell density. The model consists of two reaction-diffusion equations describing cell migration, proliferation and a phenotypic switch. We use a combination of numerical and analytical techniques to characterize the development of spatio-temporal instabilities and travelling wave solutions generated by our model. We demonstrate that the density-dependent go-or-grow mechanism can produce complex dynamics similar to those associated with tumour heterogeneity and invasion. 相似文献
4.
Cancer is a complex, multiscale process, in which genetic mutations occurring at a subcellular level manifest themselves as functional and morphological changes at the cellular and tissue scale. The importance of interactions between tumour cells and their microenvironment is currently of great interest in experimental as well as computational modelling. Both the immediate microenvironment (e.g. cell-cell signalling or cell-matrix interactions) and the extended microenvironment (e.g. nutrient supply or a host tissue structure) are thought to play crucial roles in both tumour progression and suppression. In this paper we focus on tumour invasion, as defined by the emergence of a fingering morphology, which has previously been shown to be dependent upon harsh microenvironmental conditions. Using three different modelling approaches at two different spatial scales we examine the impact of nutrient availability as a driving force for invasion. Specifically we investigate how cell metabolism (the intrinsic rate of nutrient consumption and cell resistance to starvation) influences the growing tumour. We also discuss how dynamical changes in genetic makeup and morphological characteristics, of the tumour population, are driven by extreme changes in nutrient supply during tumour development. The simulation results indicate that aggressive phenotypes produce tumour fingering in poor nutrient, but not rich, microenvironments. The implication of these results is that an invasive outcome appears to be co-dependent upon the evolutionary dynamics of the tumour population driven by the microenvironment. 相似文献
5.
The brain tumour glioblastoma is characterised by diffuse and infiltrative growth into surrounding brain tissue. At the macroscopic level, the progression speed of a glioblastoma tumour is determined by two key factors: the cell proliferation rate and the cell migration speed. At the microscopic level, however, proliferation and migration appear to be mutually exclusive phenotypes, as indicated by recent in vivo imaging data. Here, we develop a mathematical model to analyse how the phenotypic switching between proliferative and migratory states of individual cells affects the macroscopic growth of the tumour. For this, we propose an individual-based stochastic model in which glioblastoma cells are either in a proliferative state, where they are stationary and divide, or in motile state in which they are subject to random motion. From the model we derive a continuum approximation in the form of two coupled reaction-diffusion equations, which exhibit travelling wave solutions whose speed of invasion depends on the model parameters. We propose a simple analytical method to predict progression rate from the cell-specific parameters and demonstrate that optimal glioblastoma growth depends on a non-trivial trade-off between the phenotypic switching rates. By linking cellular properties to an in vivo outcome, the model should be applicable to designing relevant cell screens for glioblastoma and cytometry-based patient prognostics. 相似文献
6.
The early development of solid tumours has been extensively studied, both experimentally via the multicellular spheroid assay, and theoretically using mathematical modelling. The vast majority of previous models apply specifically to multicell spheroids, which have a characteristic structure of a proliferating rim and a necrotic core, separated by a band of quiescent cells. Many previous models represent these as discrete layers, separated by moving boundaries. Here, the authors develop a new model, formulated in terms of continuum densities of proliferating, quiescent and necrotic cells, together with a generic nutrient/growth factor. The model is oriented towards an in vivo rather than in vitro setting, and crucially allows for nutrient supply from underlying tissue, which will arise in the two-dimensional setting of a tumour growing within an epithelium. In addition, the model involves a new representation of cell movement, which reflects contact inhibition of migration. Model solutions are able to reproduce the classic three layer structure familiar from multicellular spheroids, but also show that new behaviour can occur as a result of the nutrient supply from underlying tissue. The authors analyse these different solution types by approximate solution of the travelling wave equations, enabling a detailed classification of wave front solutions. 相似文献
7.
Yamaoka H Matsushita S Shimada Y Adachi T 《Biomechanics and modeling in mechanobiology》2012,11(3-4):291-302
The adaptive structure and functional changes of the actin cytoskeleton are induced by its mechanical behavior at various temporal and spatial scales. In particular, the mechanical behaviors at different scales play important roles in the mechanical functions of various cells, and these multiscale phenomena require clarification. To establish a milestone toward achieving multiscale modeling and simulation, this paper reviews mathematical analyses and simulation methods applied to the mechanics of the filamentous actin cytoskeleton. The actin cytoskeleton demonstrates characteristic behaviors at every temporal and spatial scale, and mathematical models and simulation methods can be applied to each level of actin cytoskeletal structure ranging from the molecular to the network level. This paper considers studies on mathematical models and simulation methods based on the molecular dynamics, coarse-graining, and continuum dynamics approaches. Every temporal and spatial scale of actin cytoskeletal structure is considered, and it is expected that discrete and continuum dynamics ranging from functional expression at the molecular level to macroscopic functional expression at the whole cell level will be developed and applied to multiscale modeling and simulation. 相似文献
8.
Gene surfing in expanding populations 总被引:3,自引:0,他引:3
Large scale genomic surveys are partly motivated by the idea that the neutral genetic variation of a population may be used to reconstruct its migration history. However, our ability to trace back the colonization pathways of a species from their genetic footprints is limited by our understanding of the genetic consequences of a range expansion. Here, we study, by means of simulations and analytical methods, the neutral dynamics of gene frequencies in an asexual population undergoing a continual range expansion in one dimension. During such a colonization period, lineages can fix at the wave front by means of a "surfing" mechanism [Edmonds, C.A., Lillie, A.S., Cavalli-Sforza, L.L., 2004. Mutations arising in the wave front of an expanding population. Proc. Natl. Acad. Sci. 101, 975-979]. We quantify this phenomenon in terms of (i) the spatial distribution of lineages that reach fixation and, closely related, (ii) the continual loss of genetic diversity (heterozygosity) at the wave front, characterizing the approach to fixation. Our stochastic simulations show that an effective population size can be assigned to the wave that controls the (observable) gradient in heterozygosity left behind the colonization process. This effective population size is markedly higher in the presence of cooperation between individuals ("pushed waves") than when individuals proliferate independently ("pulled waves"), and increases only sub-linearly with deme size. To explain these and other findings, we develop a versatile analytical approach, based on the physics of reaction-diffusion systems, that yields simple predictions for any deterministic population dynamics. Our analytical theory compares well with the simulation results for pushed waves, but is less accurate in the case of pulled waves when stochastic fluctuations in the tip of the wave are important. 相似文献
9.
Antonio Z. Politi Graham M. Donovan Merryn H. Tawhai Anne-Marie Lauzon James Sneyd 《Journal of theoretical biology》2010,266(4):614-624
We present a multiscale, spatially distributed model of lung and airway behaviour with the goal of furthering the understanding of airway hyper-responsiveness and asthma. The model provides an initial computational framework for linking events at the cellular and molecular levels, such as Ca2+ and crossbridge dynamics, to events at the level of the entire organ. At the organ level, parenchymal tissue is modelled using a continuum approach as a compressible, hyperelastic material in three dimensions, with expansion and recoil of lung tissue due to tidal breathing. The governing equations of finite elasticity deformation are solved using a finite element method. The airway tree is embedded in this tissue, where each airway is modelled with its own airway wall, smooth muscle and surrounding parenchyma. The tissue model is then linked to models of the crossbridge mechanics and their control by Ca2+ dynamics, thus providing a link to molecular and cellular mechanisms in airway smooth muscle cells. By incorporating and coupling the models at these scales, we obtain a detailed, computational multiscale model incorporating important physiological phenomena associated with asthma. 相似文献
10.
Vascular development and homeostasis are underpinned by two fundamental features: the generation of new vessels to meet the metabolic demands of under-perfused regions and the elimination of vessels that do not sustain flow. In this paper we develop the first multiscale model of vascular tissue growth that combines blood flow, angiogenesis, vascular remodelling and the subcellular and tissue scale dynamics of multiple cell populations. Simulations show that vessel pruning, due to low wall shear stress, is highly sensitive to the pressure drop across a vascular network, the degree of pruning increasing as the pressure drop increases. In the model, low tissue oxygen levels alter the internal dynamics of normal cells, causing them to release vascular endothelial growth factor (VEGF), which stimulates angiogenic sprouting. Consequently, the level of blood oxygenation regulates the extent of angiogenesis, with higher oxygenation leading to fewer vessels. Simulations show that network remodelling (and de novo network formation) is best achieved via an appropriate balance between pruning and angiogenesis. An important factor is the strength of endothelial tip cell chemotaxis in response to VEGF. When a cluster of tumour cells is introduced into normal tissue, as the tumour grows hypoxic regions form, producing high levels of VEGF that stimulate angiogenesis and cause the vascular density to exceed that for normal tissue. If the original vessel network is sufficiently sparse then the tumour may remain localised near its parent vessel until new vessels bridge the gap to an adjacent vessel. This can lead to metastable periods, during which the tumour burden is approximately constant, followed by periods of rapid growth. 相似文献
11.
Nikolaos Sfakianakis Niklas Kolbe Nadja Hellmann Mária Lukáčová-Medvid’ová 《Bulletin of mathematical biology》2017,79(1):209-235
We propose a multiscale model for the invasion of the extracellular matrix by two types of cancer cells, the differentiated cancer cells and the cancer stem cells. We investigate the epithelial mesenchymal-like transition between them being driven primarily by the epidermal growth factors. We moreover take into account the transdifferentiation program of the cancer stem cells towards the cancer-associated fibroblast cells as well as the fibroblast-driven remodelling of the extracellular matrix. The proposed haptotaxis model combines the macroscopic phenomenon of the invasion of the extracellular matrix by both types of cancer cells with the microscopic dynamics of the epidermal growth factors. We analyse our model in a component-wise manner and compare our findings with the literature. We investigate pathological situations regarding the epidermal growth factors and accordingly propose “mathematical-treatment” scenarios to control the aggressiveness of the tumour. 相似文献
12.
Natasha K. Martin Eamonn A. Gaffney Philip K. Maini 《Journal of theoretical biology》2010,267(3):461-470
It is well established that the tumour microenvironment can both promote and suppress tumour growth and invasion, however, most mathematical models of invasion view the normal tissue as inhibiting tumour progression via immune modulation or spatial constraint. In particular, the production of acid by tumour cells and the subsequent creation of a low extracellular pH environment has been explored in several ‘acid-mediated tumour invasion’ models where the acidic environment facilitates normal cell death and permits tumour invasion. In this paper, we extend the acid-invasion model developed by Gatenby and Gawlinski (1996) to include both the competitive and cooperative interactions between tumour and normal cells, by incorporating the influence of extracellular matrix and protease production at the tumour-stroma interface. Our model predicts an optimal level of tumour acidity which produces both cell death and matrix degradation. Additionally, very aggressive tumours prevent protease production and matrix degradation by excessive normal cell destruction, leading to an acellular (but matrix filled) gap between the tumour and normal tissue, a feature seen in encapsulated tumours. These results sugest, counterintuitively, that increasing tumour acidity may, in some cases, prevent tumour invasion. 相似文献
13.
Nele Vandersickel Ivan V. Kazbanov Anita Nuitermans Louis D. Weise Rahul Pandit Alexander V. Panfilov 《PloS one》2014,9(1)
Sudden cardiac death is often caused by cardiac arrhythmias. Recently, special attention has been given to a certain arrhythmogenic condition, the long-QT syndrome, which occurs as a result of genetic mutations or drug toxicity. The underlying mechanisms of arrhythmias, caused by the long-QT syndrome, are not fully understood. However, arrhythmias are often connected to special excitations of cardiac cells, called early afterdepolarizations (EADs), which are depolarizations during the repolarizing phase of the action potential. So far, EADs have been studied mainly in isolated cardiac cells. However, the question on how EADs at the single-cell level can result in fibrillation at the tissue level, especially in human cell models, has not been widely studied yet. In this paper, we study wave patterns that result from single-cell EAD dynamics in a mathematical model for human ventricular cardiac tissue. We induce EADs by modeling experimental conditions which have been shown to evoke EADs at a single-cell level: by an increase of L-type Ca currents and a decrease of the delayed rectifier potassium currents. We show that, at the tissue level and depending on these parameters, three types of abnormal wave patterns emerge. We classify them into two types of spiral fibrillation and one type of oscillatory dynamics. Moreover, we find that the emergent wave patterns can be driven by calcium or sodium currents and we find phase waves in the oscillatory excitation regime. From our simulations we predict that arrhythmias caused by EADs can occur during normal wave propagation and do not require tissue heterogeneities. Experimental verification of our results is possible for experiments at the cell-culture level, where EADs can be induced by an increase of the L-type calcium conductance and by the application of I blockers, and the properties of the emergent patterns can be studied by optical mapping of the voltage and calcium. 相似文献
14.
Pearce IG Chaplain MA Schofield PG Anderson AR Hubbard SF 《Journal of theoretical biology》2006,241(4):876-886
A mathematical model of the spatio-temporal dynamics of a two host, two parasitoid system is presented. There is a coupling of the four species through parasitism of both hosts by one of the parasitoids. The model comprises a system of four reaction-diffusion equations. The underlying system of ordinary differential equations, modelling the host-parasitoid population dynamics, has a unique positive steady state and is shown to be capable of undergoing Hopf bifurcations, leading to limit cycle kinetics which give rise to oscillatory temporal dynamics. The stability of the positive steady state has a fundamental impact on the spatio-temporal dynamics: stable travelling waves of parasitoid invasion exhibit increasingly irregular periodic travelling wave behaviour when key parameter values are increased beyond their Hopf bifurcation point. These irregular periodic travelling waves give rise to heterogeneous spatio-temporal patterns of host and parasitoid abundance. The generation of heterogeneous patterns has ecological implications and the concepts of temporary host refuge and niche formation are considered. 相似文献
15.
We analyse the coalescence of invasive cell populations by studying both the temporal and steady behaviour of a system of coupled reaction-diffusion equations. This problem is relevant to recent experimental observations of the dynamics of opposingly directed invasion waves of cells. Two cell types, u and v, are considered with the cell motility governed by linear or nonlinear diffusion. The cells proliferate logistically so that the long-term total cell density, u+v approaches a carrying capacity. The steady-state solutions for u and v are denoted u(s) and v(s). The steady solutions are spatially invariant and satisfy u(s)+v(s)=1. However, this expression is underdetermined so the relative proportion of each cell type u(s) and v(s) cannot be determined a priori. Various properties of this model are studied, such as how the relative proportion of u(s) and v(s) depends on the relative motility and relative proliferation rates. The model is analysed using a combination of numerical simulations and a comparison principle. This investigation unearths some novel outcomes regarding the role of overcrowding and cell death in this type of cell migration assay. These observations have relevance to experimental design and interpretation regarding the identification and parameterisation of mechanisms involved in cell invasion. 相似文献
16.
In this paper we present a multiscale, individual-based simulation environment that integrates CompuCell3D for lattice-based modelling on the cellular level and Bionetsolver for intracellular modelling. CompuCell3D or CC3D provides an implementation of the lattice-based Cellular Potts Model or CPM (also known as the Glazier-Graner-Hogeweg or GGH model) and a Monte Carlo method based on the metropolis algorithm for system evolution. The integration of CC3D for cellular systems with Bionetsolver for subcellular systems enables us to develop a multiscale mathematical model and to study the evolution of cell behaviour due to the dynamics inside of the cells, capturing aspects of cell behaviour and interaction that is not possible using continuum approaches. We then apply this multiscale modelling technique to a model of cancer growth and invasion, based on a previously published model of Ramis-Conde et al. (2008) where individual cell behaviour is driven by a molecular network describing the dynamics of E-cadherin and β-catenin. In this model, which we refer to as the centre-based model, an alternative individual-based modelling technique was used, namely, a lattice-free approach. In many respects, the GGH or CPM methodology and the approach of the centre-based model have the same overall goal, that is to mimic behaviours and interactions of biological cells. Although the mathematical foundations and computational implementations of the two approaches are very different, the results of the presented simulations are compatible with each other, suggesting that by using individual-based approaches we can formulate a natural way of describing complex multi-cell, multiscale models. The ability to easily reproduce results of one modelling approach using an alternative approach is also essential from a model cross-validation standpoint and also helps to identify any modelling artefacts specific to a given computational approach. 相似文献
17.
Patricia Alamo Alberto Gallardo Miguel A. Pavón Isolda Casanova Manuel Trias Maria A. Mangues Esther Vázquez Antonio Villaverde Ramon Mangues Maria V. Céspedes 《Disease models & mechanisms》2014,7(3):387-396
Mouse colorectal cancer (CRC) models generated by orthotopic microinjection of human CRC cell lines reproduce the pattern of lymphatic, haematological and transcoelomic spread but generate low metastatic efficiency. Our aim was to develop a new strategy that could increase the metastatic efficiency of these models. We used subcutaneous implantation of the human CRC cell lines HCT116 or SW48 prior to their orthotopic microinjection in the cecum of nude mice (SC+ORT). This subcutaneous preconditioning significantly enhanced metastatic dissemination. In the HCT116 model it increased the number and size of metastatic foci in lymph nodes, lung, liver and peritoneum, whereas, in the SW48 model, it induced a shift from non-metastatic to metastatic. In both models the number of apoptotic bodies in the primary tumour in the SC+ORT group was significantly reduced compared with that in the direct orthotopic injection (ORT) group. Moreover, in HCT116 tumours the number of keratin-positive tumour buddings and single epithelial cells increased at the invasion front in SC+ORT mice. In the SW48 tumour model, we observed a trend towards a higher number of tumour buds and single cells in the SC+ORT group but this did not reach statistical significance. At a molecular level, the enhanced metastatic efficiency observed in the HCT116 SC+ORT model was associated with an increase in AKT activation, VEGF-A overexpression and downregulation of β1 integrin in primary tumour tissue, whereas, in SW48 SC+ORT mice, the level of expression of these proteins remained unchanged. In summary, subcutaneous preconditioning increased the metastatic dissemination of both orthotopic CRC models by increasing tumour cell survival and invasion at the tumour invasion front. This approach could be useful to simultaneously study the mechanisms of metastases and to evaluate anti-metastatic drugs against CRC.KEY WORDS: Collective invasion, Colorectal cancer model, Metastasis, Orthotopic injection, Single tumour cell, Subcutaneous preconditioning 相似文献
18.
Joseph Malinzi 《Journal of biological dynamics》2017,11(1):244-274
Chemovirotherapy is a combination therapy with chemotherapy and oncolytic viruses. It is gaining more interest and attracting more attention in the clinical setting due to its effective therapy and potential synergistic interactions against cancer. In this paper, we develop and analyse a mathematical model in the form of parabolic non-linear partial differential equations to investigate the spatiotemporal dynamics of tumour cells under chemovirotherapy treatment. The proposed model consists of uninfected and infected tumour cells, a free virus, and a chemotherapeutic drug. The analysis of the model is carried out for both the temporal and spatiotemporal cases. Travelling wave solutions to the spatiotemporal model are used to determine the minimum wave speed of tumour invasion. A sensitivity analysis is performed on the model parameters to establish the key parameters that promote cancer remission during chemovirotherapy treatment. Model analysis of the temporal model suggests that virus burst size and virus infection rate determine the success of the virotherapy treatment, whereas travelling wave solutions to the spatiotemporal model show that tumour diffusivity and growth rate are critical during chemovirotherapy. Simulation results reveal that chemovirotherapy is more effective and a good alternative to either chemotherapy or virotherapy, which is in agreement with the recent experimental studies. 相似文献
19.
Tumour cell invasion is crucial for cancer metastasis, which is the main cause of cancer mortality. An important group of proteins involved in cancer invasion are the Heat Shock Proteins (HSPs). According to experimental data, inhibition of one of these proteins, Hsp90, slows down cancer cells while they are invading tissue, but does not affect the synthesis of matrix metalloproteinases (MMP2 and MMP9), which are very important for cancer metastasis, acting as extracellular matrix (ECM) degrading enzymes. To test different biological hypotheses regarding how precisely Hsp90 influences tumour invasion, in this paper we use a model of solid tumour growth which accounts for the interactions between Hsp90 dynamics and the migration of cancer cells and, alternatively, between Hsp90 dynamics and the synthesis of matrix degrading enzymes (MDEs). The model consists of a system of reaction-diffusion-taxis partial differential equations describing interactions between cancer cells, MDE, and the host tissue (ECM). Using numerical simulations we investigate the effects of the administration of Hsp90 inhibitors on the dynamics of tumour invasion. Alternative mechanisms of reduction of cancer invasiveness result in different simulated patterns of the invading tumour cells. Therefore, predictions of the model suggest experiments which might be performed to develop a deeper understanding of the tumour invasion process. 相似文献
20.
Breakspear M Stam CJ 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2005,360(1457):1051-1074
The architecture of the brain is characterized by a modular organization repeated across a hierarchy of spatial scales-neurons, minicolumns, cortical columns, functional brain regions, and so on. It is important to consider that the processes governing neural dynamics at any given scale are not only determined by the behaviour of other neural structures at that scale, but also by the emergent behaviour of smaller scales, and the constraining influence of activity at larger scales. In this paper, we introduce a theoretical framework for neural systems in which the dynamics are nested within a multiscale architecture. In essence, the dynamics at each scale are determined by a coupled ensemble of nonlinear oscillators, which embody the principle scale-specific neurobiological processes. The dynamics at larger scales are 'slaved' to the emergent behaviour of smaller scales through a coupling function that depends on a multiscale wavelet decomposition. The approach is first explicated mathematically. Numerical examples are then given to illustrate phenomena such as between-scale bifurcations, and how synchronization in small-scale structures influences the dynamics in larger structures in an intuitive manner that cannot be captured by existing modelling approaches. A framework for relating the dynamical behaviour of the system to measured observables is presented and further extensions to capture wave phenomena and mode coupling are suggested. 相似文献