810 research outputs found
Modeling Three-dimensional Invasive Solid Tumor Growth in Heterogeneous Microenvironment under Chemotherapy
A systematic understanding of the evolution and growth dynamics of invasive
solid tumors in response to different chemotherapy strategies is crucial for
the development of individually optimized oncotherapy. Here, we develop a
hybrid three-dimensional (3D) computational model that integrates
pharmacokinetic model, continuum diffusion-reaction model and discrete cell
automaton model to investigate 3D invasive solid tumor growth in heterogeneous
microenvironment under chemotherapy. Specifically, we consider the effects of
heterogeneous environment on drug diffusion, tumor growth, invasion and the
drug-tumor interaction on individual cell level. We employ the hybrid model to
investigate the evolution and growth dynamics of avascular invasive solid
tumors under different chemotherapy strategies. Our simulations reproduce the
well-established observation that constant dosing is generally more effective
in suppressing primary tumor growth than periodic dosing, due to the resulting
continuous high drug concentration. In highly heterogeneous microenvironment,
the malignancy of the tumor is significantly enhanced, leading to inefficiency
of chemotherapies. The effects of geometrically-confined microenvironment and
non-uniform drug dosing are also investigated. Our computational model, when
supplemented with sufficient clinical data, could eventually lead to the
development of efficient in silico tools for prognosis and treatment strategy
optimization.Comment: 41 pages, 8 figure
Colorectal Cancer Through Simulation and Experiment
Colorectal cancer has continued to generate a huge amount of research interest over several decades, forming a canonical example of tumourigenesis since its use in Fearon and Vogelstein’s linear model of genetic mutation. Over time, the field has witnessed a transition from solely experimental work to the inclusion of mathematical biology and computer-based modelling. The fusion of these disciplines has the potential to provide valuable insights into oncologic processes, but also presents the challenge of uniting many diverse perspectives. Furthermore, the cancer cell phenotype defined by the ‘Hallmarks of Cancer’ has been extended in recent times and provides an excellent basis for future research. We present a timely summary of the literature relating to colorectal cancer, addressing the traditional experimental findings, summarising the key mathematical and computational approaches, and emphasising the role of the Hallmarks in current and future developments. We conclude with a discussion of interdisciplinary work, outlining areas of experimental interest which would benefit from the insight that mathematical and computational modelling can provide
Blood Vessel Tortuosity Selects against Evolution of Agressive Tumor Cells in Confined Tissue Environments: a Modeling Approach
Cancer is a disease of cellular regulation, often initiated by genetic
mutation within cells, and leading to a heterogeneous cell population within
tissues. In the competition for nutrients and growth space within the tumors
the phenotype of each cell determines its success. Selection in this process is
imposed by both the microenvironment (neighboring cells, extracellular matrix,
and diffusing substances), and the whole of the organism through for example
the blood supply. In this view, the development of tumor cells is in close
interaction with their increasingly changing environment: the more cells can
change, the more their environment will change. Furthermore, instabilities are
also introduced on the organism level: blood supply can be blocked by increased
tissue pressure or the tortuosity of the tumor-neovascular vessels. This
coupling between cell, microenvironment, and organism results in behavior that
is hard to predict. Here we introduce a cell-based computational model to study
the effect of blood flow obstruction on the micro-evolution of cells within a
cancerous tissue. We demonstrate that stages of tumor development emerge
naturally, without the need for sequential mutation of specific genes.
Secondly, we show that instabilities in blood supply can impact the overall
development of tumors and lead to the extinction of the dominant aggressive
phenotype, showing a clear distinction between the fitness at the cell level
and survival of the population. This provides new insights into potential side
effects of recent tumor vasculature renormalization approaches
Modelling the response of vascular tumours to chemotherapy: A multiscale approach
An existing multiscale model is extended to study the response of a vascularised tumour to treatment with chemotherapeutic drugs which target proliferating cells. The underlying hybrid cellular automaton model couples tissue-level processes (e.g. blood flow, vascular adaptation, oxygen and drug transport) with cellular and subcellular phenomena (e.g. competition for space, progress through the cell cycle, natural cell death and drug-induced cell kill and the expression of angiogenic factors). New simulations suggest that, in the absence of therapy, vascular adaptation induced by angiogenic factors can stimulate spatio-temporal oscillations in the tumour's composition.\ud
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Numerical simulations are presented and show that, depending on the choice of model parameters, when a drug which kills proliferating cells is continuously infused through the vasculature, three cases may arise: the tumour is eliminated by the drug; the tumour continues to expand into the normal tissue; or, the tumour undergoes spatio-temporal oscillations, with regions of high vascular and tumour cell density alternating with regions of low vascular and tumour cell density. The implications of these results and possible directions for future research are also discussed
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