Analysis of the roles of microvessel endothelial cell random motility and chemotaxis in angiogenesis

Stokes, Cynthia L.; Lauffenburger, Douglas A.

doi:10.1016/s0022-5193(05)80201-2

Cited by 294 publications

(228 citation statements)

References 30 publications

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“…However we estimate that the maximum effect of this is to increase the parameter D 10-fold to around 0.003 which still means that the taxis components in the cell migration dominate [simulations performed using this value of D in the discrete model generated capillary networks that were very similar in structure to those shown in Fig The results of the numerical simulations of the above system showed interesting spatio-temporal dynamics and demonstrated two important aspects of capillary network formation: (i) in agreement with previous models, (Stokes and Lauffenburger, 1991;Chaplain and Stuart, 1993) a sufficiently strong chemotactic response is necessary for the initial outgrowth of the capillary network; (ii) interactions between endothelial cells and the extracellular matrix are very important for the successful development of the network. Full details can be found in Anderson and Chaplain (1998).…”

Section: The Mathematical Model Of Network Growthsupporting

confidence: 75%

“…There have been several approaches using spatially discrete representations e.g., Stokes and Lauffenburger (1991), Nekka et al (1996), Anderson and Chaplain (1998) and Gödde and Kurz (2001). In this paper we will utilize the approach of Anderson and Chaplain (1998) in order to generate our theoretical capillary networks, and details of the model are given in Section 2.1 [see also Anderson et al (1997)].…”

Section: Introductionmentioning

confidence: 99%

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Mathematical Modelling of Flow Through Vascular Networks: Implications for Tumour-induced Angiogenesis and Chemotherapy Strategies

McDougall

Anderson

Chaplain

et al. 2002

Bulletin of Mathematical Biology

282

207

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Angiogenesis, the formation of blood vessels from a pre-existing vasculature, is a process whereby capillary sprouts are formed in response to externally supplied chemical stimuli. The sprouts then grow and develop, driven initially by endothelial cell migration, and organize themselves into a branched, connected network structure. Subsequent cell proliferation near the sprout-tip permits further extension of the capillary and ultimately completes the process. Angiogenesis occurs during embryogenesis, wound healing, arthritis and during the growth of solid tumours. In this paper we initially generate theoretical capillary networks (which are morphologically similar to those networks observed in vivo) using the discrete mathematical model of Anderson and Chaplain. This discrete model describes the formation of a capillary sprout network via endothelial cell migratory and proliferative responses to external chemical stimuli (tumour angiogenic factors, TAF) supplied by a nearby solid tumour, and also the endothelial cell interactions with the extracellular matrix. The main aim of this paper is to extend this work to examine fluid flow through these theoretical network structures. In order to achieve this we make use of flow modelling tools and techniques (specifically, flow through interconnected networks) from the field of petroleum engineering. Having modelled the flow of a basic fluid through our network, we then examine the effects of fluid viscosity, blood vessel size (i.e., diameter of the capillaries), and network structure/geometry, upon: (i) the rate of flow through the network; (ii) the amount of fluid present in the complete network at any one time; and (iii) the amount of fluid reaching the tumour. The incorporation of fluid flow through the generated vascular networks has highlighted issues that may have major implications for the study of nutrient supply to the tumour (blood/oxygen supply) and, more importantly, for the delivery of chemotherapeutic drugs to the tumour. Indeed, there are also implications for the delivery of anti-angiogenesis drugs to the network itself. Results clearly highlight the important roles played by the structure and morphology of the network, which is, in turn, linked to the size and geometry of the nearby tumour. The connectedness of the network, as measured by the number of loops formed in the network (the anastomosis density), is also found to be of primary significance. Moreover, under certain conditions, the results of our flow simulations show that an injected chemotherapy drug may bypass the tumour altogether.

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Section: The Mathematical Model Of Network Growthsupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Mathematical Modelling of Flow Through Vascular Networks: Implications for Tumour-induced Angiogenesis and Chemotherapy Strategies

McDougall

Anderson

Chaplain

et al. 2002

Bulletin of Mathematical Biology

282

207

View full text Add to dashboard Cite

show abstract

“…Furthermore, our results show that, in addition to its improved antiproliferative activity, ENMD-1198 also more potently inhibits endothelial cell motility, chemotaxis, and morphogenesis into capillary-like structures. Endothelial cell motility is of critical importance in tumor angiogenesis especially in capillary growth and vascular network structure (32). Treatment with ENMD-1198 decreased the mean velocity of endothelial cells as well as their random motility coefficient (μ), which reflects the capacity of cells to explore and colonize a new area, and increased the time between significant direction changes (P).…”

Section: Discussionmentioning

confidence: 99%

ENMD-1198, a New Analogue of 2-Methoxyestradiol, Displays Both Antiangiogenic and Vascular-Disrupting Properties

Pasquier

Sinnappan

Munoz

et al. 2010

Molecular Cancer Therapeutics

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The formation of a new vascular network by angiogenesis is a key driver in tumor growth and metastasis, making this an attractive therapeutic target. Different strategies are being developed to either prevent tumor angiogenesis or disrupt the tumor vasculature already in place. In this in vitro study, we investigated the antivascular properties of ENMD-1198, a new anticancer drug currently in clinical trials. ENMD-1198 is a new analogue of 2-methoxyestradiol, a microtubule-targeting agent that has shown promising results in the treatment of multiple myeloma and hormone-refractory prostate cancer. Using both bone marrowderived and dermal microvascular endothelial cell lines, we analyzed the effect of ENMD-1198 on the different functions of endothelial cells involved in angiogenesis. In both cell lines, ENMD-1198 was more potent than 2-methoxyestradiol at inhibiting endothelial cell proliferation, motility, migration, and morphogenesis. In addition, ENMD-1198 induced a significant decrease in vascular endothelial growth factor receptor-2 protein expression in endothelial cells. Furthermore, videomicroscopy experiments showed that ENMD-1198 was able to completely disrupt preformed vascular structures within 2 hours. This vascular-disrupting activity was associated with extensive depolymerization of the microtubule network and accumulation of actin stress fibers and large focal adhesions in vascular endothelial cells. Collectively, our results show that this new compound displays potent antivascular properties, and this study provides important insights into the mechanism of action of this promising new anticancer drug.

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“…These often contain a stochastic element and model at the level of the individual cell, see for example (Stokes and Lauffenburger, 1991) and (Turner and Sherratt, 2002). (Anderson and Chaplain, 1998) derived a discrete model for EC movement in angiogenesis via a discretisation of a continuous model.…”

Section: Previous Modellingmentioning

confidence: 99%

Vascular remodelling of an arterio-venous blood vessel network during solid tumour growth

Welter

Bartha

Rieger

2009

Journal of Theoretical Biology

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d m a n u s c r i p t AbstractWe formulate a theoretical model to analyse the vascular remodelling process of an arterio-venous vessel network during solid tumour growth. The model incorporates a hierarchically organized initial vasculature comprising arteries, veins and capillaries, and involves sprouting angiogenesis, vessel cooption, dilation and regression as well as tumour cell proliferation and death. The emerging tumour vasculature is non-hierarchical, compartmentalized into well characterized zones and transports efficiently an injected drug-bolus. It displays a complex geometry with necrotic zones and "hot spots" of increased vascular density and blood flow of varying size. The corresponding cluster size distribution is algebraic, reminiscent of a self-organized critical state.The intra-tumour vascular-density fluctuations correlate with pressure drops in the initial vasculature suggesting a physical mechanism underlying hot-spot formation.

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Analysis of the roles of microvessel endothelial cell random motility and chemotaxis in angiogenesis

Cited by 294 publications

References 30 publications

Mathematical Modelling of Flow Through Vascular Networks: Implications for Tumour-induced Angiogenesis and Chemotherapy Strategies

Mathematical Modelling of Flow Through Vascular Networks: Implications for Tumour-induced Angiogenesis and Chemotherapy Strategies

ENMD-1198, a New Analogue of 2-Methoxyestradiol, Displays Both Antiangiogenic and Vascular-Disrupting Properties

Vascular remodelling of an arterio-venous blood vessel network during solid tumour growth

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