Cellular dynamics models of angiogenesis

Mención Internacional en el título de doctorCancer kills 26.4% of Spanish people. It is the second cause of death, just behind diseases of the circulatory system, 28.3% [1]. The growth of new blood vessels from the existing vasculature in response to chemical signals from a tumor is called tumorinduced angiogenesis and it is closely related to cancer and metastasis. The growth rate of a tumor is considerably increased in its vascular stage compared to its avascular and solid stage, therefore treating cancer turns excessively difficult and the survival rates rapidly decrease [2]. Among diseases that cause disability but not substantial mortality, age-related macular degeneration may cause severe loss of vision or blindness in many people, particularly the elderly. It is projected that 196 million people will be affected by age-related macular degeneration in 2020, increasing to 288 million by 2040 [3], which is likely an underestimation [4]. With age, Bruch’s membrane gets thicker and some damaged cells in the retina become inflamed. The secretion of chemical signals from those cells due to their inflammation induces angiogenesis, but the new blood vessels are disorganized and leaky causing the loss of vision. John Hunter was the pioneer in describing the vessel formation process in 1787 [5], but the first person who coined the word “angiogenesis” was Arthur T. Hertig in 1935 [6]. He was studying the formation of new blood vessel in the primary placenta of the macaque monkey when this word was used for the first time. Years later, in 1971, Judah Folkman hypothesized that tumors emit Tumor Angiogenic Factors (TAF) to attract blood vessels to them [7]. This investigation triggered the research field of angiogenesis in cancer and in 1989 one of the most important angiogenic factors was discovered: the Vascular Endothelial Growth Factor (VEGF). Since then, drugs with antiangiogenic effects have been investigated for cancer, age-related macular degeneration and other diseases, as it is involved in more than seventy different diseases. However, angiogenesis also occurs in normal and vital processes such as wound healing or the growth of a fetus. The difference between physiological and pathological angiogenic processes is a matter of balance. In a healthy process, angiogenesis develops to its proper extent and then stops, while in pathological processes angiogenesis does not stop or it does not develop sufficiently. Angiogenesis keeps the number of blood vessels needed in balance: few blood vessels cause tissue death, while uncontrolled vascular proliferation can lead to cancer, macular degeneration and other diseases. Angiogenesis is a complex, multistep and well regulated process where biochemistry and physics are intertwined. The process entails signaling in vessel cells being driven by both chemical and mechanical mechanisms that result in vascular cell movement, deformation and proliferation. In a later stage of angiogenesis, vessel cells rearrange to form lumen and allow the perfusion of the blood inside the sprout. Depending on what induces the angiogenesis, different environments and cells should be considered, for instance in the retina. A detailed review of the processes involved in angiogenesis from the biological point of view is given in section 1.1. Beyond experimental investigations, mathematical models of angiogenesis try to help in understanding the process and how the relevant mechanisms of angiogenesis interact. The approach of some models focus on a single scale or a single process of those involved to deepen the knowledge about it. Others span multiple scales or the whole process to give an idea about how to prevent or favor angiogenesis. In section 1.2, we briefly review the mathematical models of angiogenesis that have been used to date as well as those when angiogenesis occurs in the retina and models of lumen formation, the late stage of angiogenesis. A crucial question about modeling is how to integrate the multiple scales and mechanisms present in angiogenesis in a mathematical model. A model is expected to be useful to explore methods for promoting and inhibiting angiogenesis. However, answering this question with this expectation is not a simple task. Assembling all the processes involved with their different time and length scales requires to develop a cellular dynamics model combined with models for the continuum fields. We achieved this objective by developing a hybrid cellular Potts model of early stage angiogenesis, given in chapter 2. In contrast to recent models, this mathematical and computational model is able to explore the role of biochemical signaling and tissue mechanics. A exhaustive description of the results of the numerical simulations complete the chapter 2. The advantages of discovering the reasons why angiogenesis starts in the retina or inhibitory mechanisms are innumerable. Unraveling the causes of neovascularization in the retina and giving possible solutions for age-related macular degeneration are our motivation to adapt the angiogenesis model of chapter 2 to the retina. In chapter 3, we present the model and the numerical results. If mathematical models of angiogenesis that incorporate multiple scales and cellular signaling processes are not that common, those that also include lumen formation are almost nonexistent. In chapter 4, we describe two models of lumen formation and their results. The lumen formation in the first model takes place in a already developed sprout. Although some restrictions in the model make its applications and possibilities limited, its study is convenient to establish the basis of the second proposed model. In this second model, the lumenization occurs while the sprout is developing and the pressure of the blood is involved, following recent experiments of lumen formation during angiogenesis. This model is work in progress, but we believe that showing the preliminary results in chapter 4 may be interesting. A critical step in the development of a mathematical and computational model is to analyze the viability of its simulations. The simulations of the model in chapter 2 have been carried out thanks to the parallel computing on Graphics Processing Units (GPUs), as well as simulations of chapters 3 and 4. The large amount of square elements of the grid, nodes, cells and sprouts make this type of computation suitable for these models. The way they have been implemented is explained in chapter 5. Finally, conclusions of this thesis and future work are drawn in the last chapter 6. This chapter highlights and summarizes the research that has been carried out and proposes future extensions and applications of this work.La investigación de esta tesis ha sido financiada por los proyectos de investigación del Ministerio de Economía y Competitividad (ahora FEDER/Ministerio de Ciencia, Innovación y Universidades–Agencia Estatal de Investigación) No. MTM2014-56948-C2-2-P y No. MTM2017-84446-C2-2-R.Programa de Doctorado en Ingeniería Matemática por la Universidad Carlos III de MadridPresidente: Ana María Carpio Rodríguez.- Secretario: Filippo Terragni.- Vocal: Stephen W. Teitswort