Computational Modelling And Simulation Of Cancer Growth And Migration Within A 3d Heterogeneous Tissue The Effects Of Fibre And Vascular Structure
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Computational Modelling And Simulation Of Cancer Growth And Migration Within A 3d Heterogeneous Tissue The Effects Of Fibre And Vascular Structure
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Author : Cicely K. Macnamara
language : en
Publisher:
Release Date : 2019
Computational Modelling And Simulation Of Cancer Growth And Migration Within A 3d Heterogeneous Tissue The Effects Of Fibre And Vascular Structure written by Cicely K. Macnamara and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2019 with categories.
The term cancer covers a multitude of bodily diseases, broadly categorised by having cells which do not behave normally. Since cancer cells can arise from any type of cell in the body, cancers can grow in or around any tissue or organ making the disease highly complex. Our research is focused on understanding the specific mechanisms that occur in the tumour microenvironment via mathematical and computational modeling. We present a 3D individual-based model which allows one to simulate the behaviour of, and spatio-temporal interactions between, cells, extracellular matrix fibres and blood vessels. Each agent (a single cell, for example) is fully realised within the model and interactions are primarily governed by mechanical forces between elements. However, as well as the mechanical interactions we also consider chemical interactions, for example, by coupling the code to a finite element solver to model the diffusion of oxygen from blood vessels to cells. The current state of the art of the model allows us to simulate tumour growth around an arbitrary blood-vessel network or along the striations of fibrous tissue.
Development Of A 3d Biomimetic Tissue Engineered Model Of Cancer
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Author : Judith Maria Pape
language : en
Publisher:
Release Date : 2020
Development Of A 3d Biomimetic Tissue Engineered Model Of Cancer written by Judith Maria Pape and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2020 with categories.
Tumor Organoids
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Author : Shay Soker
language : en
Publisher: Humana Press
Release Date : 2017-10-20
Tumor Organoids written by Shay Soker and has been published by Humana Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 2017-10-20 with Medical categories.
Cancer cell biology research in general, and anti-cancer drug development specifically, still relies on standard cell culture techniques that place the cells in an unnatural environment. As a consequence, growing tumor cells in plastic dishes places a selective pressure that substantially alters their original molecular and phenotypic properties.The emerging field of regenerative medicine has developed bioengineered tissue platforms that can better mimic the structure and cellular heterogeneity of in vivo tissue, and are suitable for tumor bioengineering research. Microengineering technologies have resulted in advanced methods for creating and culturing 3-D human tissue. By encapsulating the respective cell type or combining several cell types to form tissues, these model organs can be viable for longer periods of time and are cultured to develop functional properties similar to native tissues. This approach recapitulates the dynamic role of cell–cell, cell–ECM, and mechanical interactions inside the tumor. Further incorporation of cells representative of the tumor stroma, such as endothelial cells (EC) and tumor fibroblasts, can mimic the in vivo tumor microenvironment. Collectively, bioengineered tumors create an important resource for the in vitro study of tumor growth in 3D including tumor biomechanics and the effects of anti-cancer drugs on 3D tumor tissue. These technologies have the potential to overcome current limitations to genetic and histological tumor classification and development of personalized therapies.
Selected Topics In Cancer Modeling
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Author : Nicola Bellomo
language : en
Publisher: Springer Science & Business Media
Release Date : 2008-12-10
Selected Topics In Cancer Modeling written by Nicola Bellomo and has been published by Springer Science & Business Media this book supported file pdf, txt, epub, kindle and other format this book has been release on 2008-12-10 with Mathematics categories.
This collection of selected chapters offers a comprehensive overview of state-of-the-art mathematical methods and tools for modeling and analyzing cancer phenomena. Topics covered include stochastic evolutionary models of cancer initiation and progression, tumor cords and their response to anticancer agents, and immune competition in tumor progression and prevention. The complexity of modeling living matter requires the development of new mathematical methods and ideas. This volume, written by first-rate researchers in the field of mathematical biology, is one of the first steps in that direction.
3d Biomimetic Model For Cellular Invasion In Angiogenesis And Cancer
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Author : Duc-Huy Tran Nguyen
language : en
Publisher:
Release Date : 2016
3d Biomimetic Model For Cellular Invasion In Angiogenesis And Cancer written by Duc-Huy Tran Nguyen and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2016 with categories.
Cell migration is an essential and highly regulated process. Cells migrate to vascularize tissues, to form tissue, and to respond to inflammation. Unfortunately, cell migration is also involved in numerous pathological conditions such as in invasive tumors. Cells can migrate as individual cells or as collective groups of cells. Particularly important in cell migration is the collective migration of cells as it is a hallmark of tissue remodeling events during embryonic morphogenesis, wound repair, and cancer invasion. Perhaps, angiogenesis is one of the most crucial collective migration processes as it is involved in multiple physiological and pathological conditions such as formation of vasculature, wound healing, cancer progression and metastasis. During angiogenesis, endothelial cells migrate collectively from existing vasculature in response to a complex biochemical and mechanical cues to form multicellular structures that eventually develop into new functional blood vessels. Angiogenesis is also a highly dynamic process where multiple cells rearrange and coordinate within a sprout. Such dynamic rearrangement requires different cytoskeletal regulators such as Rho GTPases proteins (RhoA, Rac, and Cdc42). Although the roles of Rho GTPase proteins have been well characterized in 2D cell migration, little is known about their contributions in angiogenic morphogenesis. Here, we engineered a 3D biomimetic microfluidic-based device, called AngioChip, where endothelial cells are induced to migrate collectively from a pre-formed biomimetic cylindrical blood vessel into a 3D interstitial collagen matrix. The sprouts in our AngioChip demonstrate in vivo-like morphogenetic features such as formation of tip-stalk cells, lumen formation, filopodial-like protrusions in leading tip cells, and formation of perfusable neovessels. Using this system, we examine the roles of Cdc42 to regulate many aspects of angiogenic morphogenesis. We find that disturbing Cdc42 activity reduces formation of branches, migration speed, and collective migration. Additionally, Cdc42 also negatively regulate filopodia formation. We also develop the AngioChip into a pancreatic ductal adenocarcinoma (PDAC) on a chip to investigate the interactions between pancreatic cancer cells and blood vessels. Vascular invasion, where PDAC cells invaded towards the vasculature during tumor progression, is a hallmark of metastatic PDAC. Nevertheless, how pancreatic tumor cells interact with the blood vessels remains largely unknown. Using our PDAC-on-a-chip, we reveal a striking observation where PDAC cells invade and de-endothelialize the blood vessels. This de-endothelialization process leads to vascular replacement in the blood vessels and is mediated by proliferation of PDAC through Nodal/Activin-ALK7 signaling.
Cellular And Extracellular Determinants Of 3d Cancer Cell Invasion
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Author : Shawn Patrick Carey
language : en
Publisher:
Release Date : 2015
Cellular And Extracellular Determinants Of 3d Cancer Cell Invasion written by Shawn Patrick Carey and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2015 with categories.
Breast cancer metastasis is a stepwise process during which cells dissociate from the primary tumor and migrate through extracellular matrix (ECM) and tissue barriers to spread to secondary sites. Metastasis is initiated when tumor cells acquire a motile phenotype and invade into the stromal ECM surrounding the tumor, which is heterogeneous and contains three-dimensional (3D) structural features including a diversity of fiber and pore microarchitectures, varying degrees of matrix alignment, and track-like structures. Notably, it is largely unknown whether, or how, these physical cues integrate with intracellular signaling to affect the behavior of invading cells. Furthermore, intratumor heterogeneity and cellular plasticity result in diverse and evolving invasive phenotypes whose molecular mechanisms are not well understood. Thus, despite the clinical importance of understanding and identifying invasive progression, the cellular and extracellular determinants that enable the invasive cancer cell phenotype remain unclear. Here, we study the process of 3D cancer cell migration within biologically inspired in vitro models that mimic key aspects of the in vivo interstitial stroma and demonstrate that the structure of a cell's local ECM regulates its invasive behavior. We show that 3D ECM microarchitecture controls the acquisition of cell motility by directing subcellular protrusion dynamics. By inducing adhesion signaling-dependent anisotropy of these cellular morphodynamics, aligned matrix guides and accelerates 3D cell spreading and migration. Furthermore, we find that physiological ECM-free microtracks provide additional pro-invasive cues that substantially reduce the mechanistic burden of 3D cell migration. We further observe in an in vitro model of intratumor heterogeneity that malignant "leader" cells create invasion-enabling microtracks within 3D ECM that can induce invasion of otherwise non-invasive "follower" cells. Through further studies, we determine that invasive fitness, which can be heterogeneous across a cell population, is an intrinsic and heritable cell trait. We exploit this finding to establish invasive and non-invasive cancer cell subpopulations, which we subsequently use to identify characteristic molecular and phenotypic attributes of invasive and non-invasive cells. Finally, we explore a potential consequence of "follow-the-leader" invasion and demonstrate that exposure to a stroma-like collagen-rich microenvironment induces mesenchymal gene expression and an invasive phenotype in non-invasive, nontransformed mammary epithelial cells. Together, our findings demonstrate that invasiveness is coordinately determined by a cell's intrinsic 3D migration propensity as well as its local 3D extracellular matrix, both of which can be heterogeneous across a given tumor-stroma microenvironment. Despite the inevitable complexity that arises from this heterogeneity, these findings contribute to our understanding of invasion-enabling extracellular features as well as the context-dependent molecular mechanisms by which cells to respond to such features during 3D cancer cell invasion.
Tissue Growth In 3d
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Author : Jian Feng
language : en
Publisher:
Release Date : 2005
Tissue Growth In 3d written by Jian Feng and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2005 with Cellular automata categories.
High Performance Inversion Algorithms For Brain Tumor Growth Models In Personalized Medicine
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Author : Shashank Subramanian
language : en
Publisher:
Release Date : 2021
High Performance Inversion Algorithms For Brain Tumor Growth Models In Personalized Medicine written by Shashank Subramanian and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2021 with categories.
This dissertation concerns the integration of biophysical macroscopic brain tumor growth models with clinical imaging data from Magnetic Resonance Imaging (MRI) scans. We focus on gliomas (and their aggressive manifestation, glioblastoma multiforme (GBM)), the most common malignant primary brain tumor diagnosed in adults. GBM is a deadly disease characterized by its highly invasive nature into surrounding healthy tissue and is uniformly fatal with a median survival of less than 15 months. The integration of mathematical models with clinical imaging data holds the enormous promise of robust, minimal, and explainable models that quantify cancer growth and connect cell-scale phenomena to organ-scale, personalized, clinical observables. These models can help facilitate diagnosis (e.g., tumor grading and patient stratification), prognosis (e.g., predicting recurrence and survival), and treatment (e.g., preoperative planning and radiotherapy). Additionally, they can advance our understanding of the disease by using imaging data to test model-driven hypotheses on disease progression and treatment. Towards this end, we develop mathematical models that capture the heterogeneous phenomenological features of GBMs as observed from patient imaging scans and provide a framework to calibrate these models for unknown patient-specific biomarkers. There are three key challenges to developing and integrating biophysical brain tumor growth models with imaging data: (i) tumor growth is a complex dynamical system with several interacting biophysical processes that are challenging to capture mathematically, (ii) the inverse problem of calibrating these growth models is notoriously difficult due to the lack of temporal resolution in imaging data, leading to severe mathematical ill-posedness, and finally, (iii) there is a prohibitive computational cost associated with the 4D (space-time) simulation and calibration of tumor growth models. We introduce novel innovations to systematically address these challenges: (i) we develop minimal phenomenological models that integrate the complex heterogeneous structure of GBM with its infiltrative and biomechanical effects on brain tissue, (ii) we introduce and analyze a new inverse problem formulation with biophysically-inspired regularization methods and ensembled fast inversion algorithms to reliably calibrate our mathematical models using imaging data, and finally, (iii) we integrate our numerical methods and algorithms within a high-performance software library that exploits heterogeneous compute substrates (distributed memory and GPU acceleration), to enable realistic solution times. Our framework provides an entirely new capability to analyze complex tumors (possibly multifocal) from a single-time-snapshot MRI scan in a fully-automatic manner. Finally, we conduct a comprehensive retrospective study using a large number of clinical images to demonstrate the utility of our calibrated tumor growth models in important clinical tasks such as medical image segmentation, patient stratification, and overall survival prediction. We envision this research to be an important stepping stone towards the precise characterization of cancer and personalization of cancer growth models for clinical decision-making support
The Association Of Tissue Architecture Changes Metabolic Heterogeneity In Epithelial Cancer Cells
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Author : Maia Al-Masri
language : en
Publisher:
Release Date : 2022
The Association Of Tissue Architecture Changes Metabolic Heterogeneity In Epithelial Cancer Cells written by Maia Al-Masri and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2022 with categories.
"Epithelial cells interact to form architecturally organized structures in tissues, with strict control of motility, proliferation and metabolic signaling, each of which is altered during cancer progression. Loss of epithelial organization and tissue architecture is associated with the acquisition of a malignant phenotype during breast cancer initiation and throughout its progression. The changes in tissue architecture that accompany the development of breast cancer is an excellent model, that develops through architecturally different preinvasive stages that include benign lesions such as ductal carcinoma in situ (DCIS), which are risk factors for the development of invasive disease (IDC). Currently, DCIS accounts for 20% of breast cancer diagnoses, and about half are expected to progress to IDC. No clear biomarkers and histological features exist to distinguish DCIS that will or will not progress to invasive disease. Metabolic plasticity enables cancer cells to switch between glycolysis and oxidative phosphorylation to adapt to changing conditions during cancer progression, whereas metabolic dependencies limit plasticity. However, understanding how metabolic programs change during cancer progression and the influence of the architectural and mechanical environments on metabolic dependency and plasticity remained to be fully established. Accordingly, to understand a role for the architectural environment in these processes we examined metabolic heterogeneity and dependencies of cancer cells using both in vitro models, cultured in flat (two-dimensional; 2D) and organotypic (three-dimensional; 3D) environments, and an in vivo model. The hypothesis of my thesis is that tissue architecture influences metabolic programs/phenotypes in epithelial cancer cells. I first examined the impact of epithelial architecture on metabolic plasticity using 2D and 3D cultures with diverse epithelial cancer cells. The propagation of cells in flat cultures is technically simple and enables maintenance of long-term exponential growth. However, they lack architectural information that regulates many epithelial cell behaviors, which are thought to be more accurately recapitulated in organotypic cultures whereby cells can more freely associate with the microenvironment on all sides. In contrast, cells in organotypic cultures preserve mechanical cell-ECM interactions and organize into tissue-relevant architectures that regulate signaling and growth. Recent studies have noted metabolic differences between 2D and 3D cultures. In this thesis I show that cancer cells in flat 2D cultures exist in a high energy state (oxidative phosphorylation), are glycolytic, and depend on glucose and glutamine for growth. In contrast, cells in organotypic culture exhibit lower energy and glycolysis, with extensive metabolic plasticity to maintain growth during glucose or amino acid deprivation. Furthermore, our metabolomic and gene-expression data indicate that the architectural environment strongly influences signaling and metabolic pathways related to amino acid metabolism. Expression of KRASG12V in organotypic cells drives glucose dependence, however cells retain metabolic plasticity to glutamine deprivation. Finally, these data reveal that mechanical properties control metabolic plasticity"--
Modeling Of Human Vascularized Colon Tumors In Three Dimensional Extracted Extracellular Matrices
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Author : Monica Romero Lopez
language : en
Publisher:
Release Date : 2016
Modeling Of Human Vascularized Colon Tumors In Three Dimensional Extracted Extracellular Matrices written by Monica Romero Lopez and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2016 with categories.
Cancer is one of the deadliest diseases; vast resources have been used to understand its root causes and to elucidate the intricacies of cancer progression in order to develop effective prevention and treatment strategies. Unfortunately, there are a lot of factors in the tumor microenvironment that contribute to cancer development and progression. Consequently, a better understanding of the tumor niche has become an important goal of cancer research. Here we have approached the problem using a combination of in vitro assays and computational modeling. Firstly we studied extracellular matrix (ECM). Recently, it has been found that the ECM surrounding tumors has significant effects on tumor cell growth and migration. However, there is a shortage of information on how cells respond to normal vs tumor ECM. In order to overcome this problem, we have isolated human tumor ECM (tECM) and compared its chemical and mechanical properties to ECM derived from matched normal tissue (nECM). We next examined the ability of each of these matrices to support the development of new vasculature --- a key event in tumor progression. We found that the capillaries that form in the tECM have characteristics similar to those seen in in vivo tumors. We also found that tumor growth and tumor metabolism is different in these two ECMs, with tumor growth being faster, and tumor cell metabolism more glycolytic, in the tECM. Taken together, these data identify the importance of the ECM in tumor progression and suggest that normalization of ECM morphology and composition could provide a novel strategy to limit tumor growth.Our second approach used mathematical models to study the interaction of different tumor cell lineages with the vascular niche. We find evidence to support the idea of endothelial cell transdifferentiation into tumor cells. And, the computational simulations of the model indicated that the transdifferentiated glioblastoma cells to have a major contribution in tumor therapy resistance.