Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 246
Filtrar
1.
Brief Bioinform ; 25(3)2024 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-38557676

RESUMO

Understanding the intricate interactions of cancer cells with the tumor microenvironment (TME) is a pre-requisite for the optimization of immunotherapy. Mechanistic models such as quantitative systems pharmacology (QSP) provide insights into the TME dynamics and predict the efficacy of immunotherapy in virtual patient populations/digital twins but require vast amounts of multimodal data for parameterization. Large-scale datasets characterizing the TME are available due to recent advances in bioinformatics for multi-omics data. Here, we discuss the perspectives of leveraging omics-derived bioinformatics estimates to inform QSP models and circumvent the challenges of model calibration and validation in immuno-oncology.


Assuntos
Neoplasias , Farmacologia , Humanos , Multiômica , Farmacologia em Rede , Neoplasias/tratamento farmacológico , Neoplasias/genética , Oncologia , Biologia Computacional , Microambiente Tumoral
2.
Brief Bioinform ; 25(5)2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-39179248

RESUMO

Advancements in imaging technologies have revolutionized our ability to deeply profile pathological tissue architectures, generating large volumes of imaging data with unparalleled spatial resolution. This type of data collection, namely, spatial proteomics, offers invaluable insights into various human diseases. Simultaneously, computational algorithms have evolved to manage the increasing dimensionality of spatial proteomics inherent in this progress. Numerous imaging-based computational frameworks, such as computational pathology, have been proposed for research and clinical applications. However, the development of these fields demands diverse domain expertise, creating barriers to their integration and further application. This review seeks to bridge this divide by presenting a comprehensive guideline. We consolidate prevailing computational methods and outline a roadmap from image processing to data-driven, statistics-informed biomarker discovery. Additionally, we explore future perspectives as the field moves toward interfacing with other quantitative domains, holding significant promise for precision care in immuno-oncology.


Assuntos
Biologia Computacional , Proteômica , Humanos , Proteômica/métodos , Biologia Computacional/métodos , Biomarcadores Tumorais/metabolismo , Neoplasias/metabolismo , Neoplasias/imunologia , Algoritmos , Biomarcadores , Processamento de Imagem Assistida por Computador/métodos
3.
Artigo em Inglês | MEDLINE | ID: mdl-38858306

RESUMO

Recently, immunotherapies for antitumoral response have adopted conditionally activated molecules with the objective of reducing systemic toxicity. Amongst these are conditionally activated antibodies, such as PROBODY® activatable therapeutics (Pb-Tx), engineered to be proteolytically activated by proteases found locally in the tumor microenvironment (TME). These PROBODY® therapeutics molecules have shown potential as PD-L1 checkpoint inhibitors in several cancer types, including both effectiveness and locality of action of the molecule as shown by several clinical trials and imaging studies. Here, we perform an exploratory study using our recently published quantitative systems pharmacology model, previously validated for triple-negative breast cancer (TNBC), to computationally predict the effectiveness and targeting specificity of a PROBODY® therapeutics drug compared to the non-modified antibody. We begin with the analysis of anti-PD-L1 immunotherapy in non-small cell lung cancer (NSCLC). As a first contribution, we have improved previous virtual patient selection methods using the omics data provided by the iAtlas database portal compared to methods previously published in literature. Furthermore, our results suggest that masking an antibody maintains its efficacy while improving the localization of active therapeutic in the TME. Additionally, we generalize the model by evaluating the dependence of the response to the tumor mutational burden, independently of cancer type, as well as to other key biomarkers, such as CD8/Treg Tcell and M1/M2 macrophage ratio. While our results are obtained from simulations on NSCLC, our findings are generalizable to other cancer types and suggest that an effective and highly selective conditionally activated PROBODY® therapeutics molecule is a feasible option.

4.
Microvasc Res ; 149: 104555, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37257688

RESUMO

OBJECTIVE: Vascular remodeling at the invasive tumor front (ITF) plays a critical role in progression and metastasis of triple negative breast cancer (TNBC). Therefore, there is a crucial need to characterize the vascular phenotype (i.e. changes in the structure and function of vasculature) of the ITF and tumor core (TC) in TNBC. This requires high-resolution, 3D structural and functional microvascular data that spans the ITF and TC (i.e. ∼4-5 mm from the tumor's edge). Since such data are often challenging to obtain with most conventional imaging approaches, we employed a unique "3D whole-tumor angiogenesis atlas" derived from orthotopic xenografts to characterize the vascular phenotype of the ITF and TC in TNBC. METHODS: First, high-resolution (8 µm) computed tomography (CT) images of "whole-tumor" microvasculature were acquired from eight orthotopic TNBC xenografts, of which three tumors were excised at post-inoculation day 21 (i.e. early-stage) and five tumors were excised at post-inoculation day 35 (i.e. advanced-stage). These 3D morphological CT data were combined with soft tissue contrast from MRI as well as functional data generated in silico using image-based hemodynamic modeling to generate a multi-layered "angiogenesis atlas". Employing this atlas, blood vessels were first spatially stratified within the ITF (i.e. ≤1 mm from the tumor's edge) and TC (i.e. >1 mm from the tumor's edge) of each tumor xenograft. Then, a novel method was developed to visualize and characterize microvascular remodeling and perfusion changes in terms of distance from the tumor's edge. RESULTS: The angiogenesis atlas enabled the 3D visualization of changes in tumor vessel growth patterns, morphology and perfusion within the ITF and TC. Early and advanced stage tumors demonstrated significant differences in terms of their edge-to-center distributions for vascular surface area density, vascular length density, intervessel distance and simulated perfusion density (p â‰ª 0.01). Elevated vascular length density, vascular surface area density and perfusion density along the circumference of the ITF was suggestive of a preferential spatial pattern of angiogenic growth in this tumor cohort. Finally, we demonstrated the feasibility of differentiating the vascular phenotypes of ITF and TC in these TNBC xenografts. CONCLUSIONS: The combination of a 3D angiogenesis atlas and image-based hemodynamic modeling heralds a new approach for characterizing the role of vascular remodeling in cancer and other diseases.


Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Remodelação Vascular , Neovascularização Patológica , Imageamento por Ressonância Magnética , Microvasos/diagnóstico por imagem , Microvasos/patologia
5.
PLoS Comput Biol ; 18(7): e1010254, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35867773

RESUMO

Quantitative systems pharmacology (QSP) models and spatial agent-based models (ABM) are powerful and efficient approaches for the analysis of biological systems and for clinical applications. Although QSP models are becoming essential in discovering predictive biomarkers and developing combination therapies through in silico virtual trials, they are inadequate to capture the spatial heterogeneity and randomness that characterize complex biological systems, and specifically the tumor microenvironment. Here, we extend our recently developed spatial QSP (spQSP) model to analyze tumor growth dynamics and its response to immunotherapy at different spatio-temporal scales. In the model, the tumor spatial dynamics is governed by the ABM, coupled to the QSP model, which includes the following compartments: central (blood system), tumor, tumor-draining lymph node, and peripheral (the rest of the organs and tissues). A dynamic recruitment of T cells and myeloid-derived suppressor cells (MDSC) from the QSP central compartment has been implemented as a function of the spatial distribution of cancer cells. The proposed QSP-ABM coupling methodology enables the spQSP model to perform as a coarse-grained model at the whole-tumor scale and as an agent-based model at the regions of interest (ROIs) scale. Thus, we exploit the spQSP model potential to characterize tumor growth, identify T cell hotspots, and perform qualitative and quantitative descriptions of cell density profiles at the invasive front of the tumor. Additionally, we analyze the effects of immunotherapy at both whole-tumor and ROI scales under different tumor growth and immune response conditions. A digital pathology computational analysis of triple-negative breast cancer specimens is used as a guide for modeling the immuno-architecture of the invasive front.


Assuntos
Neoplasias , Farmacologia , Terapia Combinada , Humanos , Imunoterapia/métodos , Modelos Biológicos , Neoplasias/terapia , Farmacologia em Rede , Farmacologia/métodos , Microambiente Tumoral
6.
PLoS Comput Biol ; 15(11): e1007468, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31738746

RESUMO

Macrophages respond to signals in the microenvironment by changing their functional phenotypes, a process known as polarization. Depending on the context, they acquire different patterns of transcriptional activation, cytokine expression and cellular metabolism which collectively constitute a continuous spectrum of phenotypes, of which the two extremes are denoted as classical (M1) and alternative (M2) activation. To quantitatively decode the underlying principles governing macrophage phenotypic polarization and thereby harness its therapeutic potential in human diseases, a systems-level approach is needed given the multitude of signaling pathways and intracellular regulation involved. Here we develop the first mechanism-based, multi-pathway computational model that describes the integrated signal transduction and macrophage programming under M1 (IFN-γ), M2 (IL-4) and cell stress (hypoxia) stimulation. Our model was calibrated extensively against experimental data, and we mechanistically elucidated several signature feedbacks behind the M1-M2 antagonism and investigated the dynamical shaping of macrophage phenotypes within the M1-M2 spectrum. Model sensitivity analysis also revealed key molecular nodes and interactions as targets with potential therapeutic values for the pathophysiology of peripheral arterial disease and cancer. Through simulations that dynamically capture the signal integration and phenotypic marker expression in the differential macrophage polarization responses, our model provides an important computational basis toward a more quantitative and network-centric understanding of the complex physiology and versatile functions of macrophages in human diseases.


Assuntos
Polaridade Celular/fisiologia , Biologia Computacional/métodos , Ativação de Macrófagos/fisiologia , Citocinas/metabolismo , Humanos , Macrófagos/metabolismo , Macrófagos/fisiologia , Fenótipo , Transdução de Sinais/fisiologia
7.
Int J Mol Sci ; 21(14)2020 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-32708100

RESUMO

Persistent inflammation is a complication associated with many ocular diseases. Changes in ocular vessels can amplify disease responses and contribute to vision loss by influencing the delivery of leukocytes to the eye, vascular leakage, and perfusion. Here, we report the anti-inflammatory activity for AXT107, a non-RGD, 20-mer αvß3 and α5ß1 integrin-binding peptide that blocks vascular endothelial growth factor (VEGF)-signaling and activates tyrosine kinase with immunoglobulin and EGF-like domains 2 (Tie2) using the normally inhibitory ligand angiopoietin 2 (Ang2). Tumor necrosis factor α (TNFα), a central inflammation mediator, induces Ang2 release from endothelial cells to enhance its stimulation of inflammation and vascular leakage. AXT107 resolves TNFα-induced vascular inflammation in endothelial cells by converting the endogenously released Ang2 into an agonist of Tie2 signaling, thereby disrupting both the synergism between TNFα and Ang2 while also preventing inhibitor of nuclear factor-κB α (IκBα) degradation directly through Tie2 signaling. This recovery of IκBα prevents nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) nuclear localization, thereby blocking NF-κB-induced inflammatory responses, including the production of VCAM-1 and ICAM-1, leukostasis, and vascular leakage in cell and mouse models. AXT107 also decreased the levels of pro-inflammatory TNF receptor 1 (TNFR1) without affecting levels of the more protective TNFR2. These data suggest that AXT107 may provide multiple benefits in the treatment of retinal/choroidal and other vascular diseases by suppressing inflammation and promoting vascular stabilization.


Assuntos
Angiopoietina-2/metabolismo , Colágeno Tipo IV/farmacologia , Células Endoteliais/metabolismo , Endotélio Vascular/efeitos dos fármacos , Quinase I-kappa B/metabolismo , Inflamação/tratamento farmacológico , Fragmentos de Peptídeos/farmacologia , Receptor TIE-2/metabolismo , Angiopoietina-1/metabolismo , Animais , Permeabilidade Capilar/efeitos dos fármacos , Doenças da Coroide/tratamento farmacológico , Colágeno Tipo IV/uso terapêutico , Endotélio Vascular/citologia , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Leucostasia/tratamento farmacológico , Leucostasia/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/uso terapêutico , Receptor TIE-2/agonistas , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Doenças Retinianas/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia , Molécula 1 de Adesão de Célula Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
8.
Int J Mol Sci ; 20(2)2019 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-30669429

RESUMO

MicroRNAs (miRs) are endogenous non-coding RNA molecules that play important roles in human health and disease by regulating gene expression and cellular processes. In recent years, with the increasing scientific knowledge and new discovery of miRs and their gene targets, as well as the plentiful experimental evidence that shows dysregulation of miRs in a wide variety of human diseases, the computational modeling approach has emerged as an effective tool to help researchers identify novel functional associations between differential miR expression and diseases, dissect the phenotypic expression patterns of miRs in gene regulatory networks, and elucidate the critical roles of miRs in the modulation of disease pathways from mechanistic and quantitative perspectives. Here we will review the recent systems biology studies that employed different kinetic modeling techniques to provide mechanistic insights relating to the regulatory function and therapeutic potential of miRs in human diseases. Some of the key computational aspects to be discussed in detail in this review include (i) models of miR-mediated network motifs in the regulation of gene expression, (ii) models of miR biogenesis and miR⁻target interactions, and (iii) the incorporation of such models into complex disease pathways in order to generate mechanistic, molecular- and systems-level understanding of pathophysiology. Other related bioinformatics tools such as computational platforms that predict miR-disease associations will also be discussed, and we will provide perspectives on the challenges and opportunities in the future development and translational application of data-driven systems biology models that involve miRs and their regulatory pathways in human diseases.


Assuntos
Regulação da Expressão Gênica , Redes Reguladoras de Genes , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , MicroRNAs/genética , Modelos Biológicos , Transdução de Sinais , Biologia Computacional/métodos , Simulação por Computador , Estudo de Associação Genômica Ampla/métodos , Humanos , Interferência de RNA , RNA Mensageiro/genética , Biologia de Sistemas
9.
J Cell Mol Med ; 22(4): 2086-2097, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29441713

RESUMO

Thrombospondin-1 (TSP-1), a matricellular protein and one of the first endogenous anti-angiogenic molecules identified, has long been considered a potent modulator of human diseases. While the therapeutic effect of TSP-1 to suppress cancer was investigated in both research and clinical settings, the mechanisms of how TSP-1 is regulated in cancer remain elusive, and the scientific answers to the question of whether TSP-1 expressions can be utilized as diagnostic or prognostic marker for patients with cancer are largely inconsistent. Moreover, TSP-1 plays crucial functions in angiogenesis, inflammation and tissue remodelling, which are essential biological processes in the progression of many cardiovascular diseases, and therefore, its dysregulated expressions in such conditions may have therapeutic significance. Herein, we critically analysed the literature pertaining to TSP-1 expression in circulating blood and pathological tissues in various types of cancer as well as cardiovascular and inflammation-related diseases in humans. We compare the secretion rates of TSP-1 by different cancer and non-cancer cells and discuss the potential connection between the expression changes of TSP-1 and vascular endothelial growth factor (VEGF) observed in patients with cancer. Moreover, the pattern and emerging significance of TSP-1 profiles in cardiovascular disease, such as peripheral arterial disease, diabetes and other related non-cancer disorders, are highlighted. The analysis of published TSP-1 data presented in this review may have implications for the future exploration of novel TSP-1-based treatment strategies for cancer and cardiovascular-related diseases.


Assuntos
Doença , Regulação da Expressão Gênica , Trombospondina 1/metabolismo , Humanos , Modelos Biológicos , Células Estromais/metabolismo , Fatores de Crescimento do Endotélio Vascular/metabolismo
10.
Breast Cancer Res ; 20(1): 54, 2018 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-29898755

RESUMO

BACKGROUND: Metastatic triple-negative breast cancer (TNBC) is a heterogeneous and incurable disease. Numerous studies have been conducted to seek molecular targets to treat TNBC effectively, but chemotherapy is still the main choice for patients with TNBC. We have previously presented evidence of the important roles of interleukin-6 (IL-6) and chemokine (C-C motif) ligand 5 (CCL5) in TNBC tumor growth and metastasis. These experiments highlighted the importance of the crosstalk between cancer cells and stromal lymphatic endothelial cells (LECs) in tumor growth and metastasis. METHODS: We examined the viability and migration of MDA-MB-231-LN, SUM149, and SUM159 cells co-cultured with LECs when treated with maraviroc (CCR5 inhibitor) and tocilizumab (anti-IL-6 receptor antibody). To assess the anti-tumor effects of the combination of these two drugs in an athymic nude mouse model, MDA-MB-231-LN cells were implanted in the mammary fat pad and maraviroc (8 mg/kg, orally daily) and cMR16-1 (murine surrogate of the anti-IL-6R antibody, 10 mg/kg, IP, 3 days a week) were administrated for 5 weeks and effects on tumor growth and thoracic metastasis were measured. RESULTS: In this study, we used maraviroc and tocilizumab to confirm that IL-6 and CCL5 signaling are key pathways promoting TNBC cell proliferation and migration. Further, in a xenograft mouse model, we showed that tumor growth was dramatically inhibited by cMR16-1, the mouse version of the anti-IL6R antibody. The combination of maraviroc and cMR16-1 caused significant reduction of TNBC tumor growth compared to the single agents. Significantly, the combination of maraviroc and cMR16-1 abrogated thoracic metastasis. CONCLUSION: Taken together, these findings show that IL-6 and CCL5 signaling, which promote crosstalk between TNBC and lymphatic vessels, are key enhancers of TNBC tumor growth and metastasis. Furthermore, these results demonstrate that a drug combination inhibiting these pathways may be a promising therapy for TNBC patients.


Assuntos
Quimiocina CCL5/antagonistas & inibidores , Interleucina-6/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quimiocina CCL5/genética , Feminino , Humanos , Interleucina-6/genética , Maraviroc/administração & dosagem , Camundongos , Metástase Neoplásica , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
11.
J Theor Biol ; 455: 212-221, 2018 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-30036530

RESUMO

Cooperation between VEGFR2 and integrin αVß3 is critical for neovascularization in wound healing, cardiovascular ischemic diseases, ocular diseases, and tumor angiogenesis. In the present study, we developed a rule-based computational model to investigate the potential mechanism by which the Src-induced integrin association with VEGFR2 enhances VEGFR2 activation. Simulations demonstrated that the main function of integrin is to reduce the degradation of VEGFR2 and hence stabilize the activation signal. In addition, receptor synthesis rate and recruitment from internal compartment were found to be sensitive determinants of the activation state of VEGFR2. The model was then applied to simulate the effect of integrin-binding peptides such as tumstatin and cilengitide on VEGFR2 signaling. Further, computational modeling proposed potential molecular mechanisms for the angiogenesis-modulating activity of other integrin-binding peptides. The model highlights the complexity of the crosstalk between αVß3 integrin and VEGFR2 and the necessity of utilizing models to elucidate potential mechanisms in angiogenesis-modulating peptide therapy.


Assuntos
Autoantígenos , Colágeno Tipo IV , Células Endoteliais/metabolismo , Integrina alfaVbeta3/metabolismo , Modelos Biológicos , Neovascularização Patológica , Transdução de Sinais/efeitos dos fármacos , Venenos de Serpentes , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Autoantígenos/farmacologia , Colágeno Tipo IV/farmacocinética , Colágeno Tipo IV/farmacologia , Humanos , Proteínas de Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Venenos de Serpentes/farmacocinética , Venenos de Serpentes/farmacologia
12.
J Theor Biol ; 452: 56-68, 2018 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-29750999

RESUMO

A hallmark of breast tumors is its spatial heterogeneity that includes its distribution of cancer stem cells and progenitor cells, but also heterogeneity in the tumor microenvironment. In this study we focus on the contributions of stromal cells, specifically macrophages, fibroblasts, and endothelial cells on tumor progression. We develop a computational model of triple-negative breast cancer based on our previous work and expand it to include macrophage infiltration, fibroblasts, and angiogenesis. In vitro studies have shown that the secretomes of tumor-educated macrophages and fibroblasts increase both the migration and proliferation rates of triple-negative breast cancer cells. In vivo studies also demonstrated that blocking signaling of selected secreted factors inhibits tumor growth and metastasis in mouse xenograft models. We investigate the influences of increased migration and proliferation rates on tumor growth, the effect of the presence on fibroblasts or macrophages on growth and morphology, and the contributions of macrophage infiltration on tumor growth. We find that while the presence of macrophages increases overall tumor growth, the increase in macrophage infiltration does not substantially increase tumor growth and can even stifle tumor growth at excessive rates.


Assuntos
Fibroblastos/patologia , Macrófagos/patologia , Células-Tronco Neoplásicas/patologia , Neovascularização Patológica/genética , Neoplasias de Mama Triplo Negativas/patologia , Animais , Comunicação Celular , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Fibroblastos/metabolismo , Regulação Neoplásica da Expressão Gênica , Heterogeneidade Genética , Humanos , Macrófagos/metabolismo , Camundongos Nus , Modelos Biológicos , Células-Tronco Neoplásicas/metabolismo , Neovascularização Patológica/metabolismo , Transplante Heterólogo , Neoplasias de Mama Triplo Negativas/irrigação sanguínea , Neoplasias de Mama Triplo Negativas/genética , Carga Tumoral/genética , Microambiente Tumoral/genética
13.
PLoS Comput Biol ; 13(2): e1005332, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28178265

RESUMO

Vascular endothelial growth factor (VEGF) is a powerful regulator of neovascularization. VEGF binding to its cognate receptor, VEGFR2, activates a number of signaling pathways including ERK1/2. Activation of ERK1/2 is experimentally shown to involve sphingosine kinase 1 (SphK1) activation and its calcium-dependent translocation downstream of ERK1/2. Here we construct a rule-based computational model of signaling downstream of VEGFR2, by including SphK1 and calcium positive feedback mechanisms, and investigate their consequences on ERK1/2 activation. The model predicts the existence of VEGF threshold in ERK1/2 activation that can be continuously tuned by cellular concentrations of SphK1 and sphingosine 1 phosphate (S1P). The computer model also predicts powerful effects of perturbations in plasma and ER calcium pump rates and the current through the CRAC channels on ERK1/2 activation dynamics, highlighting the critical role of intracellular calcium in shaping the pERK1/2 signal. The model is then utilized to simulate anti-angiogenic therapeutic interventions targeting VEGFR2-ERK1/2 axis. Simulations indicate that monotherapies that exclusively target VEGFR2 phosphorylation, VEGF, or VEGFR2 are ineffective in shutting down signaling to ERK1/2. By simulating therapeutic strategies that target multiple nodes of the pathway such as Raf and SphK1, we conclude that combination therapy should be much more effective in blocking VEGF signaling to EKR1/2. The model has important implications for interventions that target signaling pathways in angiogenesis relevant to cancer, vascular diseases, and wound healing.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Cálcio/metabolismo , Células Endoteliais/fisiologia , Sistema de Sinalização das MAP Quinases/fisiologia , Modelos Cardiovasculares , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Sinalização do Cálcio/fisiologia , Células Cultivadas , Simulação por Computador , Humanos
14.
PLoS Comput Biol ; 13(1): e1005272, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-28045898

RESUMO

Hypoxia is an important physiological stress signal that drives angiogenesis, the formation of new blood vessels. Besides an increase in the production of pro-angiogenic signals such as vascular endothelial growth factor (VEGF), hypoxia also stimulates the production of anti-angiogenic signals. Thrombospondin-1 (TSP-1) is one of the anti-angiogenic factors whose synthesis is driven by hypoxia. Cellular synthesis of TSP-1 is tightly regulated by different intermediate biomolecules including proteins that interact with hypoxia-inducible factors (HIFs), transcription factors that are activated by receptor and intracellular signaling, and microRNAs which are small non-coding RNA molecules that function in post-transcriptional modification of gene expression. Here we present a computational model that describes the mechanistic interactions between intracellular biomolecules and cooperation between signaling pathways that together make up the complex network of TSP-1 regulation both at the transcriptional and post-transcriptional level. Assisted by the model, we conduct in silico experiments to compare the efficacy of different therapeutic strategies designed to modulate TSP-1 synthesis in conditions that simulate tumor and peripheral arterial disease microenvironment. We conclude that TSP-1 production in endothelial cells depends on not only the availability of certain growth factors but also the fine-tuned signaling cascades that are initiated by hypoxia.


Assuntos
Regulação da Expressão Gênica/genética , Modelos Biológicos , Trombospondina 1/genética , Trombospondina 1/metabolismo , Hipóxia Celular/fisiologia , Biologia Computacional , Simulação por Computador , Humanos , Oxigênio/metabolismo , Proteínas Smad/metabolismo , Trombospondina 1/análise , Fatores de Transcrição
16.
PLoS Comput Biol ; 11(11): e1004612, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26588727

RESUMO

HRMs (hypoxia-responsive miRNAs) are a specific group of microRNAs that are regulated by hypoxia. Recent studies revealed that several HRMs including let-7 family miRNAs were highly induced in response to HIF (hypoxia-inducible factor) stabilization in hypoxia, and they potently participated in angiogenesis by targeting AGO1 (argonaute 1) and upregulating VEGF (vascular endothelial growth factor). Here we constructed a novel computational model of microRNA control of HIF-VEGF pathway in endothelial cells to quantitatively investigate the role of HRMs in modulating the cellular adaptation to hypoxia. The model parameters were optimized and the simulations based on these parameters were validated against several published in vitro experimental data. To advance the mechanistic understanding of oxygen sensing in hypoxia, we demonstrated that the rate of HIF-1α nuclear import substantially influences its stabilization and the formation of HIF-1 transcription factor complex. We described the biological feedback loops involving let-7 and AGO1 in which the impact of external perturbations were minimized; as a pair of master regulators when low oxygen tension was sensed, they coordinated the critical process of VEGF desuppression in a controlled manner. Prompted by the model-motivated discoveries, we proposed and assessed novel pathway-specific therapeutics that modulate angiogenesis by adjusting VEGF synthesis in tumor and ischemic cardiovascular disease. Through simulations that capture the complex interactions between miRNAs and miRNA-processing molecules, this model explores an innovative perspective about the distinctive yet integrated roles of different miRNAs in angiogenesis, and it will help future research to elucidate the dysregulated miRNA profiles found in cancer and various cardiovascular diseases.


Assuntos
Hipóxia Celular/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , MicroRNAs/genética , Neoplasias/fisiopatologia , Doença Arterial Periférica/fisiopatologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Linhagem Celular Tumoral , Biologia Computacional , Simulação por Computador , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , MicroRNAs/metabolismo , Modelos Biológicos , Reprodutibilidade dos Testes , Transdução de Sinais/genética , Fator A de Crescimento do Endotélio Vascular/genética
17.
Physiol Genomics ; 47(8): 331-43, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26058837

RESUMO

Peripheral arterial disease (PAD) results from an obstruction of blood flow in the arteries other than the heart, most commonly the arteries that supply the legs. The complexity of the known signaling pathways involved in PAD, including various growth factor pathways and their cross talks, suggests that analyses of high-throughput experimental data could lead to a new level of understanding of the disease as well as novel and heretofore unanticipated potential targets. Such bioinformatic analyses have not been systematically performed for PAD. We constructed global protein-protein interaction networks of angiogenesis (Angiome), immune response (Immunome), and arteriogenesis (Arteriome) using our previously developed algorithm GeneHits. The term "PADPIN" refers to the angiome, immunome, and arteriome in PAD. Here we analyze four microarray gene expression datasets from ischemic and nonischemic gastrocnemius muscles at day 3 posthindlimb ischemia (HLI) in two genetically different C57BL/6 and BALB/c mouse strains that display differential susceptibility to HLI to identify potential targets and signaling pathways in angiogenesis, immune, and arteriogenesis networks. We hypothesize that identification of the differentially expressed genes in ischemic and nonischemic muscles between the strains that recovers better (C57BL/6) vs. the strain that recovers more poorly (BALB/c) will help for the prediction of target genes in PAD. Our bioinformatics analysis identified several genes that are differentially expressed between the two mouse strains with known functions in PAD including TLR4, THBS1, and PRKAA2 and several genes with unknown functions in PAD including EphA4, TSPAN7, SLC22A4, and EIF2a.


Assuntos
Artérias/crescimento & desenvolvimento , Inflamação/genética , Neovascularização Fisiológica/genética , Doença Arterial Periférica/genética , Mapas de Interação de Proteínas , Software , Animais , Artérias/patologia , Western Blotting , Morte Celular , Bases de Dados Genéticas , Modelos Animais de Doenças , Regulação para Baixo/genética , Perfilação da Expressão Gênica , Membro Posterior/irrigação sanguínea , Membro Posterior/patologia , Isquemia/genética , Isquemia/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Músculos/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Perfusão , Regulação para Cima/genética
18.
Angiogenesis ; 18(2): 125-36, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25408417

RESUMO

Translational vasculature-specific MRI biomarkers were used to measure the effects of a novel anti-angiogenic biomimetic peptide in an orthotopic MDA-MB-231 human triple-negative breast cancer model at an early growth stage. In vivo diffusion-weighted and steady-state susceptibility contrast (SSC) MRI was performed pre-treatment and 2 weeks post-treatment in tumor volume-matched treatment and control groups (n = 5/group). Treatment response was measured by changes in tumor volume; baseline transverse relaxation time (T2); apparent diffusion coefficient (ADC); and SSC-MRI metrics of blood volume, vessel size, and vessel density. These vasculature-specific SSC-MRI biomarkers were compared to the more conventional, non-vascular biomarkers (tumor growth, ADC, and T2) in terms of their sensitivity to anti-angiogenic treatment response. After 2 weeks of peptide treatment, tumor growth inhibition was evident but not yet significant, and the changes in ADC or T2 were not significantly different between treated and control groups. In contrast, the vascular MRI biomarkers revealed a significant anti-angiogenic response to the peptide after 2 weeks­blood volume and vessel size decreased, and vessel density increased in treated tumors; the opposite was seen in control tumors. The MRI results were validated with histology­H&E staining showed no difference in tumor viability between groups, while peptide-treated tumors exhibited decreased vascularity. These results indicate that translational SSC-MRI biomarkers are able to detect the differential effects of anti-angiogenic therapy on the tumor vasculature before significant tumor growth inhibition or changes in tumor viability.


Assuntos
Inibidores da Angiogênese/farmacologia , Biomimética , Neoplasias da Mama/patologia , Imageamento por Ressonância Magnética/métodos , Neovascularização Patológica , Peptídeos/uso terapêutico , Animais , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Expert Rev Mol Med ; 17: e3, 2015 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-25634527

RESUMO

Tumour and organ microenvironments are crucial for cancer progression and metastasis. Crosstalk between multiple non-malignant cell types in the microenvironments and cancer cells promotes tumour growth and metastasis. Blood and lymphatic endothelial cells (BEC and LEC) are two of the components in the microenvironments. Tumour blood vessels (BV), comprising BEC, serve as conduits for blood supply into the tumour, and are important for tumour growth as well as haematogenous tumour dissemination. Lymphatic vessels (LV), comprising LEC, which are relatively leaky compared with BV, are essential for lymphogenous tumour dissemination. In addition to describing the conventional roles of the BV and LV, we also discuss newly emerging roles of these endothelial cells: their crosstalk with cancer cells via molecules secreted by the BEC and LEC (also called angiocrine and lymphangiocrine factors). This review suggests that BEC and LEC in various microenvironments can be orchestrators of tumour progression and proposes new mechanism-based strategies to discover new therapies to supplement conventional anti-angiogenic and anti-lymphangiogenic therapies.


Assuntos
Microambiente Celular , Células Endoteliais/metabolismo , Neoplasias/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células Endoteliais/patologia , Humanos , Neoplasias/patologia , Células-Tronco Neoplásicas/patologia
20.
J Cell Mol Med ; 18(8): 1491-508, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24237862

RESUMO

Blood travels throughout the body in an extensive network of vessels - arteries, veins and capillaries. This vascular network is not static, but instead dynamically remodels in response to stimuli from cells in the nearby tissue. In particular, the smallest vessels - arterioles, venules and capillaries - can be extended, expanded or pruned, in response to exercise, ischaemic events, pharmacological interventions, or other physiological and pathophysiological events. In this review, we describe the multi-step morphogenic process of angiogenesis - the sprouting of new blood vessels - and the stability of vascular networks in vivo. In particular, we review the known interactions between endothelial cells and the various blood cells and plasma components they convey. We describe progress that has been made in applying computational modelling, quantitative biology and high-throughput experimentation to the angiogenesis process.


Assuntos
Endotélio Vascular/citologia , Neovascularização Fisiológica , Biologia de Sistemas , Animais , Humanos , Modelos Biológicos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA