A multiscale hybrid model for pro-angiogenic calcium signals in a vascular endothelial cell

Cytosolic calcium machinery is one of the principal signaling mechanisms by which endothelial cells (ECs) respond to external stimuli during several biological processes, including vascular progression in both physiological and pathological conditions. Low concentrations of angiogenic factors (such as VEGF) activate in fact complex pathways involving, among others, second messengers arachidonic acid (AA) and nitric oxide (NO), which in turn control the activity of plasma membrane calcium channels. The subsequent increase in the intracellular level of the ion regulates fundamental biophysical properties of ECs (such as elasticity, intrinsic motility, and chemical strength), enhancing their migratory capacity. Previously, a number of continuous models have represented cytosolic calcium dynamics, while EC migration in angiogenesis has been separately approached with discrete, lattice-based techniques. These two components are here integrated and interfaced to provide a multiscale and hybrid Cellular Potts Model (CPM), where the phenomenology of a motile EC is realistically mediated by its calcium-dependent subcellular events. The model, based on a realistic 3-D cell morphology with a nuclear and a cytosolic region, is set with known biochemical and electrophysiological data. In particular, the resulting simulations are able to reproduce and describe the polarization process, typical of stimulated vascular cells, in various experimental conditions.Moreover, by analyzing the mutual interactions between multilevel biochemical and biomechanical aspects, our study investigates ways to inhibit cell migration: such strategies have in fact the potential to result in pharmacological interventions useful to disrupt malignant vascular progressio

VEGF(164)-mediated inflammation is required for pathological, but not physiological, ischemia-induced retinal neovascularization

Hypoxia-induced VEGF governs both physiological retinal vascular development and pathological retinal neovascularization. In the current paper, the mechanisms of physiological and pathological neovascularization are compared and contrasted. During pathological neovascularization, both the absolute and relative expression levels for VEGF(164) increased to a greater degree than during physiological neovascularization. Furthermore, extensive leukocyte adhesion was observed at the leading edge of pathological, but not physiological, neovascularization. When a VEGF(164)-specific neutralizing aptamer was administered, it potently suppressed the leukocyte adhesion and pathological neovascularization, whereas it had little or no effect on physiological neovascularization. In parallel experiments, genetically altered VEGF(164)-deficient (VEGF(120/188)) mice exhibited no difference in physiological neovascularization when compared with wild-type (VEGF(+/+)) controls. In contrast, administration of a VEGFk-1/Fc fusion protein, which blocks all VEGF isoforms, led to significant suppression of both pathological and physiological neovascularization. In addition, the targeted inactivation of monocyte lineage cells with clodronate-liposomes led to the suppression of pathological neovascularization. Conversely, the blockade of T lymphocyte-mediated immune responses with an anti-CD2 antibody exacerbated pathological neovascularization. These data highlight important molecular and cellular differences between physiological and pathological retinal neovascularization. During pathological neovascularization, VEGF(164) selectively induces inflammation and cellular immunity. These processes provide positive and negative angiogenic regulation, respectively. Together, new therapeutic approaches for selectively targeting pathological, but not physiological, retinal neovascularization are outlined

Comparison of Path Tracking Flat Control and Working Point Linearization Based Set Point Control of Tumor Growth with Angiogenic Inhibition

Targeted molecular therapies (TMT) represent new perspectives in cancer treatment, fighting against the specific characteristic of the investigated tumor. Antiangiogenic therapy represents a specific TMT and its role is to stop the angiogenesis of the tumor, the process of forming new blood vessels; hence, to stop tumor growth. Proper control algorithms for tumor growth control with angiogenic inhibition are analyzed in the current article in order to find optimal therapeutic protocols. Two slightly different approaches are compared: nonlinear control by exact linearization with path tracking control, and linear control by working point linearization with set point control. The control strategies are compared in terms of the characteristics of the input signal (the inhibitor, drug intake) that is crucial if the therapy will be put into practice

Study of Modern Control Methodologies Applied to Tumor Growth under Angiogenic Inhibition

Cancer treatment is one of the most important research fields of modern medicine. In the last decades, targeted molecular therapies showed pr osperous results. These treatments achieve tumor regression with limited side-effects. Mathem atical models were posed which describe the dynamics of tumor regression under the applied control. The current paper investigates antiangiogenic therapy, which inhibits the t umor to grow its own endothelial capillaries and thus inhibits tumor to grow over a certain si ze. Many different control approaches were elaborated and published since the model formulation w as posed. The aim of this paper is to give an overview of these methods and results, and to rev iew the work carried out by the authors

Potential Benefits of Discrete-Time Controllerbased Treatments over Protocol-based Cancer Therapies

In medical practice, the effectiveness of fighting cancer is not only determined by the composition of the used drug, but determ ined by the administration method as well. As a result, having drugs with a suitable action profile is just a promising beginning, but without appropriate delivery method s , the therapy still can be ineffective. Finding the optimal biologic dose is an empir ical process in medical practice; however, using controllers, an automated optimal administration can be determined . In this paper , we evaluate the effectiveness of different drug delivery protocols; using in silico simulations (like bolus dose s, low - dose metron omic regimen and continuous infusion therapy ). In addition, we compare these results with discrete - time controller - based treatments containing state feedback, setpoint control, actual state observer and load estimation

Parameter optimization of H∞ controller designed for tumor growth in the light of physiological aspects

According to the fact that cancer diseases are leading causes of death all around the world, development of cancer fighting therapies is necessary. Beside the medical knowledge, there is an extra need for engineering approach to solve this complex problem. The aim of this paper is to design controller for tumor growth under angiogenic inhibition, which on the one hand minimizes the input signal as far as possible (in order to have less side effects and greater cost-effectiveness) and on the other hand results in appropriately low tumor volume. Since the model contains uncertainties and measurement noise, the controller was designed using modern robust control methodology. Choosing of the ideal system and the weighting functions were done in the light of physiological aspects

Imatinib inhibits VEGF-independent angiogenesis by targeting neuropilin 1-dependent ABL1 activation in endothelial cells.

To enable new blood vessel growth, endothelial cells (ECs) express neuropilin 1 (NRP1), and NRP1 associates with the receptor tyrosine kinase VEGFR2 after binding the vascular endothelial growth factor A (VEGF) to enhance arteriogenesis. We report that NRP1 contributes to angiogenesis through a novel mechanism. In human and mouse ECs, the integrin ligand fibronectin (FN) stimulated actin remodeling and phosphorylation of the focal adhesion component paxillin (PXN) in a VEGF/VEGFR2-independent but NRP1-dependent manner. NRP1 formed a complex with ABL1 that was responsible for FN-dependent PXN activation and actin remodeling. This complex promoted EC motility in vitro and during angiogenesis on FN substrates in vivo. Accordingly, both physiological and pathological angiogenesis in the retina were inhibited by treatment with Imatinib, a small molecule inhibitor of ABL1 which is widely used to prevent the proliferation of tumor cells that express BCR-ABL fusion proteins. The finding that NRP1 regulates angiogenesis in a VEGF- and VEGFR2-independent fashion via ABL1 suggests that ABL1 inhibition provides a novel opportunity for anti-angiogenic therapy to complement VEGF or VEGFR2 blockade in eye disease or solid tumor growth

Developmental and Tumor Angiogenesis Requires the Mitochondria-Shaping Protein Opa1

While endothelial cell (EC) function is influenced by mitochondrial metabolism, the role of mitochondrial dynamics in angiogenesis, the formation of new blood vessels from existing vasculature, is unknown. Here we show that the inner mitochondrial membrane mitochondrial fusion protein optic atrophy 1 (OPA1) is required for angiogenesis. In response to angiogenic stimuli, OPA1 levels rapidly increase to limit nuclear factor kappa-light-chain-enhancer of activated B cell (NFκB) signaling, ultimately allowing angiogenic genes expression and angiogenesis. Endothelial Opa1 is indeed required in an NFκB-dependent pathway essential for developmental and tumor angiogenesis, impacting tumor growth and metastatization. A first-in-class small molecule-specific OPA1 inhibitor confirms that EC Opa1 can be pharmacologically targeted to curtail tumor growth. Our data identify Opa1 as a crucial component of physiological and tumor angiogenesis

Model-based Angiogenic Inhibition of Tumor Growth using Adaptive Fuzzy Techniques

Fighting tumors is one of the most important problems of medical research. In this paper, antiangiogenic cancer therapy is investigated through its mathematical model.This tumor treatment method targets the endothelium of a growing tumor and belongs to the targeted molecular therapies.The aim of the therapy is not to eliminate the entire tumor,but to decrease the tumor to a minimal volume. An advantage of applying antiangiogenic treatment is that tumor cells show lower tendency of becoming resistant to the applied drugs.Adaptive fuzzy control is implemented for a simplified model to elaborate a control technique which is able to handle the effects of parameter perturbations and uncertainties while keeping the daily and total inhibitor inlet under a given limit

Quercetin Inhibits Angiogenesis Mediated Human Prostate Tumor Growth by Targeting VEGFR- 2 Regulated AKT/mTOR/P70S6K Signaling Pathways

Angiogenesis is a crucial step in the growth and metastasis of cancers, since it enables the growing tumor to receive oxygen and nutrients. Cancer prevention using natural products has become an integral part of cancer control. We studied the antiangiogenic activity of quercetin using ex vivo, in vivo and in vitro models. Rat aortic ring assay showed that quercetin at non-toxic concentrations significantly inhibited microvessel sprouting and exhibited a significant inhibition in the proliferation, migration, invasion and tube formation of endothelial cells, which are key events in the process of angiogenesis. Most importantly, quercetin treatment inhibited ex vivo angiogenesis as revealed by chicken egg chorioallantoic membrane assay (CAM) and matrigel plug assay. Western blot analysis showed that quercetin suppressed VEGF induced phosphorylation of VEGF receptor 2 and their downstream protein kinases AKT, mTOR, and ribosomal protein S6 kinase in HUVECs. Quercetin (20 mg/kg/d) significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model, indicating that quercetin inhibited tumorigenesis by targeting angiogenesis. Furthermore, quercetin reduced the cell viability and induced apoptosis in prostate cancer cells, which were correlated with the downregulation of AKT, mTOR and P70S6K expressions. Collectively the findings in the present study suggest that quercetin inhibits tumor growth and angiogenesis by targeting VEGF-R2 regulated AKT/mTOR/P70S6K signaling pathway, and could be used as a potential drug candidate for cancer therapy