scholarly journals Towards integration of time-resolved confocal microscopy of a 3D in vitro microfluidic platform with a hybrid multiscale model of tumor angiogenesis

2021 ◽  
Author(s):  
Caleb Phillips ◽  
Ernesto A. B. F. Lima ◽  
Manasa Gadde ◽  
Angela M. Jarrett ◽  
Marissa Nichole Rylander ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Tumor Angiogenesis ◽  
Multiscale Model ◽  
Scale Model ◽  
Vascular Endothelial ◽  
Time Resolved ◽  
Microfluidic Platform ◽  
Time Points ◽  
Multi Scale ◽  
Endothelial Growth Factor

The goal of this study is to calibrate a multiscale model of tumor angiogenesis with time-resolved data to allow for systematic testing of mathematical predictions of vascular sprouting. The multi-scale model consists of an agent-based description of tumor and endothelial cell dynamics coupled to a continuum model of vascular endothelial growth factor concentration. First, we calibrate ordinary differential equation models to time-resolved protein expression data to estimate the rates of secretion and consumption of vascular endothelial growth factor by endothelial and tumor cells, respectively. These parameters are then input into the multiscale tumor angiogenesis model, and the remaining model parameters are then calibrated to time resolved confocal microscopy images obtained within a 3D vascularized microfluidic platform. The microfluidic platform mimics a functional blood vessel with a surrounding collagen matrix seeded with inflammatory breast cancer cells, which induce tumor angiogenesis. Once the multi-scale model is fully parameterized, we forecast the spatiotemporal distribution of vascular sprouts at future time points and directly compare the predictions to experimentally measured data. We assess the ability of our model to globally recapitulate angiogenic vasculature density, resulting in an average relative calibration error of 17.7% ± 6.3% and an average prediction error of 20.2% ± 4% and 21.7% ±3.6% using one and four calibrated parameters, respectively. We then assess the model's ability to predict local vessel morphology (individualized vessel structure as opposed to global vascular density), initialized with the first time point and calibrated with two intermediate time points. To the best of our knowledge, this represents the first study to integrate well-controlled, experimental data into a mechanism-based, multiscale, mathematical model of angiogenic sprouting to make specific, testable predictions.

The Role of Vascular Endothelial Growth Factor in Tumor Angiogenesis

1998 ◽  
pp. 305-318
Author(s):  
Georg Breier ◽  
Annette Damert ◽  
Sabine Blum ◽  
Ernst Reichmann ◽  
Karl H. Plate ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Tumor Angiogenesis ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

Placental Growth Factor-1 Attenuates Vascular Endothelial Growth Factor-A–Dependent Tumor Angiogenesis during β Cell Carcinogenesis

2007 ◽  
Vol 67 (22) ◽  
pp. 10840-10848 ◽  
Author(s):  
Tibor Schomber ◽  
Lucie Kopfstein ◽  
Valentin Djonov ◽  
Imke Albrecht ◽  
Vanessa Baeriswyl ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Tumor Angiogenesis ◽  
Placental Growth Factor ◽  
Vascular Endothelial ◽  
Β Cell ◽  
Endothelial Growth Factor

Abstract 1066: Ultrasound-targeted Plasmid Delivery of Vascular Endothelial Growth Factor and Angiopoietin-1: Combination Gene Therapy for Therapeutic Angiogenesis

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Alexandra H Smith ◽  
Michael A Kuliszewski ◽  
Hiroko Fujii ◽  
Duncan J Stewart ◽  
Jonathan R Lindner ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Plasmid Dna ◽  
Therapeutic Angiogenesis ◽  
Blood Velocity ◽  
Control Group ◽  
List Type ◽  
Vascular Endothelial ◽  
Time Points ◽  
Endothelial Growth Factor

We have previously shown that ultrasound-mediated (UM) delivery of vascular endothelial growth factor (VEGF) plasmid-bearing microbubbles promotes therapeutic angiogenesis. While VEGF is important during the initiation of angiogenesis, it results in primarily immature vessels, which are prone to late regression. Angiopoietin (Ang)-1 is a potent growth factor that acts to stabilize the neovasculature, later in the angiogenic process. We hypothesized that temporal delivery of VEGF and Ang-1 plasmid DNA would result in a more sustained angiogenic response, as compared to VEGF alone, in the setting of severe chronic ischemia. Methods : Unilateral hindlimb ischemia was produced by iliac artery ligation in 30 rats. At day 14 post-ligation, microvascular blood velocity (β) and flow (MBF) in the proximal hindlimb muscles were assessed by contrast-enhanced ultrasound (CEU). UM-delivery of plasmid (500 μg cDNA)-bearing microbubbles (1×109), was then performed at pre-specified time points, with treatment groups including VEGF alone at day 14; VEGF at day 14 followed by Ang-1 at day 28; and control rats receiving no therapy (n=10 per group). β and MBF were re-assessed at day 28 and 8 wks post-ligation. Results : Relative MBF (normalized to the contralateral normal leg) remained reduced at all time points after ligation in the control group. In VEGF-alone treated animals, MBF in the ischemic leg increased 2 wks after delivery (0.48 ± 0.19 to 0.82 ± 0.23, p < 0.001), but regressed over the next 4 wks (0.61 ± 0.14 at 8 wk, NS vs. 2 wks). In the VEGF/Ang-1 treated animals, MBF in the ischemic leg also increased 2 weeks after VEGF delivery (0.39 ± 0.19 to 0.69 ± 0.28, p < 0.01); however, vascular regression was prevented by late Ang1 delivery (0.83 ± 0.20 at 8 wks, p < 0.005 vs. 2 wks and p<0.01 vs VEGF alone at 8 wks). At week 8, relative β values were greater in VEGF/Ang-1 treated compared to VEGF-alone treated animals (0.87 ± 0.33 to 0.60 ± 0.23, p < 0.05). Conclusions : Compared to delivery of VEGF alone, delivery of Ang-1 plasmid DNA at 2 wks post-VEGF gene delivery results in sustained improvement in MBF, with prevention of late vascular regression. The greater microvascular blood velocity in VEGF/Ang-1 treated muscle may signify improved vascular functionality with late Ang-1 therapy.

scholarly journals Harmine suppresses bladder tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis

2019 ◽  
Vol 39 (5) ◽  
Author(s):  
Cai Hai-rong ◽  
Huang Xiang ◽  
Zhang Xiao-rong
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Bladder Cancer ◽  
Growth Factor ◽  
Natural Product ◽  
Tumor Angiogenesis ◽  
Bladder Tumor ◽  
Growth Factor Receptor ◽  
Vascular Endothelial ◽  
Human Bladder ◽  
Endothelial Growth Factor

Abstract Angiogenesis is a vital step during the process of oncogenesis of a lot of tumors, with no exception in bladder cancer. One of the useful strategies for the development of new drugs against cancer is targeting angiogenesis. In the present study, we found that a small-molecule natural product, which belonged to the β-carboline alkaloid, named harmine, could strongly inhibit tumor angiogenesis thus exhibiting its ideal treatment efficacy in bladder cancer. In vivo study verified that harmine had the effect of inhibition on human bladder tumor xenograft growth. The inhibitory effect of harmine to bladder cancer growth was coordinated by the effects shown on angiogenesis. To further explore the pharmacological activities of harmine, we tested harmine’s influence on blood vessel formation and found that harmine effectively blocked the microvessel sprouting in rat aortic ring assay when stimulated by vascular endothelial growth factor (VEGF). Furthermore, harmine inhibited human umbilical vein endothelial cell (HUVEC) proliferation as well as chemotactic motility, and when we treated HUVEC cell with harmine, the formation of capillary-like structures was also restrained. Moreover, harmine induced bladder cancer cell apoptosis through triggering the caspase-dependent apoptotic pathway and the downstream vascular endothelial growth factor receptor 2 (VEGFR2) kinase pathway was down-regulated, thus suppressing tumor development signals. Herein, our study demonstrated that natural product harmine might have potential in curing human bladder tumor because of its pharmacological function on tumor angiogenesis, trigged by VEGFR2 signaling pathways.

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