Quantitative fluorescent profiling of<scp>VEGFR</scp>s reveals tumor cell and endothelial cell heterogeneity in breast cancer xenografts

Imoukhuede, P. I.; Popel, Aleksander S.

doi:10.1002/cam4.188

Cited by 48 publications

(64 citation statements)

References 110 publications

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“…The tumor size and VEGFR1/2 surface levels on tumor cells and tumor endothelial cells (tEC) were obtained from mouse xenografts [13]. It is observed that receptor distributions on the tumor cells and tEC exhibited multiple distributions.…”

Section: Resultsmentioning

confidence: 99%

Quantitative Characterization of Cellular Membrane-Receptor Heterogeneity through Statistical and Computational Modeling

Weddell

Imoukhuede

2014

PLoS ONE

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Cell population heterogeneity can affect cellular response and is a major factor in drug resistance. However, there are few techniques available to represent and explore how heterogeneity is linked to population response. Recent high-throughput genomic, proteomic, and cellomic approaches offer opportunities for profiling heterogeneity on several scales. We have recently examined heterogeneity in vascular endothelial growth factor receptor (VEGFR) membrane localization in endothelial cells. We and others processed the heterogeneous data through ensemble averaging and integrated the data into computational models of anti-angiogenic drug effects in breast cancer. Here we show that additional modeling insight can be gained when cellular heterogeneity is considered. We present comprehensive statistical and computational methods for analyzing cellomic data sets and integrating them into deterministic models. We present a novel method for optimizing the fit of statistical distributions to heterogeneous data sets to preserve important data and exclude outliers. We compare methods of representing heterogeneous data and show methodology can affect model predictions up to 3.9-fold. We find that VEGF levels, a target for tuning angiogenesis, are more sensitive to VEGFR1 cell surface levels than VEGFR2; updating VEGFR1 levels in the tumor model gave a 64% change in free VEGF levels in the blood compartment, whereas updating VEGFR2 levels gave a 17% change. Furthermore, we find that subpopulations of tumor cells and tumor endothelial cells (tEC) expressing high levels of VEGFR (>35,000 VEGFR/cell) negate anti-VEGF treatments. We show that lowering the VEGFR membrane insertion rate for these subpopulations recovers the anti-angiogenic effect of anti-VEGF treatment, revealing new treatment targets for specific tumor cell subpopulations. This novel method of characterizing heterogeneous distributions shows for the first time how different representations of the same data set lead to different predictions of drug efficacy.

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Section: Resultsmentioning

confidence: 99%

Quantitative Characterization of Cellular Membrane-Receptor Heterogeneity through Statistical and Computational Modeling

Weddell

Imoukhuede

2014

PLoS ONE

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“…Computational models can predict the dynamics of free and bound VEGF in vivo, but the current models assume that the number of cell surface receptors remains constant;24–28 thus, the models are limited in their predictions of antiangiogenic therapy. Previous studies have been effective at measuring the numbers of VEGFRs in vitro29 and in vivo 30,31. Although the changes in VEGFRs have been investigated under ischemia,32 to our knowledge, the changes in surface receptors after antiangiogenic treatment have not been studied.…”

Section: Introductionmentioning

confidence: 99%

Antiangiogenic cancer drug sunitinib exhibits unexpected proangiogenic effects on endothelial cells

Norton¹,

Han²,

Popel³

et al. 2014

OTT

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Angiogenesis, the formation of new blood vessels, is an essential step for cancer progression, but antiangiogenic therapies have shown limited success. Therefore, a better understanding of the effects of antiangiogenic treatments on endothelial cells is necessary. In this study, we evaluate the changes in cell surface vascular endothelial growth factor receptor (VEGFR) expression on endothelial cells in culture treated with the antiangiogenic tyrosine kinase inhibitor drug sunitinib, using quantitative flow cytometry. We find that proangiogenic VEGFR2 cell surface receptor numbers are increased with sunitinib treatment. This proangiogenic effect might account for the limited effects of sunitinib as a cancer therapy. We also find that this increase is inhibited by brefeldin A, an inhibitor of protein transport from the endoplasmic reticulum to the Golgi apparatus. The complex dynamics of cell surface VEGFRs may be important for successful treatment of cancer with antiangiogenic therapeutics.

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“…26,27 Quantitative measurements also show the cell-to-cell variations in the density of VEGF receptors across different cell lines. 24,25 This heterogeneity is thought to influence prognosis and response to treatment, which has been observed in various experimental settings. The VEGFR2 heterogeneity was proved to influence the response to anti-angiogenic cyclophosphamide treatment in a pre-clinical model.…”

Section: Discussionmentioning

confidence: 99%

“…It has been observed experimentally that tissue samples from patients with different types of cancer and different samples from patients with the same type of cancer have different receptor expressions. [24][25][26][27] Additionally, the VEGFR2 heterogeneity was shown to affect the response to an anti-angiogenic cyclophosphamide treatment in an in vitro experimental setting. 28 The patient-to-patient VEGFR1 and neuropilin variability has been associated with the response to bevacizumab treatment as intra-tumoral biomarkers.…”

Section: Introductionmentioning

confidence: 99%

“…The cell surface expression of these receptors was measured via flow cytometry. 24,25 For the TSP1 receptor numbers, we referred to the qualitative measurements reported in the Human Protein Atlas, 27 assuming ''high'', ''medium'', and ''low'' expression levels correspond to 10 000, 5000, and 2500 receptors per cell, respectively. Secretion and clearance rates (34 parameters).…”

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confidence: 99%

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The impact of tumor receptor heterogeneity on the response to anti-angiogenic cancer treatment

Ding

Finley

2018

Integrative Biology

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Multiple promoters and inhibitors mediate angiogenesis, the formation of new blood vessels, and these factors represent potential targets for impeding vessel growth in tumors. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor targeted in anti-angiogenic cancer therapies. In addition, thrombospondin-1 (TSP1) is a major endogenous inhibitor of angiogenesis, and TSP1 mimetics are being developed as an alternative type of anti-angiogenic agent. The combination of bevacizumab, an anti-VEGF agent, and ABT-510, a TSP1 mimetic, has been tested in clinical trials to treat advanced solid tumors.However, the patients' responses are highly variable and show disappointing outcomes. To obtain mechanistic insight into the effects of this combination anti-angiogenic therapy, we have constructed a novel whole-body systems biology model including the VEGF and TSP1 reaction networks. Using this molecular-detailed model, we investigated how the combination anti-angiogenic therapy changes the amounts of pro-angiogenic and anti-angiogenic complexes in cancer patients. We particularly focus on answering the question of how the effect of the combination therapy is influenced by tumor receptor expression, one aspect of patient-to-patient variability. Overall, this model complements the clinical administration of combination anti-angiogenic therapy, highlights the role of tumor receptor variability in the heterogeneous responses to anti-angiogenic therapy, and identifies the tumor receptor profiles that correlate with a high likelihood of a positive response to the combination therapy. Our model provides novel understanding of the VEGF-TSP1 balance in cancer patients at the systems-level and could be further used to optimize combination anti-angiogenic therapy. Insight, innovation, integrationThis work reports a novel multi-compartment model integrating the reaction networks of VEGF and TSP1, two potent angiogenic factors, in human cancer patients. With the model, we gain new insight into the impact of tumor receptor heterogeneity on the response to a clinically tested combination antiangiogenic therapy targeting both VEGF and TSP1 signaling and we identify potential tissue biomarkers. The model predictions provide mechanistic explanations of several important results reported in clinical trials of anti-angiogenic therapy, including the heterogeneous response to treatment and the importance of VEGFR1 as a predictive biomarker. Overall, this computational framework can be applied to improve combination anti-angiogenic therapy by increasing our understanding of the heterogeneous response, identifying potential biomarkers, and optimizing the pre-clinical and clinical studies.

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Quantitative fluorescent profiling ofVEGFRs reveals tumor cell and endothelial cell heterogeneity in breast cancer xenografts

Cited by 48 publications

References 110 publications

Quantitative Characterization of Cellular Membrane-Receptor Heterogeneity through Statistical and Computational Modeling

Quantitative Characterization of Cellular Membrane-Receptor Heterogeneity through Statistical and Computational Modeling

Antiangiogenic cancer drug sunitinib exhibits unexpected proangiogenic effects on endothelial cells

The impact of tumor receptor heterogeneity on the response to anti-angiogenic cancer treatment

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