Effect of VEGF and VEGF Trap on vascular endothelial cell signaling in tumors

Lassoued, Wiem; Murphy, Danielle; Tsai, Jeff H.; Oueslati, Ridha; Thurston, Gavin; Lee, William M. F.

doi:10.4161/cbt.10.12.14009

Cited by 41 publications

(39 citation statements)

References 35 publications

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“…Aflibercept is a recombinant fusion protein, consisting of the extracellular domain of the human vegf receptor (vegfr), fused to the hinge region of the human immunoglobulin G1 Fc domain 25 . Commonly called "vegf trap," it binds all isoforms of serum vegf, vegf-b, and human placental growth factor.…”

Section: Other Antiangiogenic Agents Evaluated In First-line Therapy mentioning

confidence: 99%

Antiangiogenic Therapies in Non-Small-Cell Lung Cancer

2018

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Angiogenesis is frequent in non-small-cell lung cancer (nsclc) and is associated with more aggressive disease. Many clinical trials have evaluated the addition of antiangiogenic therapy to standard therapies for patients with nsclc. Bevacizumab, a monoclonal antibody directed against serum vascular endothelial growth factor, in combination with carboplatin-paclitaxel chemotherapy, has been shown to improve survival for patients with nsclc. However, bevacizumab-based therapy is not suitable for many nsclc patients, including those with squamous histology, poor performance status, brain metastases, and the presence of bleeding or thrombotic disorders. Similar efficacy has also been seen with carboplatin-pemetrexed followed by maintenance pemetrexed chemotherapy. In the second-line setting, the addition of ramucirumab to docetaxel-or the addition of bevacizumab to paclitaxel-has resulted in a modest improvement in efficacy, although the clinical importance of those findings is questionable. Many trials in nsclc have also evaluated oral antiangiogenic compounds, both in the first line in combination with chemotherapy and upon disease progression either as combination or single-agent therapy. No clear improvements in overall survival have been observed, although a subgroup analysis of a trial evaluating the addition of nintedanib to docetaxel showed improved survival that was limited to patients with adenocarcinoma. Those findings require validation, however.All of the oral antiangiogenic agents result in added toxicities. Some agents have resulted in an increased risk of death, limiting their development. Available evidence supports a limited number of antiangiogenic therapies for patients with nsclc, but no biomarkers to help in patient selection are currently available, and additional translational research is needed to identify predictive biomarkers for antiangiogenic therapy.

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Section: Other Antiangiogenic Agents Evaluated In First-line Therapy mentioning

confidence: 99%

Antiangiogenic Therapies in Non-Small-Cell Lung Cancer

2018

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“…We implemented our techniques to focus on proteins such as extracellular regulated kinase (ERK), Akt, and c-Src. These intracellular proteins have been reported to be phosphorylated subsequent to VEGF 165 binding to VEGFR-2, therefore, increasing cell proliferation, the survival of apoptosis-inducing events, and cell migration, respectively (15,19,27) (Fig. 1).…”

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confidence: 96%

Covalently grafted VEGF₁₆₅ in hydrogel models upregulates the cellular pathways associated with angiogenesis

Porter

Klinge²,

Gobin

2011

American Journal of Physiology-Cell Physiology

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Angiogenesis is an important biological response known to be involved in many physiological and pathophysiological situations. Cellular responses involved in the formation of new blood vessels, such as increases in endothelial cell proliferation, cell migration, and the survival of apoptosis-inducing events, have been associated with vascular endothelial growth factor isoform 165 (VEGF(165)). Current research in the areas of bioengineering and biomedical science has focused on developing polyethylene glycol (PEG)-based systems capable of initiating and sustaining angiogenesis in vitro. However, a thorough understanding of how endothelial cells respond at the molecular level to VEGF(165) incorporated into these systems has not yet been established in the literature. The goal of the current study was to compare the upregulation of key intracellular proteins involved in angiogenesis in human umbilical vein endothelial cells (HUVEC) and human microvascular endothelial cells (HMEC) seeded on PEG hydrogels containing grafted VEGF(165) and adhesion peptides Arg-Gly-Asp-Ser (RGDS). Our data suggest that the covalent incorporation of VEGF(165) into PEG hydrogels encourages the upregulation of signaling proteins responsible for increases in endothelial cell proliferation, cell migration, and the survival after apoptosis-inducing events.

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“…It signals through its receptors, primarily VEGFR2.The upregulation of this receptor in tumor cells is due to the activation of oncogenes and inactivation of tumor suppressor genes during neoplastic transformation. After binding with its ligand, this receptor responds by signaling through the Raf-MEK-ERK and PI3K-Akt kinase cascades [14,15]. Novel therapeutic agents that target angiogenic mechanisms would serve as a valuable adjunct to treat cancer including colon cancer.…”

Section: Introductionmentioning

confidence: 99%

Upregulation of RASSF1A in Colon Cancer by Suppression of Angiogenesis Signaling and Akt Activation

Blanchard

Lapidus

Banerjee

et al. 2018

Cell Physiol Biochem

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Background/Aims: Silencing of tumor suppressor genes (TSGs) and promotion of angiogenesis are associated with tumor development and metastasis. However, little is known if angiogenic molecules directly control TSGs and vice versa. Methods: A regulatory link between angiogenesis and down regulation of TSGs was evaluated using an anti-cancer agent, andrographolide (AGP) in cancer cells, mouse xenograft tissues and patient derived organoids through gene/protein expression, gene silencing, and immunohistochemical analyses. Results: AGP treatment demonstrated significant expression of RASSF1A and PTEN TSGs in colon cancer and other cancer cells, mouse tissues and organoids. Depletion of RASSF1A with siRNA limited cyclin D1 and BAX expression. SiRNA depletion of PTEN, upstream regulator of RASSF1A resulted in a 50% reduction in RASSF1A expression. Histopathological analysis of the AGP treated tumor sections showed significant reduction in vessel size, microvascular density and tumor mitotic index suggesting suppression of angiogenesis. This was corroborated by protein analysis demonstrating significant reductions in angiogenesis signaling pathway molecules VEGF₁₆₅, FOXM1, and pAkt, but significant elevation of the endogenous angiogenesis inhibitor Tsp-2. Treatment of cells with exogenous VEGF prevented the suppression of angiogenesis signaling by AGP, resulting in sustained expression of pAkt, an upstream down-regulator of RASSF1A. RASSF1A expression remained low in VEGF treated cells despite the addition of AGP. Conclusion: Our results demonstrate for the first time that AGP induces RASSF1A expression in colon cancer cells and is dependent on angiogenesis signaling events. Therefore, our research may facilitate novel therapeutic options for advanced colon cancer therapy.

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Effect of VEGF and VEGF Trap on vascular endothelial cell signaling in tumors

Cited by 41 publications

References 35 publications

Antiangiogenic Therapies in Non-Small-Cell Lung Cancer

Antiangiogenic Therapies in Non-Small-Cell Lung Cancer

Covalently grafted VEGF₁₆₅ in hydrogel models upregulates the cellular pathways associated with angiogenesis

Upregulation of RASSF1A in Colon Cancer by Suppression of Angiogenesis Signaling and Akt Activation

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Effect of VEGF and VEGF Trap on vascular endothelial cell signaling in tumors

Cited by 41 publications

References 35 publications

Antiangiogenic Therapies in Non-Small-Cell Lung Cancer

Antiangiogenic Therapies in Non-Small-Cell Lung Cancer

Covalently grafted VEGF165 in hydrogel models upregulates the cellular pathways associated with angiogenesis

Upregulation of RASSF1A in Colon Cancer by Suppression of Angiogenesis Signaling and Akt Activation

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Covalently grafted VEGF₁₆₅ in hydrogel models upregulates the cellular pathways associated with angiogenesis