Tumor VEGF:VEGFR2 autocrine feed-forward loop triggers angiogenesis in lung cancer

Chatterjee, Sampurna; Heukamp, Lukas C.; Siobal, Maike; Schöttle, Jakob; Wieczorek, Caroline; Peifer, Martin; Frasca, Davide; Koker, Mirjam; König, Katharina; Meder, Lydia; Rauh, Daniel; Buettner, Reinhard; Wolf, J.; Brekken, Rolf A.; Neumaier, Bernd; Thomas, Roman K.; Ullrich, Roland T.

doi:10.1172/jci65385

Cited by 168 publications

(137 citation statements)

References 20 publications

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“…The mTOR pathway downstream of several receptor tyrosine kinases, including VEGFR2, 24 regulates the rate of protein synthesis. We explored whether mTOR signaling is involved in the regulation of endothelial Sox7 and Sox17 expression.…”

Section: Vegf Upregulates Sox7 and Sox17 Expression Via The Mtor Pathwaymentioning

confidence: 99%

SoxF Transcription Factors Are Positive Feedback Regulators of VEGF Signaling

Kim

Yang

et al. 2016

Circulation Research

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Rationale: Vascular endothelial growth factor (VEGF) signaling is a key pathway for angiogenesis and requires highly coordinated regulation. Although the Notch pathway-mediated suppression of excessive VEGF activity via negative feedback is well known, the positive feedback control for augmenting VEGF signaling remains poorly understood. Transcription factor Sox17 is indispensable for angiogenesis, but its association with VEGF signaling is largely unknown. The contribution of other Sox members to angiogenesis also remains to be determined. Objective:

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Section: Vegf Upregulates Sox7 and Sox17 Expression Via The Mtor Pathwaymentioning

confidence: 99%

SoxF Transcription Factors Are Positive Feedback Regulators of VEGF Signaling

Kim

Yang

et al. 2016

Circulation Research

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“…VEGF-α is an important cytokine that induces angiogenesis in cancer. 48 49 We found that gastric cancer cells express endogenous levels of VEGF-α that are not modulated by DARPP-32. While our data demonstrate that DARPP-32 proteins induce angiogenesis, mainly through the regulation of ANGPT2, we cannot rule out the contribution of other existing factors such as VEGF-α in this process.…”

Section: Discussionmentioning

confidence: 84%

Gastric tumour-derived ANGPT2 regulation by DARPP-32 promotes angiogenesis

Chen

Zhu

Hong

et al. 2015

Gut

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Objective Overexpression of dopamine and cAMP-regulated phosphoprotein, Mr 32000 (DARPP-32), and its truncated isoform (t-DARPP) are associated with gastric tumorigenesis. Herein, we investigated the role of DARPP-32 proteins in regulating angiopoietin 2 (ANGPT2) and promoting tumor angiogenesis. Design Quantitative real-time RT-PCR, immunoblotting, luciferase reporter, immunofluorescence, immunohistochemistry, and angiogenesis assays were applied to investigate the regulation of angiogenesis by DARPP-32 proteins. Results Overexpression of DARPP-32 significantly increased the mRNA and protein levels of ANGPT2 in gastric cancer cells. The overexpression of DARPP-32 T34A mutant or the N-terminal truncated isoform, t-DARPP, led to similar effects ruling out the T34-dependent regulation of protein phosphatase 1 activity in regulating ANGPT2. DARPP-32 proteins induced a secreted form of ANGPT2, which was detectable in the media, functionally active, and able to induce angiogenesis, measured by the HUVEC tube formation assay. Antibody blocking of the secreted ANGPT2 abrogated its function. To identify the mechanism by which DARPP-32 regulates ANGPT2, we examined the activities of NF-κB and STAT3, known regulators of angiogenesis. The results ruled out NF-κB and showed induction of STAT3 phosphorylation, activation, and nuclear localization. Inhibition or knockdown of STAT3 significantly attenuated the induction of ANGPT2 by DARPP-32 proteins. In vivo xenografts models demonstrated that overexpression of DARPP-32 promotes angiogenesis and tumor growth. Analyses of human gastric cancer tissues showed a strong correlation between DARPP-32 and ANGPT2. Conclusion Our novel findings establish the role of DARPP-32-STAT3 axis in regulating ANGPT2 in cancer cells to promote angiogenesis and tumorigenesis.

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“…For example, as an essential tyrosine kinase receptor for VEGF-mediated physiological responses, VEGFR2 is not only found in endothelial cells, but may also be upregulated on the surface of some tumor cells (33,34). Recent studies suggest that VEGF-VEGFR2 interplay is a novel and attractive target in therapy of malignant tumors (35), therefore, BC001 was developed. However, little information is available on the functions of the potential drug in tumor angiogenesis and tumor growth.…”

Section: Discussionmentioning

confidence: 99%

Fully human VEGFR2 monoclonal antibody BC001 attenuates tumor angiogenesis and inhibits tumor growth

Xuan

Zhang

et al. 2014

International Journal of Oncology

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The critical role of VEGFR2 in tumor neovascularization and progression has allowed the design of clinically beneficial therapies based on it. Here we show that BC001, a new fully human anti-VEGFR2 monoclonal antibody, inhibits VEGF-stimulated endothelial cell migration, tube formation, and effectively suppressed the transdifferentiation of cancer stem cells into endothelial cells in vitro. Since BC001 exhibited no activity against the mouse VEGFR2 and mouse based study was required to confirm its efficacy in vivo, BC101, the mouse analogue of BC001, was developed. BC101 significantly attenuated angiogenesis according to Matrigel plug assay and resulted in ~80% growth inhibition of mouse B16F10 homograft tumors relative to vehicle control. Similarly, human analogue BC001 suppressed the growth of human xenograft tumors HCT116 and BGC823. Furthermore, immunohistochemical results showed reduced expression of CD31, VEGFR2 and Ki-67, as well as increased expression of Caspase 3 in BC001-treated tumor, which indicated BC001 was able to significantly decrease microvessel density, suppress proliferation and promote apoptosis. These results demonstrate the fully human VEGFR2 monoclonal antibody BC001 can work as an effective inhibitor of tumor angiogenesis and tumor growth both in vitro and in vivo.

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Tumor VEGF:VEGFR2 autocrine feed-forward loop triggers angiogenesis in lung cancer

Cited by 168 publications

References 20 publications

SoxF Transcription Factors Are Positive Feedback Regulators of VEGF Signaling

SoxF Transcription Factors Are Positive Feedback Regulators of VEGF Signaling

Gastric tumour-derived ANGPT2 regulation by DARPP-32 promotes angiogenesis

Fully human VEGFR2 monoclonal antibody BC001 attenuates tumor angiogenesis and inhibits tumor growth

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