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, Jürgen; Brekken, Rolf A.; Neumaier, Bernd; Thomas, Roman K.; Ullrich, Roland T.

doi:10.1172/jci70810

Cited by 38 publications

(53 citation statements)

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“…Thus, a concentration of CLE-C14A at EC junctions may be important for the formation of a well-organized vascular network. Conversely, impaired vascular integrity and the resultant hemorrhaging may have stemmed from weakened junctions upon the loss of C-type lectins as well as enhanced VEGFR-2 activity, which results in unstable and increased tumor angiogenesis (44,45), upon the loss of CLE-C14A-VEGFR-3 interaction.…”

Section: Methodsmentioning

confidence: 99%

Carbohydrate-binding protein CLEC14A regulates VEGFR-2– and VEGFR-3–dependent signals during angiogenesis and lymphangiogenesis

Lee

Rho

Park

et al. 2016

Journal of Clinical Investigation

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Section: Methodsmentioning

confidence: 99%

Carbohydrate-binding protein CLEC14A regulates VEGFR-2– and VEGFR-3–dependent signals during angiogenesis and lymphangiogenesis

Lee

Rho

Park

et al. 2016

Journal of Clinical Investigation

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“…Western blotting was performed as described previously (15). For Western blotting, the following antibodies were used: b-actin (clone C4; MPBiomedicals LLC), pEGFR, pAKT (S473), pERK (Cell Signaling Technology), anti-rabbit-horseradish peroxidase (HRP) antibody, and anti-mouse-HRP antibody (Millipore).…”

Section: Western Blottingmentioning

confidence: 99%

Transient Antiangiogenic Treatment Improves Delivery of Cytotoxic Compounds and Therapeutic Outcome in Lung Cancer

et al. 2014

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Extensive oncologic experience argues that the most efficacious applications of antiangiogenic agents rely upon a combination with cytotoxic drugs. Yet there remains a lack of clarity about how to optimize scheduling for such drug combinations. Prudent antiangiogenic therapy might transiently normalize blood vessels to improve tumor oxygenation and drug exposure. Using [ 15 O]H 2 O positron emission tomography imaging in a preclinical mouse model of non-small cell lung cancer, we observed that short-term treatment with the vascular endothelial growth factor receptor/platelet-derived growth factor receptor inhibitor PTK787 licensed a transient window of improved tumor blood flow. The improvement observed was associated with a reduced leakiness from tumor vessels, consistent with induction of a vascular normalization process. Initiation of a cytotoxic treatment in this window of tumor vessel normalization resulted in increased efficacy, as illustrated by improved outcomes of erlotinib administration after initial PTK787 treatment. Notably, intermittent PTK787 treatment also facilitated long-term tumor regression. In summary, our findings offer strong evidence that short-term antiangiogenic therapy can promote a transient vessel normalization process that improves the delivery and efficacy of a targeted cytotoxic drug. Cancer Res; 74(10); 2816-24. Ó2014 AACR.

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“…However, additional roles for VEGF-A in tumorigenesis are emerging. VEGF-A was shown to promote tumor cell growth in an autocrine manner, in skin and lung cancer cells expressing VEGFRs ( 22,23 ). Moreover, VEGF-A also has nonangiogenic functions in normal physiology.…”

Section: Introductionmentioning

confidence: 99%

Human and Mouse VEGFA-Amplified Hepatocellular Carcinomas Are Highly Sensitive to Sorafenib Treatment

et al. 2014

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Death rates from hepatocellular carcinoma (HCC) are steadily increasing, yet therapeutic options for advanced HCC are limited. We identify a subset of mouse and human HCCs harboring VEGFA genomic amplifi cation, displaying distinct biologic characteristics. Unlike common tumor amplifi cations, this one seems to work via heterotypic paracrine interactions; stromal VEGF receptors (VEGFR), responding to tumor VEGF-A, produce hepatocyte growth factor (HGF) that reciprocally affects tumor cells. VEGF-A inhibition results in HGF downregulation and reduced proliferation, specifi cally in amplicon-positive mouse HCCs. Sorafenib-the fi rst-line drug in advanced HCC-targets multiple kinases, including VEGFRs, but has only an overall mild benefi cial effect. We found that VEGFA amplifi cation specifi es mouse and human HCCs that are distinctly sensitive to sorafenib. FISH analysis of a retrospective patient cohort showed markedly improved survival of sorafenib-treated patients with VEGFA -amplifi ed HCCs, suggesting that VEGFA amplifi cation is a potential biomarker for HCC response to VEGF-A-blocking drugs. SIGNIFICANCE:Using a mouse model of infl ammation-driven cancer, we identifi ed a subclass of HCC carrying VEGFA amplifi cation, which is particularly sensitive to VEGF-A inhibition. We found that a similar amplifi cation in human HCC identifi es patients who favorably responded to sorafenib-the fi rst-line treatment of advanced HCC-which has an overall moderate therapeutic effi cacy. Cancer Discov; 4(6);

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

Cited by 38 publications

References 0 publications

Carbohydrate-binding protein CLEC14A regulates VEGFR-2– and VEGFR-3–dependent signals during angiogenesis and lymphangiogenesis

Carbohydrate-binding protein CLEC14A regulates VEGFR-2– and VEGFR-3–dependent signals during angiogenesis and lymphangiogenesis

Transient Antiangiogenic Treatment Improves Delivery of Cytotoxic Compounds and Therapeutic Outcome in Lung Cancer

Human and Mouse VEGFA-Amplified Hepatocellular Carcinomas Are Highly Sensitive to Sorafenib Treatment

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