Autocrine VEGF-VEGFR2—Neuropilin-1 signaling promotes glioma stem-like cell viability and tumor growth

Hamerlik, Petra; Lathia, Justin D.; Rasmussen, Rikke; Wu, Qing; Bártková, Jiřina; Lee, Myung‐Hee; Moudrý, Pavel; Fischer, Walter; Lukáš, Jiří; Rich, Jeremy; Bártek, Jiří

doi:10.1083/jcb1966oia9

Cited by 68 publications

(99 citation statements)

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“…Indeed, blocking angiogenesis by bevacizumab may promote subsequent tumor growth due to hypoxia-driven CSC self-renewal. 64,65 Present work, together with other recent studies, 19,20 suggest that one factor driving hypoxia-stimulated CSCs is VEGF itself. Increasing data indicate that tumor populations surviving chemotherapy are enriched in stem cells.…”

Section: Discussionmentioning

confidence: 55%

“…49 Autocrine VEGF-VEGFR-2-Neuropilin-1 signaling was shown to promote glioma growth by regulating stem-like cell viability. 19 Similarly, VEGF was also shown to stimulate squamous cell skin carcinoma CSCs, suggesting that VEGF not only creates a perivascular niche for CSCs, but may also directly promote their expansion. 20 A CSC self-renewal pathway in which VEGF acts via Neuroplin-2 to drive Gli was also recently reported in triplenegative breast models.…”

Section: Discussionmentioning

confidence: 97%

“…14 VEGF also stimulates stem cell self-renewal in normal hemopoietic, 15 endothelial, 14,16 neuronal 17 and adipose tissues. 15,18 Recent data indicate that VEGF drives CSC self-renewal in glioma 19 and skin cancer models, 20 but mechanisms thereof and the spectrum of tumor types affected are not fully characterized. Here, we investigated whether and how VEGF may stimulate CSCs independent of mitogenic or angiogenic effects in breast and lung cancers, two highly prevalent and lethal human malignancies.…”

Section: Introductionmentioning

confidence: 99%

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VEGF drives cancer-initiating stem cells through VEGFR-2/Stat3 signaling to upregulate Myc and Sox2

et al. 2014

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Vascular endothelial growth factor-A (VEGF), a potent angiogenic factor, is also implicated in self-renewal in several normal tissue types. VEGF has been shown to drive malignant stem cells but mechanisms thereof and tumor types affected are not fully characterized. Here, we show VEGF promotes breast and lung cancer stem cell (CSC) self-renewal via VEGF receptor-2 (VEGFR-2)/STAT3-mediated upregulation of Myc and Sox2. VEGF increased tumor spheres and aldehyde dehydrogenase activity, both proxies for stem cell function in vitro, in triple-negative breast cancer (TNBC) lines and dissociated primary cancers, and in lung cancer lines. VEGF exposure before injection increased breast cancer-initiating cell abundance in vivo yielding increased orthotopic tumors, and increased metastasis from orthotopic primaries and following tail vein injection without further VEGF treatment. VEGF rapidly stimulated VEGFR-2/JAK2/STAT3 binding and activated STAT3 to bind MYC and SOX2 promoters and induce their expression. VEGFR-2 knockdown or inhibition abrogated VEGF-mediated STAT3 activation, MYC and SOX2 induction and sphere formation. Notably, knockdown of either STAT3, MYC or SOX2 impaired VEGF-upregulation of pSTAT3, MYC and SOX2 expression and sphere formation. Each transcription factor, once upregulated, appears to promote sustained activation of the others, creating a feed-forward loop to drive self-renewal. Thus, in addition to angiogenic effects, VEGF promotes tumor-initiating cell self-renewal through VEGFR-2/STAT3 signaling. Analysis of primary breast and lung cancers (>1300 each) showed high VEGF expression, was prognostic of poor outcome and strongly associated with STAT3 and MYC expression, supporting the link between VEGF and CSC self-renewal. High-VEGF tumors may be most likely to escape anti-angiogenics by upregulating VEGF, driving CSC self-renewal to re-populate post-treatment. Our work highlights the need to better define VEGF-driven cancer subsets and supports further investigation of combined therapeutic blockade of VEGF or VEGFR-2 and JAK2/STAT3.

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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VEGF drives cancer-initiating stem cells through VEGFR-2/Stat3 signaling to upregulate Myc and Sox2

et al. 2014

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“…VEGFR-2 is critical for VEGF-mediated tumor angiogenesis and lymphangiogenesis [18,19], and its expression is associated with tumor invasion and metastasis [14,20,29,30]. A VEGFR-2 antagonist can significantly inhibit VEGFinduced tumor growth and metastasis [31].…”

Section: Discussionmentioning

confidence: 99%

“…Gab1, which is widely expressed in various body tissues, can exert numerous biological effects through interactions with PIP3, PI3K, Grb2, SHP2, and many other important signaling molecules [16,17]. Gab1 also interacts with vascular endothelial growth factor receptor 2 (VEGFR-2), which plays a key role in angiogenesis and lymphangiogenesis, enhancing the growth, invasion, and metastasis of malignant tumors and resulting in poor prognosis [18][19][20]. VEGFR-2 activates the PI3K/Akt signaling pathway through its interaction with Gab1, contributing to tumor c e l l i n v a s i o n t h r o u g h i n d u c t i o n o f m a t r i x metallopeptidase 9 (MMP-9) [14,[21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%

Gab1 regulates proliferation and migration through the PI3K/Akt signaling pathway in intrahepatic cholangiocarcinoma

Sang

et al. 2015

Tumor Biol.

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Intrahepatic cholangiocarcinoma is the second most common primary malignant tumor of the liver, and it originates from the intrahepatic biliary duct epithelium. Prognosis is poor due to lack of effective comprehensive treatments. In this study, we assessed the expression of Gab1, VEGFR-2, and MMP-9 in intrahepatic cholangiocarcinoma solid tumors by immunohistochemistry and determined whether their expression was associated with clinical and pathological features. We found that expression of Gab1, VEGFR-2, and MMP-9 was highly and positively correlated with each other and with lymph node metastasis and TNM stage in intrahepatic cholangiocarcinoma tissues. Interference of Gab1 and VEGFR-2 expression via siRNA in the intrahepatic cholangiocarcinoma cell line RBE resulted in decreased PI3K/Akt pathway activity. Inhibition of Gab1 and VEGFR-2 expression also caused decreased cell proliferation, cell cycle arrested in G1 phase, increased apoptosis, and decreased invasion in RBE cells. These results suggest that Gab1, VEGFR-2, and MMP-9 contribute significantly to the highly malignant behavior of intrahepatic cholangiocarcinoma. The regulation of growth, apoptosis, and invasion by Gab1 through the VEGFR-2/Gab1/PI3K/Akt signaling pathway may represent potential targets for improving the treatment of intrahepatic cholangiocarcinoma.

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CRISPR‐mediated knockout of VEGFR2/KDR inhibits cell growth in a squamous thyroid cancer cell line

et al. 2022

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Squamous and anaplastic thyroid cancers are the most aggressive and life‐threatening cancer types in humans, with the involvement of lymph nodes in 59% of cases and distant metastases in 26% of cases of all thyroid cancers. The median survival of squamous thyroid cancer patients is < 8 months and therefore is of high clinical concern. Here, we show that both VEGFC and VEGFR2/KDR are overexpressed in thyroid cancers, indicating that VEGF/VEGFR signaling plays a carcinogenic role in thyroid cancer development. Using CRISPR/Cas9, we established a KDR knockout (KO) SW579 squamous thyroid cancer cell line that exhibited dramatically decreased colony formation and invasion abilities (30% and 60% reduction, respectively) when compared to scrambled control cells. To validate the potential of KDR as a therapeutic target for thyroid cancers, we used the KDR RTK inhibitor sunitinib. Protein analysis and live/dead assay were performed to demonstrate that sunitinib significantly inhibited cell growth signal transduction and induced cell apoptosis of SW579 cells. These results suggest that selective targeting of KDR may have potential for development into novel anti‐cancer therapies to suppress VEGF/VEGFR‐mediated cancer development in patients with clinical advanced thyroid cancer.

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Autocrine VEGF-VEGFR2—Neuropilin-1 signaling promotes glioma stem-like cell viability and tumor growth

Cited by 68 publications

References 1 publication

VEGF drives cancer-initiating stem cells through VEGFR-2/Stat3 signaling to upregulate Myc and Sox2

VEGF drives cancer-initiating stem cells through VEGFR-2/Stat3 signaling to upregulate Myc and Sox2

Gab1 regulates proliferation and migration through the PI3K/Akt signaling pathway in intrahepatic cholangiocarcinoma

CRISPR‐mediated knockout of VEGFR2/KDR inhibits cell growth in a squamous thyroid cancer cell line

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