C‐X‐C motif chemokine receptor 4 promotes tumor angiogenesis in gastric cancer via activation of JAK2/STAT3

Zhang, Qing; Xu, Feng; Shi, Yi; Chen, Yiwen; Wang, Haiping; Yu, Xue-Zhong; Li, Yong

doi:10.1002/cbin.10794

Cited by 12 publications

(8 citation statements)

References 30 publications

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“…In addition, gefitinib obviously inhibited the phosphorylation of ERK1/2 and STAT3 in H3255 xenograft model. Previous results showed that STAT3 could be activated by EGFR to participate in oncogenesis and was simultaneously involved in angiogenesis, especially the expression of VEGF‐A . In our study, gefitinib also inhibited the expression VEGF‐A in H3255 xenograft model.…”

Section: Discussionsupporting

confidence: 72%

CM082, a novel angiogenesis inhibitor, enhances the antitumor activity of gefitinib on epidermal growth factor receptor mutant non‐small cell lung cancer in vitro and in vivo

et al. 2020

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Background: CM082 is a novel angiogenesis inhibitor targeting vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR). The purpose of this research was to evaluate the antitumor activity of CM082 combined with gefitinib on epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) in vitro and in vivo. Methods: The effect of CM082 on human umbilical vein endothelial cells (HUVECs) was assessed. In vitro and in vivo efficacy of CM082 combined with gefitinib on EGFR NSCLC cell lines (HCC827 harboring E746_A750 deletion and H3255 harboring L858R) and a xenograft model was evaluated. Results: CM082 inhibited VEGF-induced cell growth, phosphorylation of VEGFR and downstream signaling molecules, tube formation, and cell migration of HUVECs. Furthermore, CM082 combined with gefitinib was more effective in inhibiting growth and colony formation and inducing apoptosis of H3255 and HCC827 cells in vitro than monotherapy. Moreover, tumor growth inhibition by the combination in a H3255 xenograft model was 107.7% more than that by gefitinib (93.6%) (P < 0.0001) and CM082 (51.4%) (P < 0.0001) alone. In addition, coadministration had a better effect on inhibiting cell proliferation, inducing apoptosis, and inhibiting the expression of CD31 and VEGF-A. The combination therapy had a stronger inhibition effect on STAT3 phosphorylation than monotherapy. Conclusions: CM082, a novel angiogenesis inhibitor, enhances the antitumor activity of gefitinib on EGFR mutant NSCLC by inhibiting proliferation and angiogenesis and promoting apoptosis of tumor cells.

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Section: Discussionsupporting

confidence: 72%

CM082, a novel angiogenesis inhibitor, enhances the antitumor activity of gefitinib on epidermal growth factor receptor mutant non‐small cell lung cancer in vitro and in vivo

et al. 2020

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“…To further elucidate the mechanism underlying these phenomenons, SystemsDock (http:// systemsdock.unit.oist.jp/), a web server for network pharmacology-based prediction and analysis was applied [20]. Emerging evidence has suggested that the JAK2/STAT3 pathway participates in the regulation of angiogenesis [26], and blockade of the JAK2/STAT3 pathway could inhibit tumor growth. To explore whether JAK2/STAT3 signaling pathway is the therapeutic targets of ORI, we applied SystemsDock.…”

Section: Discussionmentioning

confidence: 99%

Oridonin inhibits tumor angiogenesis and induces vessel normalization in experimental colon cancer

Zhou¹,

Li²,

Shi³

et al. 2021

J. Cancer

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Purpose: Tumor blood vessels exhibit morphological and functional aberrancies. Its maturity and functionality are closely associated with colon cancer progression and therapeutic efficacy. The direct evidence proving whether oridonin (ORI) has vascular normalization promoting effect from which combination therapies will benefit is still lacking. Methods: We established a subcutaneous xenograft model of human colon cancer. The animals were divided into the Control and ORI-treated groups. Immunohistochemical analysis and TUNEL staining was applied to evaluate the proliferation, apoptosis and angiogenesis. Western blot analysis was employed to characterize the angiogenesis-related factors and JAK2/STAT3 signaling. Then, vascular normalization and macrophage reprogramming were assessed by immunofluorescence analysis. Results: The results showed that ORI obviously reduced tumor growth, diminished the numbers of Ki67 + cells and CD31 + microvessel density, while increased the numbers of TUNEL + cells. The expression levels of VEGF and bFGF proteins were dramatically down-regulated while the angiostatin and endostatin levels were increased in the ORI-treated group. Moreover, ORI therapy remarkably promoted the pericyte coverage of tumor vessels from days 5 to 10, with the highest pericyte coverage rate occurred at day 7. In the time window of vascular normalization, hypoxia of the tumor microenvironment was improved by ORI, the expression of HIF-1a was downregulated. Moreover, CD206 + macrophage cells were diminished in the ORI-treated group. These anticancer effects of ORI maybe partly mediated by suppressing JAK2/STAT3 signaling pathway. Conclusions: These results highlight the potential effect of ORI on anti-angiogenesis and inducing vessel normalization roles of ORI, and probably provide optimum time point for the ORI therapy in conjunction with the chemoradiotherapy or immunotherapy.

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“…Chen et al [34] confirmed the role of JAK2/STAT3 pathway in mediating VEGF expression upon Ginkgolide K treatment after ischemic stroke. Zhang et al [35] demonstrated that C-X-C motif chemokine receptor 4 induced JAK2/STAT3 activation and enhanced STAT3 binding to VEGF promoter and then potentiated VEGF production in gastric cancer cells. Meanwhile, recent studies also revealed that autophagy directly regulats JAK2/STAT3 signaling pathway in lung cancer cells [19].…”

Section: Discussionmentioning

confidence: 99%

Autophagy inhibition potentiates the anti-angiogenic property of multikinase inhibitor anlotinib through JAK2/STAT3/VEGFA signaling in non-small cell lung cancer cells

Liang

Hui

et al. 2019

J Exp Clin Cancer Res

122

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BackgroundThe efficacy and safety of multikinase inhibitor anlotinib have been confirmed in the treatment of advanced non-small cell lung cancer (NSCLC). However, the direct functional mechanisms of tumor lethality mediated by anlotinib were not fully elucidated, and the underlying mechanisms related to resistance remain largely elusive.MethodsCell viability, colony formation, apoptosis and tumor growth assays were performed to examine the effect of anlotinib on lung cancer cells in vitro and in vivo. The punctate patterns of LC3-I/II were detected by confocal microscopy. HUVECs motility was detected using Transwell and scratch wound-healing assay. To visualize the microvessels, tubular formation assay was performed. The expression of LC3-I/II and beclin-1 and the changes of JAK2/STAT3/VEGFA pathway were detected by western blotting. The VEGFA levels in tumor supernatant were measured by ELISA.ResultsAnlotinib treatment decreased cell viability and induced apoptosis in Calu-1 and A549 cells. Moreover, anlotinib induced human lung cancer cell autophagy in a dose- and time-dependent manner. Blocking autophagy enhanced the cytotoxicity and anti-angiogenic ability of anlotinib as evidenced by HUVECs migration, invasion, and tubular formation assay. Co-administration of anlotinib and chloroquine (CQ) further reduced VEGFA level in the tumor supernatant, compared with that of anlotinib or CQ treatment alone. When autophagy was induced by rapamycin, the JAK2/STAT3 pathway was activated and VEGFA was elevated, which was attenuated after deactivating STAT3 by S3I-201. Further in vivo studies showed that anlotinib inhibited tumor growth, induced autophagy and suppressed JAK2/STAT3/VEGFA pathway, and CQ enhanced this effect.ConclusionAnlotinib induced apoptosis and protective autophagy in human lung cancer cell lines. Autophagy inhibition further enhanced the cytotoxic effects of anlotinib, and potentiated the anti-angiogenic property of anlotinib through JAK2/STAT3/VEGFA signaling.

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C‐X‐C motif chemokine receptor 4 promotes tumor angiogenesis in gastric cancer via activation of JAK2/STAT3

Cited by 12 publications

References 30 publications

CM082, a novel angiogenesis inhibitor, enhances the antitumor activity of gefitinib on epidermal growth factor receptor mutant non‐small cell lung cancer in vitro and in vivo

CM082, a novel angiogenesis inhibitor, enhances the antitumor activity of gefitinib on epidermal growth factor receptor mutant non‐small cell lung cancer in vitro and in vivo

Oridonin inhibits tumor angiogenesis and induces vessel normalization in experimental colon cancer

Autophagy inhibition potentiates the anti-angiogenic property of multikinase inhibitor anlotinib through JAK2/STAT3/VEGFA signaling in non-small cell lung cancer cells

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