Endostar, a Recombined Humanized Endostatin, Inhibits Lymphangiogenesis and Lymphatic Metastasis of Lewis Lung Carcinoma Xenograft in Mice

Dong, Xiaopeng; Zhao, Xiaoting; Xiao, Tian-Hui; Huang, Tian; Yun, Chae Ok

doi:10.1055/s-0030-1250152

Cited by 12 publications

(9 citation statements)

References 26 publications

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“…In addition, this hypothesis is also supported by our previous studies demonstrating that delivery of exogenous TGF-␤1 to tail wounds markedly delays lymphatic repair and worsens tail edema (11). For example, endostatin treatment has been shown to decrease lung tumor metastasis in mice (13), decrease lymph node metastasis (15), and decrease lymphangiogenesis (8,28). More importantly, we found that the expression of anti-lymphangiogenic cytokines was markedly increased in the distal tail tissues harvested from wild-type animals compared with that of nude animals.…”

Section: Discussionsupporting

confidence: 58%

Lymphatic function is regulated by a coordinated expression of lymphangiogenic and anti-lymphangiogenic cytokines

Zampell

Avraham

Yoder

et al. 2012

American Journal of Physiology-Cell Physiology

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Lymphangiogenic cytokines such as vascular endothelial growth factor-C (VEGF-C) are critically required for lymphatic regeneration; however, in some circumstances, lymphatic function is impaired despite normal or elevated levels of these cytokines. The recent identification of anti-lymphangiogenic molecules such as interferon-γ (IFN-γ), transforming growth factor-β1, and endostatin has led us to hypothesize that impaired lymphatic function may represent a dysregulated balance in the expression of pro/anti-lymphangiogenic stimuli. We observed that nude mice have significantly improved lymphatic function compared with wild-type mice in a tail model of lymphedema. We show that gradients of lymphatic fluid stasis regulate the expression of lymphangiogenic cytokines (VEGF-A, VEGF-C, and hepatocyte growth factor) and that paradoxically the expression of these molecules is increased in wild-type mice. More importantly, we show that as a consequence of T-cell-mediated inflammation, these same gradients also regulate expression patterns of anti-lymphangiogenic molecules corresponding temporally and spatially with impaired lymphatic function in wild-type mice. We show that neutralization of IFN-γ significantly increases inflammatory lymph node lymphangiogenesis independently of changes in VEGF-A or VEGF-C expression, suggesting that alterations in the balance of pro- and anti-lymphangiogenic cytokine expression can regulate lymphatic vessel formation. In conclusion, we show that gradients of lymphatic fluid stasis regulate not only the expression of pro-lymphangiogenic cytokines but also potent suppressors of lymphangiogenesis as a consequence of T-cell inflammation and that modulation of the balance between these stimuli can regulate lymphatic function.

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Section: Discussionsupporting

confidence: 58%

Lymphatic function is regulated by a coordinated expression of lymphangiogenic and anti-lymphangiogenic cytokines

Zampell

Avraham

Yoder

et al. 2012

American Journal of Physiology-Cell Physiology

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“…Researchers have focused on hot-spots of treating carcinoma by inhibition or destroying of tumor lymphatic tube formation early, i.e., lymphangiogenesis (9,10,18). These lymphangiogenic inhibitors such as deguelin, endostar, silencing Id-1, liposomal honokiol, mF4-31C1, Ki23057, sVEGFR3-Ig, VEGFR31-Ig, artemisinin, etodolac, MMI270, CSDA and AZM475271 have been reported as adjuvant anti-lymphangiogenic and anti-tumor drugs against some metastatic cancers in experimental and in clinical setting (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37). NCTD has been reported to possess potent anti-angiogenesis and antitumor properties in several cell lines and tumor models (11)(12)(13)(14)(15)(16)(38)(39)(40)(41).…”

Section: Discussionmentioning

confidence: 99%

Suppression of lymphangiogenesis in human lymphatic endothelial cells by simultaneously blocking VEGF-C and VEGF-D/VEGFR-3 with norcantharidin

Liu¹,

Qiu²,

Yuan³

et al. 2012

International Journal of Oncology

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Lymph node metastasis of tumors is a crucial early step in the metastatic process. Tumor lymphangiogenesis plays an important role in promoting tumor metastasis to regional lymph nodes. Norcantharidin (NCTD) has been reported to possess potent anti-angiogenesis and antitumor properties in several cell lines and xenograft tumor models. However, its role in tumor-associated lymphangiogenesis and lymphatic metastasis remains unclear. Here, we investigated the effect of NCTD on proliferation, apoptosis, migration, invasion and the lymphatic tube formation, lymphangiogenesis, of human lymphatic endothelial cells (HLECs) in vitro by MTT, proliferation assay, Hoechst staining and flow cytometry, scraping line method, Matrigel invasion assay, inverted or fluorescence microscope and transmission electron microscope. Moreover, the underlying mechanisms, such as VEGF-C, VEGF-D, VEGFR-3 at protein and mRNA levels in lymphangiogenesis using 3-dimensional (3-D) culture of HLECs were measured by immunohistochemistry, western blotting and real-time polymerase chain reaction (RT-PCR). It was shown that NCTD inhibited proliferation, migration, invasion and lymphatic tube formation (forming-lymphatic and/or formed-lymphatic) of HLECs, induced HLEC apoptosis (all P<0.01) significantly, in a dose- and time-dependent manner (IC50 6.8 µg/ml); and downregulated the expression of VEGF-C, VEGF-D and VEGFR-3 at protein or/and mRNA levels (P<0.01) in HLEC lymphatic tube formation. Thus, we identified for the first time that NCTD inhibited HLEC lymphangiogenesis by simultaneously blocking VEGF-C and VEGF-D/VEGFR-3 in vitro. The present findings may be of importance to explore the therapeutical target or strategy of NCTD for tumor lymphangiogenesis and lymphatic metastasis.

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“…Investigators have previously reported that endostatin exerts antiangiogenic effects by blocking vascular endothelial growth factor (VEGF)-induced tyrosine phosphorylation of KDR/Flk-1 of endothelial cells (21). Dong et al (22) and Brideau et al (23) found that endostatin inhibits lymphangiogenesis by downregulating the tumor expression of VEGF-C. By contrast, the osteopontin-related mechanism may be mediated in endostatin antitumor activity (24). These data indicate that endostatin remains to be adequately elucidated.…”

Section: Discussionmentioning

confidence: 99%

Clinical significance of serum and tumor tissue endostatin evaluation in operable non-small cell lung cancer

Zhang

et al. 2014

Biomedical Reports

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Abstract. Endostatin, as the most potential antiangiogenic factor, is a naturally occurring fragment of collagen XVIII in bloodstream capable of inhibiting tumor growth and metastasis. This study was conducted to explore the clinical value of endostatin in serum and tumor tissue in patients with operable non-small cell lung cancer (NSCLC). ELISA and immunohistochemistry were applied to detect the expression of endostatin in serum and tumor tissue in 105 patient-matched operable NSCLC patients. The serum level of endostatin was significantly higher in NSCLC patients than healthy individuals (P=0.0018). Cases with poorer differentiation showed a higher endostatin serum level (P=0.008). There was no significant correlation between tumor tissue expression and clinical parameters, such as TNM stage, differentiation degree, histological type and lymph node invasion status. A stronger expression of endostain in tumor tissue was associated with a higher serum level (r=0.223). The univariate and multivariate analyses with Cox proportional hazards model for overall survival showed that tumor stage and node status were independent prognostic factors, whereas neither endostatin levels in serum nor in tumor tissue showed potential in predicting the long-term survival of operable NSCLC patients. In conclusion, the results observed in the present study did not support the prediction of overall survival in operable NSCLC based on the expression levels of endostatin in serum and tumor tissue.

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Endostar, a Recombined Humanized Endostatin, Inhibits Lymphangiogenesis and Lymphatic Metastasis of Lewis Lung Carcinoma Xenograft in Mice

Abstract: Endostar significantly inhibits the lymphatic tumor growth, lymphangiogenesis and lymphatic metastasis of Lewis lung carcinoma xenografts, and its inhibitory effect is due to its ability to partially regulate the tumor expression of VEGF-C.

Cited by 12 publications

References 26 publications

Lymphatic function is regulated by a coordinated expression of lymphangiogenic and anti-lymphangiogenic cytokines

Lymphatic function is regulated by a coordinated expression of lymphangiogenic and anti-lymphangiogenic cytokines

Suppression of lymphangiogenesis in human lymphatic endothelial cells by simultaneously blocking VEGF-C and VEGF-D/VEGFR-3 with norcantharidin

Clinical significance of serum and tumor tissue endostatin evaluation in operable non-small cell lung cancer

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