Clinical significance of angiopoietin-2 expression at the deepest invasive tumor site of advanced colorectal carcinoma

Ochiumi, Takehiko; Tanaka, Shinji; Oka, Shiro; Hiyama, Toru; Ito, Masanori; Kitadai, Yasuhiko; Haruma, Ken; Chayama, Kazuaki

doi:10.3892/ijo.24.3.539

Cited by 34 publications

(45 citation statements)

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“…The Ang-2 knockout perinatal mouse showed defects in the overall organization of their lymphatic vasculature, and Ang-2 was thought to relate to lymphatic vessel formation or lymphangiogenesis (20). A correlation between lymph node involvement and Ang-2 expression was found in colon and breast carcinomas (21,22), but is controversial (23). VEGF and/or VEGF-C expression was reported to be present in tumors overexpressing Ang-2 (22).…”

Section: Discussionmentioning

confidence: 98%

Lymphatic microvessel density using D2-40 is associated with nodal metastasis in non-small cell lung cancer

Takanami

2006

Oncol Rep

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Abstract. The monoclonal antibody D2-40 is a new selective marker for lymphatic endothelium. The lymphatic microvessel density (LMVD) using D2-40 has not yet been evaluated in non-small cell lung cancer (NSCLC). The aim of this study was to evaluate LMVD using D2-40 in NSCLC. We investigated LMVD in 77 patients with NSCLC who underwent curative tumor resection. We also determined the relation between LMVD and clinicopathologic factors, VEGF-C and Ang-2 and microvessel density (MVD) using factor VIII-related antigen. The median number of D2-40-positive vessels in the highest LMVD was 25 (range, 5-71). LMVD was significantly associated with tumor status, lymph node metastasis, stage, lymphatic invasion, VEGF-C protein and MVD (p=0.0149 for tumor status; p<0.0001 for nodal status; p<0.0001 for stage; p=0.0153 for lymphatic invasion; p=0.0030 for VEGF-C, and p=0.0029 for MVD). Furthermore, LMVD using D2-40 expression was shown to be an independent predictor of lymph node metastasis by multivariate analysis (p=0.0070). These data indicate that a high LMVD by D2-40 may be an indicator of lymph node metastasis in NSCLC.

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Section: Discussionmentioning

confidence: 98%

Lymphatic microvessel density using D2-40 is associated with nodal metastasis in non-small cell lung cancer

Takanami

2006

Oncol Rep

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“…Ang2 plays a complementary role to VEGF in the tumor angiogenesis (35,36). The increased expression of both VEGF and Ang2 has also been shown to correlate with poor survival (37). In human tumor xenograft studies in mice, the physical combination of VEGF and Ang2 antagonists showed enhanced efficacy relative to the use of either single agent (38,39).…”

Section: Discussionmentioning

confidence: 99%

Chemical generation of bispecific antibodies

Doppalapudi

Huang

Liu

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

114

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Bispecific antibodies (BsAbs) are regarded as promising therapeutic agents due to their ability to simultaneously bind two different antigens. Several bispecific modalities have been developed, but their utility is limited due to problems with stability and manufacturing complexity. Here we report a versatile technology, based on a scaffold antibody and pharmacophore peptide heterodimers, that enables rapid generation and chemical optimization of bispecific antibodies, which are termed bispecific CovX-Bodies. Two different peptides are joined together using a branched azetidinone linker and fused to the scaffold antibody under mild conditions in a site-specific manner. Whereas the pharmacophores are responsible for functional activities, the antibody scaffold imparts long half-life and Ig-like distribution. The pharmacophores can be chemically optimized or replaced with other pharmacophores to generate optimized or unique bispecific antibodies. As a prototype, we developed a bispecific antibody that binds both vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang2) simultaneously, inhibits their function, shows efficacy in tumor xenograft studies, and greatly augments the antitumor effects of standard chemotherapy. This unique antiangiogenic bispecific antibody is in phase-1 clinical trials.

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“…Although Ang-2 has been shown to be highly expressed in a vast array of malignant tissues (16,17,(19)(20)(21)(22)(23)(24), the factors which control its up-regulation in cancer are not fully understood. Hypoxia results in increases in both Ang-1 and Ang-2 levels, but Ang-2 is elevated to a far greater extent (33)(34)(35)(36)(37).…”

Section: Discussionmentioning

confidence: 99%

“…Ang-2 also acts in concert with vascular endothelial growth factor (VEGF) to regulate vessel growth. In human cancers, increased expression of Ang-2 in tumor cells is closely correlated to the progression, invasiveness, and metastases of lung, gastric, colon, and breast cancers (16,17,(19)(20)(21)(22)(23)(24). Furthermore, gene transduction studies have shown that overexpression of Ang-2 by human tumor cells promotes tumor growth, angiogenesis, and metastases in animals (15,25,26).…”

Section: Introductionmentioning

confidence: 99%

Human Epidermal Growth Factor Receptor 2 Regulates Angiopoietin-2 Expression in Breast Cancer via AKT and Mitogen-Activated Protein Kinase Pathways

Niu

Carter

2007

Cancer Research

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Abnormal activation of human epidermal growth factor receptor 2 (HER2; ErbB-2) in breast tumors results in increased metastasis and angiogenesis, as well as reduced survival. Here, we show that angiopoietin-2 (Ang-2) expression correlates with HER2 activity in human breast cancer cell lines. Inhibiting HER2 activity with anti-HER2 monoclonal antibody trastuzumab (Herceptin) or HER2 short interfering RNA in tumor cells down-regulates Ang-2 expression. Consistent with the important roles of AKT and mitogen-activated protein kinase in the HER2 signaling pathway, AKT and ERK mitogen-activated protein kinase (MAPK) kinase activity is necessary for Ang-2 up-regulation by HER2. Moreover, overexpression of HER2 protein up-regulates Ang-2 expression. Heregulin-B1-induced Ang-2 up-regulation is abrogated when AKT and ERK kinase activity are blocked. Immunohistochemical analysis of HER2 and Ang-2 proteins in human breast carcinomas shows that Ang-2 expression in breast cancer correlates with HER2 expression. These studies provide evidence that the Ang-2 gene is regulated by HER2 activity in breast cancer, and propose an additional mechanism for HER2 contributing to tumor angiogenesis and metastasis.

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Clinical significance of angiopoietin-2 expression at the deepest invasive tumor site of advanced colorectal carcinoma

Cited by 34 publications

References 0 publications

Lymphatic microvessel density using D2-40 is associated with nodal metastasis in non-small cell lung cancer

Lymphatic microvessel density using D2-40 is associated with nodal metastasis in non-small cell lung cancer

Chemical generation of bispecific antibodies

Human Epidermal Growth Factor Receptor 2 Regulates Angiopoietin-2 Expression in Breast Cancer via AKT and Mitogen-Activated Protein Kinase Pathways

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