Expression and prognostic significance of angiopoietin in colorectal carcinoma

Chung, Yi‐Chang; Hou, Yung-Chi; Chang, Ching-Nien; Hseu, Tzong-Hsiung

doi:10.1002/jso.20423

Cited by 38 publications

(35 citation statements)

References 35 publications

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“…Patients with high Ang-2 had 10 times the risk of recurrence compared with those with low Ang-2 expression [hazard ratio (HR), 10.18]. This is in accordance with former findings indicating that high Ang-2 expression is associated with adverse prognosis in several tumors (11,31,32). The prognostic significance of Ang-2 was not so obvious in muscle invasive bladder cancer.…”

Section: Discussionsupporting

confidence: 86%

Angiogenic Switch of Angiopietins-Tie2 System and Its Prognostic Value in Bladder Cancer

Szarvas

Jäger

Tötsch³

et al. 2008

Clinical Cancer Research

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Purpose: Vascular endothelial growth factor (VEGF), angiopoietins (Ang-1and Ang-2), and their receptor Tie2 are critically involved in both normal and pathologic angiogenesis. The aim of this study was to explore the role of Ang-1, Ang-2,VEGF, andTie2 in the development and progression of bladder cancer as well as to examine their prognostic value in this tumor type. Experimental Design:Tumor samples of 113 bladder cancer patients, normal bladder epithelium of 5 noncancer patients, and two low-grade (UMUC3 and RT4) and two high-grade (J82 and T24) bladder cancer cell lines were analyzed by quantitative real-time PCR. The expression data were analyzed performing Wilcoxon rank-sum and Kaplan-Meier log-rank tests as well as univariate Cox analyses and Cox proportional hazards regression model. Results: In tissues of noninvasive bladder tumors, Ang-1 expression was significantly lower (P < 0.001), whereasVEGF expression was significantly higher (P = 0.031) than in normal bladder tissue. These findings were also confirmed at the protein level by immunohistochemistry. In contrast, Tie2 and Ang-2 abundance in tumor did not differ significantly from that in normal bladder tissue. Multivariate analysis identified Ang-2 as a strong and independent predictor of tumor recurrence [hazard ratio (HR), 10.18; 95% confidence interval (95% CI), 2.69-38.49; P < 0.001] andTie2 expression as an independent favorable prognostic factor for both metastasis (HR, 0.31; 95% CI, 0.11-0.89; P = 0.029) and disease-specific survival (HR, 0.25; 95% CI, 0.10-0.62; P = 0.003). Conclusions: These data show the strongest change in expression of VEGF and Ang-1 in superficial bladder cancer in comparison with normal bladder epithelium and the invasive tumor stages. The prognostic significance of Ang-2 and Tie2 underlines the essential role of angiopoietins-Tie2 system in progression of bladder cancer.

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Section: Discussionsupporting

confidence: 86%

Angiogenic Switch of Angiopietins-Tie2 System and Its Prognostic Value in Bladder Cancer

Szarvas

Jäger

Tötsch³

et al. 2008

Clinical Cancer Research

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“…Ang2 overexpression in many cancers correlates with poor survival and more invasive cancers (3,7). No clear correlation was found between Ang1 expression and prognosis in several solid tumors, such as colorectal carcinoma (8), bladder cancer (9), or non-small-cell lung cancer (NSCLC; ref. 10).…”

Section: Introductionmentioning

confidence: 99%

Specifically Targeting Angiopoietin-2 Inhibits Angiogenesis, Tie2-Expressing Monocyte Infiltration, and Tumor Growth

Huang

Lai²,

Do³

et al. 2011

Clinical Cancer Research

132

123

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Purpose: Angiopoietin-1 (Ang1) plays a key role in maintaining stable vasculature, whereas in a tumor Ang2 antagonizes Ang1's function and promotes the initiation of the angiogenic switch. Specifically targeting Ang2 is a promising anticancer strategy. Here we describe the development and characterization of a new class of biotherapeutics referred to as CovX-Bodies, which are created by chemical fusion of a peptide and a carrier antibody scaffold.Experimental Design: Various linker tethering sites on peptides were examined for their effect on CovXBody in vitro potency and pharmacokinetics. Ang2 CovX-Bodies with low nmol/L IC 50 s and significantly improved pharmacokinetics were tested in tumor xenograft studies alone or in combination with standard of care agents. Tumor samples were analyzed for target engagement, via Ang2 protein level, CD31-positive tumor vasculature, and Tie2 expressing monocyte penetration.Results: Bivalent Ang2 CovX-Bodies selectively block the Ang2-Tie2 interaction (IC 50 < 1 nmol/L) with dramatically improved pharmacokinetics (T ½ > 100 hours). Using a staged Colo-205 xenograft model, significant tumor growth inhibition (TGI) was observed (40%-63%, P < 0.01). Ang2 protein levels were reduced by approximately 50% inside tumors (P < 0.01), whereas tumor microvessel density (P < 0.01) and intratumor proangiogenic Tie2 CD11bþ cells (P < 0.05) were significantly reduced. When combined with sunitinib, sorafenib, bevacizumab, irinotecan, or docetaxel, Ang2 CovX-Bodies produced even greater efficacy ($80% TGI, P < 0.01). Conclusion: CovX-Bodies provide an elegant solution to overcome the pharmacokinetic-pharmacodynamic problems of peptides. Long-acting Ang2 specific CovX-Bodies will be useful as single agents and in combination with standard-of-care agents.

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“…Malignant cells transverse such limitations by accumulating mutations that stoke angiogenic response or by sequestrating circulating growth inhibitors (2). Intratumoral microvascular density is now recognized as an important and independent prognostic marker for metastasis and overall survival in patients with breast, cervical, colon, lung, renal, ovarian, and esophageal carcinomas (3)(4)(5)(6)(7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Angiopoietin: A TIE(d) Balance in Tumor Angiogenesis

Shim

Wong

2007

Molecular Cancer Research

152

111

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Angiopoietins (ANG-1 and ANG-2) and their TIE-2 receptor tyrosine kinase have wide-ranging effects on tumor malignancy that includes angiogenesis, inflammation, and vascular extravasation. These multifaceted pathways present a valuable opportunity in developing novel inhibition strategies for cancer treatment. However, the regulatory role of ANG-1 and ANG-2 in tumor angiogenesis remains controversial. There is a complex interplay between complementary yet conflicting roles of both the ANGs in shaping the outcome of angiogenesis. Embryonic vascular development suggests that ANG-1 is crucial in engaging interaction between endothelial and perivascular cells. However, recruitment of perivascular cells by ANG-1 has recently been implicated in its antiangiogenic effect on tumor growth. It is becoming clear that TIE-2 signaling may function in a paracrine and autocrine manner directly on tumor cells because the receptor has been increasingly found in tumor cells. In addition, A 5 B 1 and A v B 5 integrins were recently recognized as functional receptors for ANG-1 and ANG-2. Therefore, both the ligands may have wide-ranging functions in cellular activities that affect overall tumor development. Collectively, these TIE-2 -dependent and TIE-2 -independent activities may account for the conflicting findings of ANG-1 and ANG-2 in tumor angiogenesis. These uncertainties have impeded development of a clear strategy to target this important angiogenic pathway. A better understanding of the molecular basis of ANG-1 and ANG-2 activity in the pathophysiologic regulation of angiogenesis may set the stage for novel therapy targeting this pathway. (Mol Cancer Res 2007;5(7):655 -65)

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Expression and prognostic significance of angiopoietin in colorectal carcinoma

Abstract: The Ang-1 expression correlated with MVD. However, Ang-2 expression was a useful prognostic marker in the management of patients with advanced colorectal carcinoma.

Cited by 38 publications

References 35 publications

Angiogenic Switch of Angiopietins-Tie2 System and Its Prognostic Value in Bladder Cancer

Angiogenic Switch of Angiopietins-Tie2 System and Its Prognostic Value in Bladder Cancer

Specifically Targeting Angiopoietin-2 Inhibits Angiogenesis, Tie2-Expressing Monocyte Infiltration, and Tumor Growth

Angiopoietin: A TIE(d) Balance in Tumor Angiogenesis

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