Interaction of endostatin with integrins implicated in angiogenesis

Rehn, Marko; Veikkola, Tanja; Kukk-Valdre, Eola; Nakamura, Hitoshi; Ilmonen, Maritta; Lombardo, Christian R.; Pihlajaniemi, Taina; Alitalo, Kari; Vuori, Kristiina

doi:10.1073/pnas.98.3.1024

Cited by 372 publications

(211 citation statements)

References 48 publications

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“…This has been demonstrated for endostatin (Rehn et al, 2001), angiostatin (Tarui et al, 2001), thrombospondin-1 (for a review, see Bornstein, 2001) and tumstatin (Maeshima et al, 2000). Indeed, when molecules such as angiostatin Mauceri et al, 1998), endostatin (Hanna et al, 2000) or neutralising anti-human VEGF 165 antibodies (Gorski et al, 1999;Lee et al, 2000) are administered together with ionising radiation, the cytotoxic effects of the latter upon endothelial cells are potentiated in vivo, resulting in an enhanced antitumoral effect.…”

Section: Discussionmentioning

confidence: 73%

Correlation between the tumoral expression of β3-integrin and outcome in cervical cancer patients who had undergone radiotherapy

et al. 2004

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Integrins are cell-surface receptors, which mediate cell-to-cell and cell-to-extracellular matrix adhesion. Besides playing an important role in tumour angiogenesis, b3-integrin is also expressed in several types of epithelial cancer cells. It was the purpose of the present study to evaluate the prognostic value of b3-integrin expression in patients with cervical cancer. Biopsies were taken from 82 patients with squamous cell or adenocarcinomas of the uterine cervix who had undergone external-beam radiotherapy with or without brachytherapy. These tissue samples were analysed immunohistochemically for the expression of b3-integrin. The impact of immunoreactivity for b3-integrin on survival end points was assessed by univariate and multivariate analyses, and its correlation with clinicopathological characteristics evaluated by crosstabulations. b3-integrin was expressed in 61% (50 of 82) of the patients. KaplanMeier curves revealed local progression-free survival, distant metastasis-free survival and cause-specific survival to be significantly shorter (P-values according to the log-rank test: 0.002, 0.04 and 0.01, respectively) in patients with b3-integrin expression. The prognostic impact of this parameter was even higher than for other well-known prognostic parameters and remained statistically significant in the multivariate analyses. b3-integrin, which is expressed in the majority of patients with advanced cervical cancer, has a significant prognostic impact on outcome according to univariate and multivariate analyses.

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Section: Discussionmentioning

confidence: 73%

Correlation between the tumoral expression of β3-integrin and outcome in cervical cancer patients who had undergone radiotherapy

et al. 2004

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“…Both endostatin and thrombospondin-1 present proapoptotic activity when present in soluble form, but support EC adhesion and survival when immobilized. [38][39][40] Figure 5 ISM interacts with AACs in mitochondria and blocks ATP transport from mitochondria to cytosol. (a) rISM co-IP with AACs in mitochondrial fraction of HUVECs.…”

Section: Discussionmentioning

confidence: 99%

Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction

Zhang

et al. 2014

Cell Death Differ

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Isthmin (ISM) is a secreted 60-kDa protein that potently induces endothelial cell (EC) apoptosis. It suppresses tumor growth and angiogenesis in mice when stably overexpressed in cancer cells. Although avb5 integrin serves as a low-affinity receptor for ISM, the mechanism by which ISM mediates antiangiogenesis and apoptosis in ECs remain to be fully resolved. In this work, we report the identification of cell-surface glucose-regulated protein 78 kDa (GRP78) as a high-affinity receptor for ISM (K d ¼ 8.6 nM). We demonstrated that ISM-GRP78 interaction triggers apoptosis not only in activated ECs but also in cancer cells expressing high level of cell-surface GRP78. Normal cells and benign tumor cells tend to express low level of cell-surface GRP78 and are resistant to ISM-induced apoptosis. Upon binding to GRP78, ISM is internalized into ECs through clathrin-dependent endocytosis that is essential for its proapoptotic activity. Once inside the cell, ISM co-targets with GRP78 to mitochondria where it interacts with ADP/ATP carriers on the inner membrane and blocks ATP transport from mitochondria to cytosol, thereby causing apoptosis. Hence, ISM is a novel proapoptotic ligand that targets cell-surface GRP78 to trigger apoptosis by inducing mitochondrial dysfunction. The restricted and high-level expression of cell-surface GRP78 on cancer cells and cancer ECs make them uniquely susceptible to ISM-targeted apoptosis. Indeed, systemic delivery of recombinant ISM potently suppressed subcutaneous 4T1 breast carcinoma and B16 melanoma growth in mice by eliciting apoptosis selectively in the cancer cells and cancer ECs. Together, this work reveals a novel ISM-GRP78 apoptosis pathway and demonstrates the potential of ISM as a cancer-specific and dual-targeting anticancer agent.

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“…Recent evidences suggested that endostatin/ C18 may promote, instead of abolish, angiogenic processes. [29][30][31] Free, soluble endostatin was demonstrated to inhibit angiogenesis, whereas immobilized form of endostatin supports the survival and migration of endothelial cells. 29,30 Besides, studies on C18-null mice indicated that C18 is essential for angiogenesis in the eyes.…”

Section: Discussionmentioning

confidence: 99%

“…[29][30][31] Free, soluble endostatin was demonstrated to inhibit angiogenesis, whereas immobilized form of endostatin supports the survival and migration of endothelial cells. 29,30 Besides, studies on C18-null mice indicated that C18 is essential for angiogenesis in the eyes. 31 Given the complexity of endostatin production and function, future studies are warranted to delineate the mechanism underlying endostatin/C18 upregulation during HCC progression.…”

Section: Discussionmentioning

confidence: 99%

Increased endostatin/collagen XVIII expression correlates with elevated VEGF level and poor prognosis in hepatocellular carcinoma

Huang

et al. 2005

Modern Pathology

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Liver is the primary source for collagen XVIII, the precursor of angiogenesis inhibitor, endostatin. However, the role of endostatin/collagen XVIII expression during liver carcinogenesis remains elusive. Therefore, we studied its expression in five hepatoma cell lines and 105 hepatocellular carcinoma specimens. The poorly differentiated hepatoma cell lines exhibited increased endostatin/collagen XVIII levels compared with the well-differentiated ones. In hepatoma tissues, endostatin/collagen XVIII expression was detected in various types of liver cells and was significantly stronger in adjacent nontumor tissues than that in tumors (Po0.001). Endostatin/collagen XVIII expression in nontumor tissues correlated with tumor stages (P ¼ 0.014) and expression of vascular endothelial growth factor (P ¼ 0.007), but not the stages of hepatic fibrosis (P40.05). Kaplan-Meier analysis showed that patients with higher endostatin/collagen XVIII expression had significantly shorter overall survival (P ¼ 0.011) and disease-free survival (P ¼ 0.0034). Moreover, endostatin/collagen XVIII level was an independent prognostic factor for tumor recurrence (P ¼ 0.034) by multivariate analysis. In conclusion, increased endostatin/collagen XVIII expression correlated with hepatoma progression and predicted poor prognosis for patients with hepatocellular carcinoma.

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Interaction of endostatin with integrins implicated in angiogenesis

Cited by 372 publications

References 48 publications

Correlation between the tumoral expression of β3-integrin and outcome in cervical cancer patients who had undergone radiotherapy

Correlation between the tumoral expression of β3-integrin and outcome in cervical cancer patients who had undergone radiotherapy

Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction

Increased endostatin/collagen XVIII expression correlates with elevated VEGF level and poor prognosis in hepatocellular carcinoma

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