Endorepellin In Vivo: Targeting the Tumor Vasculature and Retarding Cancer Growth and Metabolism

Bix, Gregory; Castelló, Remedios; Burrows, Michelle; Zoeller, Jason J.; Weech, Michelle; Iozzo, Rex A.; Cardi, Christopher; Thakur, Mathew L.; Barker, Christopher A.; Camphausen, Kevin; Iozzo, Renato V.

doi:10.1093/jnci/djj441

Cited by 105 publications

(91 citation statements)

References 55 publications

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“…On the day tumors became visible, the mice were randomized into two groups, and one group received intraperitoneal injections of human recombinant endorepellin, whereas the other received vehicle (PBS) alone (20). Tumor sectioning and immunostains were performed as previously described (20).…”

Section: Syngeneic Tumor Xenografts and Quantification Of Tumor Angiomentioning

confidence: 99%

“…Endorepellin is a potent inhibitor in several angiogenesis assays such as endothelial cell migration, collagen-induced capillary morphogenesis, blood vessel recruitment into Matrigel plugs, and chicken chorioallontoic membrane (7,19). It also effectively retards in vivo tumor growth by specifically targeting tumor angiogenesis (20). We hypothesize that endorepellin takes effect via the LG3 domain binding to the integrin ␣2␤1 causing actin disassembly and therefore affecting three key steps of angiogenesis: endothelial cell adhesion, migration, and morphogenesis.…”

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confidence: 97%

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Integrin α2β1 Is the Required Receptor for Endorepellin Angiostatic Activity

Woodall

Nyström

Iozzo

et al. 2008

Journal of Biological Chemistry

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102

106

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Endorepellin, the C-terminal module of perlecan, has angiostatic activity. Here we provide definitive genetic and biochemical evidence that the functional endorepellin receptor is the ␣2␤1 integrin. Notably, the specific endorepellin binding to the receptor was cation-independent and was mediated by the ␣2 I domain. We show that the anti-angiogenic effects of endorepellin cannot occur in the absence of ␣2␤1. Microvascular endothelial cells from ␣2␤1 ؊/؊ mice, but not those isolated from either wild-type or ␣1␤1 ؊/؊ mice, did not respond to endorepellin. Moreover, syngeneic Lewis lung carcinoma xenografts in ␣2␤1 ؊/؊ mice failed to respond to systemic delivery of endorepellin. In contrast, endorepellin inhibited tumor growth and angiogenesis in the wild-type mice expressing integrin ␣2␤1. We conclude that the angiostatic effects of endorepellin in vivo are mediated by a specific interaction of endorepellin with the ␣2␤1 integrin receptor.The incorporation of new blood vessels into growing neoplasms is a prerequisite for tumor viability and progression. Accordingly, much attention has been invested in the search for and characterization of anti-angiogenic agents to enable regulated and inhibited tumor angiogenesis as part of cancer therapies (1). The proteoglycan perlecan plays a key role in the angiogenic process, primarily by modulating the availability and activity of growth factors involved in angiogenesis such as fibroblast growth factor 2, VEGF, 3 and platelet-derived growth factor (2-6). The most C-terminal part of perlecan (domain V), named endorepellin, is a powerful angiogenic inhibitor (7). Endorepellin carries three laminin-like globular (LG) domains separated by epidermal growth factor-like repeats (8) and binds to numerous extracellular matrix proteins, growth factors, and receptors including collagen XVIII, fibulin-2, nidogen, fibroblast growth factor 7, fibroblast growth factor-binding protein, ECM1 (7, 9 -12), ␣-dystroglycan, and integrin ␣2␤1 (9, 13-16). The endorepellin anti-angiogenic effect is parallel to several proteolytically released fragments from vascular basement membrane such as endostatin, the NC-1 domain of collagen type XVIII, and tumstatin, the NC-1 domain the of type IV collagen ␣3 chain (8,17,18). These fragments principally act on endothelial cells as "negative" ligands for specific integrin receptors. Endorepellin is a potent inhibitor in several angiogenesis assays such as endothelial cell migration, collagen-induced capillary morphogenesis, blood vessel recruitment into Matrigel plugs, and chicken chorioallontoic membrane (7,19). It also effectively retards in vivo tumor growth by specifically targeting tumor angiogenesis (20). We hypothesize that endorepellin takes effect via the LG3 domain binding to the integrin ␣2␤1 causing actin disassembly and therefore affecting three key steps of angiogenesis: endothelial cell adhesion, migration, and morphogenesis.Here we have further investigated the endorepellin-␣2␤1 integrin interactions by using cell-free experiments with a solub...

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Section: Syngeneic Tumor Xenografts and Quantification Of Tumor Angiomentioning

confidence: 99%

mentioning

confidence: 97%

Integrin α2β1 Is the Required Receptor for Endorepellin Angiostatic Activity

Woodall

Nyström

Iozzo

et al. 2008

Journal of Biological Chemistry

Self Cite

102

106

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“…In vivo studies have shown that endorepellin specifically targets the tumor vasculature and inhibits tumor angiogenesis (46). This bioactivity leads to inhibition of tumor growth without inducing apoptosis.…”

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confidence: 99%

Endorepellin-evoked Autophagy Contributes to Angiostasis

Goyal

Gubbiotti

Chery

et al. 2016

Journal of Biological Chemistry

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Endorepellin, the C-terminal domain of perlecan, is an angiostatic molecule that acts as a potent inducer of autophagy via its interaction with VEGFR2. In this study, we examined the effect of endorepellin on endothelial cells using atomic force microscopy. Soluble endorepellin caused morphological and biophysical changes such as an increase in cell surface roughness and cell height. Surprisingly, these changes were not accompanied by alterations in the endothelial cell elastic modulus. We discovered that endorepellin-induced autophagic flux led to co-localization of mammalian target of rapamycin with LC3-positive autophagosomes. Endorepellin functioned upstream of AMPactivated kinase ␣, as compound C, an inhibitor of AMP-activated kinase ␣, abrogated endorepellin-mediated activation and co-localization of Beclin 1 and LC3, thereby reducing autophagic progression. Functionally, we discovered that both endorepellin and Torin 1, a canonical autophagic inducer, blunted ex vivo angiogenesis. We conclude that autophagy is a novel mechanism by which endorepellin promotes angiostasis independent of nutrient deprivation.

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“…Methods: Using digital autoradiography of coinjected 18 F-labeled azomycin arabinoside ( 8 F-FAZA) (assessing regional hypoxia) and a glycosylated RGD-containing peptide ( 125 I-3-iodo-DTyr 4 -cyclo(-Arg-Gly-AspDTyr-Lys(SAA)-), or 125 I-Gluco-RGD) (assessing angiogenesis via binding to avb3 integrin receptors on endothelial cells) performed on 22 EMT6 tumor xenografts, we investigated the intratumoral spatial distribution of these tracers. We applied a Bayesian bivariate image analysis using the mean tumor-tomuscle ratio as a discriminator, resulting in 4 groups: FAZA high/RGD high (Q1), FAZA low/RGD high (Q2), FAZA low/RGD low (Q3), and FAZA high/RGD low (Q4).…”

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confidence: 99%

“…Indeed, when given in combination with chemotherapy, bevacizumab, an antibody targeted against the potent angiogenic vascular endothelial growth factor, significantly increased survival in colorectal cancer patients (2). However, destroying the vasculature should severely compromise oxygen delivery and reduce the delivery of therapeutics to the solid tumor, producing or enhancing hypoxia (3), which is well known to counteract the effects of many chemotherapeutics and radiation treatment (4). Indeed, some studies have demonstrated that antiangiogenic therapy may interrupt the delivery of chemotherapeutic drugs to tumors (5) and diminish the effects of radiation therapy (6).…”

mentioning

confidence: 99%

Intratumoral Spatial Distribution of Hypoxia and Angiogenesis Assessed by ¹⁸F-FAZA and ¹²⁵I-Gluco-RGD Autoradiography

Picchio¹,

Beck²,

Haubner³

et al. 2008

J Nucl Med

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The hypoxia-inducible factor-1a (HIF-1a) activates angiogenesis in response to cellular hypoxia, suggesting a spatial correlation between angiogenesis and tissue hypoxia. Methods: Using digital autoradiography of coinjected 18 F-labeled azomycin arabinoside ( 8 F-FAZA) (assessing regional hypoxia) and a glycosylated RGD-containing peptide ( 125 I-3-iodo-DTyr 4 -cyclo(-Arg-Gly-AspDTyr-Lys(SAA)-), or 125 I-Gluco-RGD) (assessing angiogenesis via binding to avb3 integrin receptors on endothelial cells) performed on 22 EMT6 tumor xenografts, we investigated the intratumoral spatial distribution of these tracers. We applied a Bayesian bivariate image analysis using the mean tumor-tomuscle ratio as a discriminator, resulting in 4 groups: FAZA high/RGD high (Q1), FAZA low/RGD high (Q2), FAZA low/RGD low (Q3), and FAZA high/RGD low (Q4). In an additional 18 xenografts, the immunohistochemically derived HIF-1a protein distribution was compared with 18 F-FAZA autoradiography. Animals were divided into groups breathing either room air or carbogen (95% oxygen, 5% CO 2 ) for 4 h until sacrifice. Results: Under room air conditions, roughly 60% of the tumor surface displayed a spatial coupling of 18 F-FAZA and 125 I-Gluco-RGD uptake: either high (Q1) or low (Q3) uptake for both tracers, with Q1 indicating spatial association of hypoxia and angiogenesis and Q3 indicating adequate oxygenation without active angiogenesis. However, the remaining approximately 40% of the tumor surface showed discordant 18 F-FAZA and 125 I-Gluco-RGD uptake, indicating that hypoxia and angiogenesis are not necessarily spatially linked to each other and highlighting substantial intratumoral heterogeneity of the 18 F-FAZA and 125 I-Gluco-RGD uptake. Although carbogen breathing conditions significantly decreased the mean 18 F-FAZA tumor-to-muscle ratio, no significant changes were observed for 125 I-Gluco-RGD, indicating that an acute increase in tumor oxygenation did not influence avb3 integrin receptor expression. The HIF-1a-positive (HIF pos ) tumor cell fraction was not significantly influenced by breathing conditions and covered between 0% and 35% of the total tumor section surface. However, the HIF pos tumor section surface was much smaller than the tumor section surface of increased 18 F-FAZA uptake, suggesting that both markers are identifying distinctly different biologic processes associated with hypoxia. Conclusion: The study revealed a substantial spatial discordance of the 18 F-FAZA and 125 I-Gluco-RGD tumor distribution suggesting that hypoxia and angiogenesis are not necessarily spatially linked in malignancies. These results may prove essential in developing advanced targeted systemic chemotherapeutic approaches (such as combinations of hypoxiaactivated cytotoxins and antiangiogenic drugs) for hypoxic tumors.

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Endorepellin In Vivo: Targeting the Tumor Vasculature and Retarding Cancer Growth and Metabolism

Abstract: Our results provide support for the hypothesis that endorepellin is an effective antitumor vasculature agent that could be used as a therapeutic modality to combat cancer.

Cited by 105 publications

References 55 publications

Integrin α2β1 Is the Required Receptor for Endorepellin Angiostatic Activity

Integrin α2β1 Is the Required Receptor for Endorepellin Angiostatic Activity

Endorepellin-evoked Autophagy Contributes to Angiostasis

Intratumoral Spatial Distribution of Hypoxia and Angiogenesis Assessed by ¹⁸F-FAZA and ¹²⁵I-Gluco-RGD Autoradiography

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Endorepellin In Vivo: Targeting the Tumor Vasculature and Retarding Cancer Growth and Metabolism

Abstract: Our results provide support for the hypothesis that endorepellin is an effective antitumor vasculature agent that could be used as a therapeutic modality to combat cancer.

Cited by 105 publications

References 55 publications

Integrin α2β1 Is the Required Receptor for Endorepellin Angiostatic Activity

Integrin α2β1 Is the Required Receptor for Endorepellin Angiostatic Activity

Endorepellin-evoked Autophagy Contributes to Angiostasis

Intratumoral Spatial Distribution of Hypoxia and Angiogenesis Assessed by 18F-FAZA and 125I-Gluco-RGD Autoradiography

Contact Info

Product

Resources

About

Intratumoral Spatial Distribution of Hypoxia and Angiogenesis Assessed by ¹⁸F-FAZA and ¹²⁵I-Gluco-RGD Autoradiography