Rapid Access of Antibodies to α5β1 Integrin Overexpressed on the Luminal Surface of Tumor Blood Vessels

Magnussen, Anette; Kasman, Ian; Norberg, Scott M.; Bałuk, Peter; Murray, Richard M.; McDonald, Donald M.

doi:10.1158/0008-5472.can-04-2691

Cited by 59 publications

(53 citation statements)

References 35 publications

(36 reference statements)

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“…3B). Consistent with recent reports (34,35), a 5 integrin (CD49e) immunoreactivity and, hence, a 5 h 1 integrin expression, because this integrin is a unique heterodimer (33), was strong and uniformly distributed throughout the tumor blood vessels and was not detectable in adjacent normal acinar blood vessels (Fig. 3C).…”

Section: Ag-013736 Treatment Decreases Rgd-4c Phage Localizationsupporting

confidence: 91%

Antiangiogenic Therapy Decreases Integrin Expression in Normalized Tumor Blood Vessels

Yao¹,

Ozawa²,

Varner³

et al. 2006

Cancer Research

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Tumor blood vessels normalized by antiangiogenic therapy may provide improved delivery of chemotherapeutic agents during a window of time but it is unknown how protein expression in tumor vascular endothelial cells changes. We evaluated the distribution of RGD-4C phage, which binds A v B 3 , A v B 5 , and A 5 B 1 integrins on tumor blood vessels before and after antiangiogenic therapy. Unlike the control phage, fd-tet, RGD-4C phage homed to vascular endothelial cells in spontaneous tumors in RIP-Tag2 transgenic mice in a dosedependent fashion. The distribution of phage was similar to A v B 3 and A 5 B 1 integrin expression. Blood vessels that survived treatment with AG-013736, a small molecule inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptors, had only 4% as much binding of RGD-4C phage compared with vessels in untreated tumors. Cellular distribution of RGD-4C phage in surviving tumor vessels matched the A 5 B 1 integrin expression. The reduction in integrin expression on tumor vessels after antiangiogenic therapy raises the possibility that integrin-targeted delivery of diagnostics or therapeutics may be compromised. Efficacious delivery of drugs may benefit from identification by in vivo phage display of targeting peptides that bind to tumor blood vessels normalized by antiangiogenic agents. (Cancer Res 2006; 66(5): 2639-49)

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Section: Ag-013736 Treatment Decreases Rgd-4c Phage Localizationsupporting

confidence: 91%

Antiangiogenic Therapy Decreases Integrin Expression in Normalized Tumor Blood Vessels

Yao¹,

Ozawa²,

Varner³

et al. 2006

Cancer Research

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“…This transgenic mouse develops pancreatic islet tumors through specific stages of neoplastic progression and is characterized by an angiogenic switch activated in premalignant stages and concomitant with tumor growth. mRNA expression analysis of isolated islets shows that α6 is strongly induced during the angiogenic stage and its modulation is comparable to that of α5 and β3 integrins, which were previously reported to be upregulated on angiogenic endothelium in both this model and in human tumors (23).…”

Section: Discussionsupporting

confidence: 75%

“…Notably, we showed that α6 integrin on angiogenic vessels is easily accessible, similar to α5 integrins (23), and a very low dosage regimen is effective in normalizing the pathologic vasculature.…”

Section: Discussionmentioning

confidence: 82%

“…To examine the potential role of α6 in adult neovascularization, we studied the effect of anti-α6 blocking antibody in the Rip-Tag2 mouse model. We first evaluated the accessibility of the blocking antibody to pancreas islet vasculature (23). Mice injected with anti-α6 antibody showed, 10 minutes after treatment, a clear localization of this antibody in the islets vessels (Fig.…”

Section: Integrin α6 Blockade Impairs Tumor Angiogenesismentioning

confidence: 99%

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Increased Expression of α6 Integrin in Endothelial Cells Unveils a Proangiogenic Role for Basement Membrane

et al. 2010

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The integrin α6 subunit is part of the α6β1 and α6β4 integrin complexes, which are known to be receptors for laminins and to mediate several biological activities such as embryogenesis, organogenesis, and invasion of carcinoma cells. However, the precise role of α6 integrin in angiogenesis has not yet been addressed. We observed that both vascular endothelial growth factor-A and fibroblast growth factor-2 strongly upregulate α6 integrin in human endothelial cells. Moreover, α6 integrin was positively modulated in angiogenic vessels in pancreatic neuroendocrine carcinoma. In this transgenic mouse model of spontaneous tumorigenesis, α6 integrin expression increased in the angiogenic stage, while being expressed at low levels in normal and hyperplastic tissue. We studied the functional role of α6 integrin during angiogenesis by lentivirus-mediated gene silencing and blocking antibody. Cell migration and morphogenesis on basement membrane extracts, a laminin-rich matrix, was reduced in endothelial cells expressing low levels of α6 integrin. However, we did not observe any differences in collagen matrices. Similar results were obtained in the aortic ring angiogenesis assay. α6 integrin was required for vessel sprouting on basement membrane gels but not on collagen gels, as shown by stably silencing this integrin in the murine aorta. Finally, a neutralizing anti-α6 integrin antibody inhibited in vivo angiogenesis in chicken chorioallantoic membrane and transgenic tumor mouse model. In summary, we showed that the α6 integrin participated in vascular endothelial growth factor-A and fibroblast growth factor-2-driven angiogenesis in vitro and in vivo, suggesting that it might be an attractive target for therapeutic approaches in angiogenesis-dependent diseases such as tumor growth. Cancer Res; 70(14); 5759-69. ©2010 AACR.

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“…As expected, the vessel density was similar in all treatment groups because of the selectivity of IIA1 for human a 5 h 1 -integrin. Still, an important role for a 5 h 1 -integrin in angiogenesis has been clearly established (36,37). We have recently shown that a human-mouse chimeric version of IIA1 can inhibit tube formation in human umbilical chord endothelial cells and also induce apoptosis in proliferating endothelial cells (38).…”

Section: Discussionmentioning

confidence: 99%

Loss of E-Cadherin Promotes Ovarian Cancer Metastasis via α5-Integrin, which Is a Therapeutic Target

et al. 2008

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E-cadherin loss is frequently associated with ovarian cancer metastasis. Given that adhesion to the abdominal peritoneum is the first step in ovarian cancer dissemination, we reasoned that down-regulation of E-cadherin would affect expression of cell matrix adhesion receptors. We show here that inhibition of E-cadherin in ovarian cancer cells causes up-regulation of A 5 -integrin protein expression and transcription. When E-cadherin was blocked, RMUG-S ovarian cancer cells were able to attach and invade more efficiently. This greater efficiency could, in turn, be inhibited both in vitro and in vivo with an A 5 B 1 -integrin-blocking antibody. When E-cadherin is silenced, A 5 -integrin is up-regulated through activation of an epidermal growth factor receptor/FAK/Erk1-mitogenactivated protein kinase-dependent signaling pathway and not through the canonical E-cadherin/B-catenin signaling pathway. In SKOV-3ip1 ovarian cancer xenografts, which express high levels of A 5 -integrin, i.p. treatment with an A 5 B 1 -integrin antibody significantly reduced tumor burden, ascites, and number of metastasis and increased survival by an average of 12 days when compared with IgG treatment (P < 0.0005). A 5 -Integrin expression was detected by immunohistochemistry in 107 advanced stage ovarian cancers using a tissue microarray annotated with disease-specific patient follow-up. Ten of 107 tissues (9%) had A 5 -integrin overexpression, and 39% had some level of A 5 -integrin expression. The median survival for patients with high A 5 -integrin levels was 26 months versus 35 months for those with low integrin expression (P < 0.05). Taken together, we have identified A 5 -integrin upregulation as a molecular mechanism by which E-cadherin loss promotes tumor progression, providing an explanation for how E-cadherin loss increases metastasis. Targeting this integrin could be a promising therapy for a subset of ovarian cancer patients.

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Rapid Access of Antibodies to α5β1 Integrin Overexpressed on the Luminal Surface of Tumor Blood Vessels

Cited by 59 publications

References 35 publications

Antiangiogenic Therapy Decreases Integrin Expression in Normalized Tumor Blood Vessels

Antiangiogenic Therapy Decreases Integrin Expression in Normalized Tumor Blood Vessels

Increased Expression of α6 Integrin in Endothelial Cells Unveils a Proangiogenic Role for Basement Membrane

Loss of E-Cadherin Promotes Ovarian Cancer Metastasis via α5-Integrin, which Is a Therapeutic Target

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