Inhibition of Tumor Growth and Angiogenesis by Soluble EphB4

Martiny-Baron, Georg; Korff, Thomas; Schaffner, Florence; Esser, N.; Eggstein, S.; Marmé, Dieter; Augustin, Hellmut G.

doi:10.1593/neo.3457

Cited by 73 publications

(73 citation statements)

References 34 publications

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“…The research focus of vascular Eph receptors and ephrin ligands has primarily been on developmental issues, unravelling the role of B-class Eph receptors and ephrin ligands in arteriovenous differentiation (Adams et al, 1999;Gerety et al, 1999;Wang et al, 1998), interactions between EC and smooth-muscle cells (Foo et al, 2006) and lymphangiogenesis (Makinen et al, 2005). Studies of interactive mechanisms between Eph receptors and ephrin ligands in the adult vascular system primarily concentrated on their role in tumor angiogenesis and tumor progression (Erber et al, 2006;Kertesz et al, 2006;Martiny-Baron et al, 2004;Noren et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Involvement of endothelial ephrin-B2 in adhesion and transmigration of EphB-receptor-expressing monocytes

Pfaff

Héroult

Riedel

et al. 2008

Journal of Cell Science

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The vascular endothelium is a crucial interface that controls the recruitment of circulating leukocytes. Based on the luminal expression of the ephrin-B2 ligand by endothelial cells (ECs) and the expression of EphB receptors (EphBRs) by circulating monocytes, we hypothesized that EphBR-ephrinB interactions are involved in monocyte adhesion. Adhesion experiments with monocytic cells were performed on ECs that overexpressed either full-length ephrin-B2 or cytoplasmically truncated ephrin-B2 (ΔC-ephrin-B2). Atomic force microscopy confirmed similar adhesive strengths of EphBR-expressing J774 cells to ECs that either overexpressed full-length ephrin-B2 or truncated ΔC-ephrin-B2 (1-minute interaction). Yet, adhesion experiments under static or flow conditions for 30 minutes demonstrated the preferential adhesion of monocytic cells to ECs that overexpressed full-length ephrin-B2 but not to ΔC-ephrin-B2 or to ECs that had been mock transduced. Adhesion was blocked by ephrin-B2-specific and EphBR-specific antibodies. Correspondingly, adhesion of EphB4-receptoroverexpressing monocytes to ephrin-B2-positive ECs was further augmented. Trafficking experiments of cell-surface molecules revealed that, prior to internalization, the resulting EphB4-receptor-ephrin-B2 complex translocated from the luminal surface to inter-endothelial junctions. Lastly, fulllength ephrin-B2 in ECs was also involved in monocyte transmigration. Collectively, our study identifies a role of EphBR-ephrinB interactions as a new step in the cascade of events leading to monocyte adhesion and transmigration through the vascular endothelium. Supplementary material available online at

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Section: Discussionmentioning

confidence: 99%

Involvement of endothelial ephrin-B2 in adhesion and transmigration of EphB-receptor-expressing monocytes

Pfaff

Héroult

Riedel

et al. 2008

Journal of Cell Science

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“…Accumulating evidence now also suggests an important role for the EphB and ephrin-B molecules in malignancy. Ephrin-B2 has been found to be overexpressed in thyroid neoplasms, colon carcinomas, and melanomas (40,41), and treatment of melanoma with soluble EphB4 protein inhibits in vivo tumor growth (42). In agreement, ephrin-B2 was shown to enhance attachment and migration of melanoma cells, indirectly suggesting that ephrin-B proteins may control metastatic behavior of cancer cells (43).…”

Section: Introductionmentioning

confidence: 90%

In Human Leukemia Cells Ephrin-B–Induced Invasive Activity Is Supported by Lck and Is Associated with Reassembling of Lipid Raft Signaling Complexes

Jiang

Freywald

Webster

et al. 2008

Molecular Cancer Research

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Proteins of the ephrin-B group operate in nonlymphoid cells through the control of their migration and attachment, and are crucial for the development of the vascular, lymphatic, and nervous systems. Ephrin-B activity is deregulated in various nonlymphoid malignancies; however, their precise role in cancer has only started to be addressed. We show here that ephrin-B1, a member of the ephrin-B group, is expressed in pediatric T-cell leukemias, including leukemia cell line Jurkat. Treatment of Jurkat cells with ephrin-Bstimulating EphB3 enhances ephrin-B1 phosphorylation and induces its relocalization into lipid rafts. These events are mediated by the T lineage -specific kinase, Lck, as ephrin-B1 phosphorylation and lipid raft association are blocked in the Lck-deficient clone of Jurkat, JCAM1.6. Ephrin-B1 also induces colocalization of the CrkL and Rac1 cytoskeleton regulators and initiates in leukemic cells a strong repulsive response. The absence of Lck blocks ephrin-B1 -induced signaling and repulsion, confirming the essential role for Lck in ephrin-B1 -mediated responses. This shows a new role for ephrin-B1 in the regulation of leukemic cells through the Lck-dependent Rac1 colocalization with its signaling partner, CrkL, in lipid rafts. In agreement with its repulsive action, ephrin-B1 seems to support metastatic properties of leukemic cells, as suppression of ephrin-B1 signaling inhibits their invasiveness. Because ephrin-B1 -activating EphB proteins are ubiquitously expressed, our findings suggest that ephrin-B1 is likely to play an important role in the regulation of malignant T lymphocytes through the control of lipid-raftassociated signaling, adhesion, and invasive activity, and therefore may represent a novel target for cancer treatment. (Mol Cancer Res 2008;6(2):291 -305)

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“…Interestingly, increased EphB4 ectodomain expression in the tumor cells increases the size of the blood vessels and the blood content of the tumors, consistent with the enlarging effects of EphB4 Fc on the chicken allantoic arteries and the enlarged ear skin blood vessels in transgenic mice overexpressing ephrin-B2 in endothelial cells (43,71). Conversely, A375 melanoma cells secreting soluble monomeric EphB4 ectodomain form much smaller tumors when injected subcutaneously in nude mice, presumably because the EphB4 ectodomain blocks the interaction between EphB2 on the surface of the tumor cells and endothelial ephrin-B2 (87). Indeed, tumor regions where the EphB4 ectodomain was present at highest levels had low microvessel densities and more collapsed vessels lacking a lumen.…”

Section: Ephrin-b2 and Ephb4mentioning

confidence: 99%

“…Eph receptors and ephrins are also emerging as new attractive targets. EphA receptor Fc fusion protein and soluble monomeric forms of EphB4 have been successfully used as antagonists in animal tumor models (14,19,48,87). Furthermore, intravitreal injection of ephrin-B2 Fc or EphB4 Fc, which presumably perturb the function of the corresponding endogenously expressed proteins, reduce the pathological neovascularization occurring in a mouse model of oxygen-induced retinopathy (90).…”

Section: Targeting Eph Receptor-ephrin Interactions To Modulate Angiomentioning

confidence: 99%

Tumor Suppressor Activity of the EphB2 Receptor in Prostate Cancer

Pasquale¹

2008

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBERThe Burham Institute La Jolla, CA 92037 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTMutations have been recently identified in the EphB2 receptor gene in prostate cancer suggesting that EphB2, a member of the large Eph receptor tyrosine kinase family, is a tumor suppressor in prostate cancer. Consistent with a tumor suppressor activity, we found that EphB2 is more highly expressed in non-transformed BPH-1 prostate epithelial cells than in several prostate cancer cell lines. Furthermore, EphB2 expression was rapidly lost in stably transfected DU145 prostate cancer cells, suggesting that EphB2 has detrimental effects on cell growth and/or survival. We have also uncovered a novel tumor suppressor pathway downstream of the related EphA2 receptor in prostate cancer cells. We found that EphA2 inhibits the AktmTOR pathway, a pathway well known to play a critical role in prostate cancer pathogenesis, and are investigating the mechanisms underlying this important function of EphA2. The tumor suppressor activities of the Eph receptors in prostate cancer represent an important area of investigation that will help understand the pathogenesis of this disease and guide the design of novel diagnostic and therapeutic strategies. SUBJECT TERMSEph receptor, ephrin, tumor suppressor, signal transduction INTRODUCTIONLoss of function of tumor suppressor genes and increased function of tumor-promoting genes are critical steps in the development and progression of cancer. It is therefore important to identify these genes and understand how they affect cancer progression in order to develop new treatments. Inactivating mutations in the EphB2 gene that were identified in clinical prostate cancer samples but not in normal tissue have provided intriguing clues sugges...

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Inhibition of Tumor Growth and Angiogenesis by Soluble EphB4

Cited by 73 publications

References 34 publications

Involvement of endothelial ephrin-B2 in adhesion and transmigration of EphB-receptor-expressing monocytes

Involvement of endothelial ephrin-B2 in adhesion and transmigration of EphB-receptor-expressing monocytes

In Human Leukemia Cells Ephrin-B–Induced Invasive Activity Is Supported by Lck and Is Associated with Reassembling of Lipid Raft Signaling Complexes

Tumor Suppressor Activity of the EphB2 Receptor in Prostate Cancer

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