Deciphering the signaling events that promote melanoma tumor cell vasculogenic mimicry and their link to embryonic vasculogenesis: Role of the Eph receptors

Hess, Angela R.; Margaryan, Naira V.; Seftor, Elisabeth A.; Hendrix, Mary J.C.

doi:10.1002/dvdy.21190

Cited by 85 publications

(73 citation statements)

References 93 publications

(105 reference statements)

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“…50,51 Hendrix and colleagues demonstrated that highly aggressive melanomas express VEcadherin, and that its function is central to the formation of vessel-like structures by melanoma cells. 36 They proposed that VE-cadherin promotes the interaction between focal adhesion kinase and EphA2 through regulation of EphA2's ability to translocate to the membrane. Interaction between EphA2 and its membrane-bound ligand would result in phosphorylation of EphA2.…”

Section: Discussionmentioning

confidence: 99%

“…This could then lead to melanoma vasculogenic mimicry via activation of MMP-2, finally resulting in cleavage of the laminin 5␥2 chain. 36 Interestingly, knock-down of VE-cadherin results in a dramatic redistribution of EphA2 on the cell surface, whereas EphA2 knockdown has no effect on VE-cadherin, 52 suggesting that VE-cadherin and EphA2 activation occurs sequentially and results in phenotypical changes in melanoma cells. Indeed, although we did not observe a decrease in the levels of EphA2 in C8161-c9 cells after Gal-3 silencing, this silencing nevertheless had a deleterious effect on the formation of tube-like structures by melanoma cells.…”

Section: Discussionmentioning

confidence: 99%

“…26 -30 On the molecular level, vascular endothelial cadherin (VE-cadherin), EphA2, focal adhesion kinase, phosphoinositide 3-kinase, and extracellular-regulated kinases 1 and 2 have been found to regulate melanoma vascular mimicry as well as melanoma aggressiveness in general. [31][32][33][34][35][36] Here, we report that silencing Gal-3 expression by small hairpin RNA (shRNA) results in a loss of melanoma cell tumorigenicity and metastasis, accompanied by impairment of angiogenesis and decreases in invasion and formation of tube-like structures (ie, vasculogenic mimicry). cDNA microarray analysis revealed that Gal-3 mediates expression of a large number of genes involved in tumor angiogenesis and endothelial cell differentiation and/or vascular mimicry.…”

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confidence: 99%

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Expression Profiling of Galectin-3-Depleted Melanoma Cells Reveals its Major Role in Melanoma Cell Plasticity and Vasculogenic Mimicry

Mourad-Zeidan

Melnikova

Wang

et al. 2008

The American Journal of Pathology

100

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Galectin-3 (Gal-3) is a ␤-galactoside-binding protein that is involved in cancer progression and metastasis. Using a progressive human melanoma tissue microarray, we previously demonstrated that melanocytes accumulate Gal-3 during the progression from benign to dysplastic nevi to melanoma and further to metastatic melanoma. Herein, we show that silencing of Gal-3 expression with small hairpin RNA results in a loss of tumorigenic and metastatic potential of melanoma cells. In vitro , Gal-3 silencing resulted in loss of tumor cell invasiveness and capacity to form tube-like structures on collagen ("vasculogenic mimicry"). cDNA microarray analysis after Gal-3 silencing revealed that Gal-3 regulates the expression of multiple genes , including endothelial cell markers that appear to be aberrantly expressed in highly aggressive melanoma cells , causing melanoma cell plasticity. These genes included vascular endothelial-cadherin , which plays a pivotal role in vasculogenic mimicry , as well as interleukin-8 , fibronectin-1 , endothelial differentiation sphingolipid G-protein receptor-1 , and matrix metalloproteinase-2. Chromatin immunoprecipitation assays and promoter analyses revealed that Gal-3 silencing resulted in a decrease of vascular endothelial-cadherin and interleukin-8 promoter activities due to enhanced recruitment of transcription factor early growth response-1. Moreover , transient overexpression of early growth response-1 in C8161-c9 cells resulted in a loss of vascular endothelial-cadherin and interleukin-8 promoter activities and protein expression. Thus , Gal-3 plays an essential role during the acquisition of vasculogenic mimicry and angiogenic properties associated with melanoma progression.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Expression Profiling of Galectin-3-Depleted Melanoma Cells Reveals its Major Role in Melanoma Cell Plasticity and Vasculogenic Mimicry

Mourad-Zeidan

Melnikova

Wang

et al. 2008

The American Journal of Pathology

100

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“…Intriguingly, the regulation may work both ways. There is evidence that the integrity of E/VEcadherin-based adhesion between cells aids in the aggregation of EphA2 receptors along the cell membrane, enhancing receptor tyrosine phosphorylation (43)(44)(45).…”

Section: Regulation Of N-cadherin and ␤-Cateninmentioning

confidence: 99%

Loss of ephrin-A5 function disrupts lens fiber cell packing and leads to cataract

Cooper

Son

Komlos³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

101

125

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Cell-cell interactions organize lens fiber cells into highly ordered structures to maintain transparency. However, signals regulating such interactions have not been well characterized. We report here that ephrin-A5, a ligand of the Eph receptor tyrosine kinases, plays a key role in lens fiber cell shape and cell-cell interactions. Lens fiber cells in mice lacking ephrin-A5 function appear rounded and irregular in cross-section, in contrast to their normal hexagonal appearance in WT lenses. Cataracts eventually develop in 87% of ephrin-A5 KO mice. We further demonstrate that ephrin-A5 interacts with the EphA2 receptor to regulate the adherens junction complex by enhancing recruitment of ␤-catenin to N-cadherin. These results indicate that the Eph receptors and their ligands are critical regulators of lens development and maintenance.␤-catenin ͉ Eph receptor ͉ N-cadherin C ataract, or the opacification of the lens, is the leading cause of visual impairment and blindness worldwide (1). The molecular events underlying lens development and the processes by which the lens maintains transparency over a lifetime are unclear (2). In addition, the cellular and biochemical mechanisms underlying the pathological changes leading to cataract remain poorly understood.The lens is composed of a single layer of epithelial cells on the anterior surface, which, over a lifetime, divide and differentiate into the underlying lens fiber cells that comprise the bulk of the lens (3, 4). Initially during lens development, primary lens fiber cells differentiate and elongate from the posterior pole. In later embryogenesis and throughout life, secondary lens fiber cells differentiate from lens epithelial cells located at the equator. In cross section, the lens fiber cells resemble flattened hexagons with two broad and four short sides (3). These cells are organized in a highly ordered and closely packed manner, and interact through extensive intercellular adhesion complexes including gap and adherens junctions (5). Fiber cell gap junctions are composed of connexins (Cx) 46 and 50 (6), inactivation of which leads to the degeneration of the inner fiber cells and the development of cataract in mice (7,8). Mutations in human Cx genes have also been associated with cataractogenesis (9, 10). As the lens is completely enclosed by an acellular, avascular capsule, it is believed that these cell-cell junctions are critical for providing nutrient transport, removal of metabolic wastes, and maintenance of homeostasis (11,12). In addition to gap junctions, widespread adherens junctions containing N-cadherin and its associated protein ␤-catenin exist between lens fiber cells (13-16), and may play important roles in lens development and function.Although cell-cell interaction is critical for maintaining lens transparency, little is known about the molecular mechanisms underlying these interactions. We have identified an unexpected regulator of lens fiber cell-cell interaction, the axon guidance molecule ephrin-A5 (17)(18)(19), and have shown that the loss...

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“…In melanoma, ephrin-A1-mediated activation of EphA2 and possibly other EphA receptors promotes proliferation (Easty and Bennett, 2000; Hess et al, 2007). Intriguingly, EphA2 has also been found to associate with vascular endothelial cadherin and promote the formation of blood vessellike structures by malignant melanoma cells, a role similar to that of EphA2 in tumor endothelial cells (see below).…”

Section: ) (Menges and Mccance 2007) Skin Cancer And Melanomamentioning

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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Deciphering the signaling events that promote melanoma tumor cell vasculogenic mimicry and their link to embryonic vasculogenesis: Role of the Eph receptors

Cited by 85 publications

References 93 publications

Expression Profiling of Galectin-3-Depleted Melanoma Cells Reveals its Major Role in Melanoma Cell Plasticity and Vasculogenic Mimicry

Expression Profiling of Galectin-3-Depleted Melanoma Cells Reveals its Major Role in Melanoma Cell Plasticity and Vasculogenic Mimicry

Loss of ephrin-A5 function disrupts lens fiber cell packing and leads to cataract

Tumor Suppressor Activity of the EphB2 Receptor in Prostate Cancer

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