Immunization against MUC18/MCAM, a novel antigen that drives melanoma invasion and metastasis

Leslie, Michael; Zhao, Yang; Lachman, Lawrence B.; Hwu, Patrick; Bar‐Eli, Menashe

doi:10.1038/sj.gt.3302864

Cited by 56 publications

(36 citation statements)

References 28 publications

(22 reference statements)

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“…51 Although an earlier study found no direct correlation between its expression and metastatic behavior of melanoma, 52 an increasing body of work has shed light on the functions of MCAM, particularly about its role in tumor growth and the progression of human malignant melanoma. 51,[53][54][55] Our MS-based quantitative proteomic data and immunostaining results (Figure 5B) consistently demonstrated the overexpression of MCAM in the metastatic over the primary melanoma cells. These results support that MCAM may serve as a diagnostic marker for monitoring the progression of melanoma.…”

Section: Characterization Of the Differential Expression Of Cell Surfmentioning

confidence: 99%

Quantitative Analysis of Surface Plasma Membrane Proteins of Primary and Metastatic Melanoma Cells

Qiu

Wang

2008

J. Proteome Res.

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Plasma membrane proteins play critical roles in cell-to-cell recognition, signal transduction and material transport. Because of their accessibility, membrane proteins constitute the major targets for protein-based drugs. Here, we described an approach, which included stable isotope labeling by amino acids in cell culture (SILAC), cell surface biotinylation, affinity peptide purification and LC-MS/MS for the identification and quantification of cell surface membrane proteins. We applied the strategy for the quantitative analysis of membrane proteins expressed by a pair of human melanoma cell lines, WM-115 and WM-266-4, which were derived initially from the primary and metastatic tumor sites of the same individual. We were able to identify more than 100 membrane and membrane-associated proteins from these two cell lines, including cell surface histones. We further confirmed the surface localization of histone H2B and three other proteins by immunocytochemical analysis with confocal microscopy. The contamination from cytoplasmic and other nonmembrane-related sources is greatly reduced by using cell surface biotinylation and affinity purification of biotinylated peptides. We also quantified the relative expression of 62 identified proteins in the two types of melanoma cells. The application to quantitative analysis of membrane proteins of primary and metastatic melanoma cells revealed great potential of the method in the comprehensive identification of tumor progression markers as well as in the discovery of new protein-based therapeutic targets.

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Section: Characterization Of the Differential Expression Of Cell Surfmentioning

confidence: 99%

Quantitative Analysis of Surface Plasma Membrane Proteins of Primary and Metastatic Melanoma Cells

Qiu

Wang

2008

J. Proteome Res.

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“…An estimated 62,480 new cases of melanoma were diagnosed in the United States during 2008, 8,420 of which resulted in death (2). The transition of melanoma from the radial growth phase to the vertical growth phase to metastasis is accompanied by multiple molecular changes (3)(4)(5)(6)(7)(8). We and others have shown that two transcription factors, activating transcription factor-1 (ATF-1) 2 and cAMP-response element-binding protein (CREB), are activated and overexpressed in melanoma during its progression toward the malignant phenotype (9 -13).…”

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confidence: 99%

Silencing cAMP-response Element-binding Protein (CREB) Identifies CYR61 as a Tumor Suppressor Gene in Melanoma

Dobroff

Wang

Melnikova

et al. 2009

Journal of Biological Chemistry

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Metastatic progression of melanoma is associated with overexpression and activity of cAMP-response element-binding protein (CREB). However, the mechanism by which CREB contributes to tumor progression and metastasis remains unclear. Here, we demonstrate that stably silencing CREB expression in two human metastatic melanoma cell lines, A375SM and C8161-c9, suppresses tumor growth and experimental metastasis. Analysis of cDNA microarrays revealed that CREB silencing leads to increased expression of cysteine-rich protein 61 (CCN1/ CYR61) known to mediate adhesion, chemostasis, survival, and angiogenesis. Promoter analysis and chromatin immunoprecipitation assays demonstrated that CREB acts as a negative regulator of CCN1/CYR61 transcription by directly binding to its promoter. Re-expression of CREB in CREB-silenced cells rescued the low CCN1/CYR61 expression phenotype. CCN1/ CYR61 overexpression resulted in reduced tumor growth and metastasis and inhibited the activity of matrix metalloproteinase-2. Furthermore, its overexpression decreased melanoma cell motility and invasion through Matrigel, which was abrogated by silencing CCN1/CYR61 in low metastatic melanoma cells. Moreover, a significant decrease in angiogenesis as well as an increase in apoptosis was seen in tumors overexpressing CCN1/CYR61. Our results demonstrate that CREB promotes melanoma growth and metastasis by down-regulating CCN1/ CYR61 expression, which acts as a suppressor of melanoma cell motility, invasion and angiogenesis.Cutaneous melanoma is the most aggressive type of skin cancer, and it can metastasize very rapidly (1). An estimated 62,480 new cases of melanoma were diagnosed in the United States during 2008, 8,420 of which resulted in death (2). The transition of melanoma from the radial growth phase to the vertical growth phase to metastasis is accompanied by multiple molecular changes (3-8). We and others have shown that two transcription factors, activating transcription factor-1 (ATF-1) 2 and cAMP-response element-binding protein (CREB), are activated and overexpressed in melanoma during its progression toward the malignant phenotype (9 -13).CREB and ATF-1 belong to the leucine zipper class of transcription factors. Stimuli such as growth factors, neurotransmitters, inflammatory biolipids, stress signals, or other factors that elevate intracellular cAMP or Ca 2ϩ levels can activate CREB/ATF-1 through phosphorylation at Ser 133 by protein kinase A or mitogen-activated protein kinases (MAPK) (14 -17). Following activation, CREB/ATF-1 regulates the expression of genes that suppress apoptosis, induce cell proliferation, and mediate inflammation and tumor metastasis by binding to cAMP-response elements (CREs) within the promoter and enhancer regions of these genes (15, 18 -20).A number of reports have suggested that CREB is involved in melanoma progression We have demonstrated previously that quenching CREB activity in metastatic melanoma cells by means of a dominant-negative form of CREB (KCREB) leads to a decrease in their tumorigenicity a...

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“…Previously, targeting CD146 with antibody against the molecule has been shown to inhibit tumor growth and angiogenesis in several types of cancer. Based on these findings (16,22,23), we chose to explore whether the induced expression of CD146 protected tumor cells from HDACiinduced death. We further tested whether the antitumoral activity of HDACi could be significantly enhanced in combination with the targeting of CD146.…”

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confidence: 99%

Synergistic Killing Effect between Vorinostat and Target of CD146 in Malignant Cells

Liu

et al. 2010

Clinical Cancer Research

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Purpose: Although histone deacetylase inhibitors (HDACi) are emerging as a new class of anticancer agents, one of the most significant concerns is that interactions with a wide array of substrates using these agents might initiate both therapeutic and undesired protective responses. Here, we sought to identify the potential protective reactions initiated by HDACi and determine whether targeting these reactions would enhance the antitumoral activity of HDACi.Experimental Design: Gene expression profiles were analyzed by cDNA microarray in Molt-4 cells before and after treatment of vorinostat. Induction of CD146 by vorinostat was examined in a wide range of tumors and nonmalignant cells. AA98, an anti-CD146 monoclonal antibody, was used to target CD146 function. Synergistic antitumoral and antiangiogenic effects between AA98 and vorinostat were examined both in vitro and in vivo. The potential effect of combined AA98 and vorinostat treatment on the AKT pathway was determined by Western blotting.Results: The induction of CD146 is a common phenomenon in vorinostat-treated cancer but not in nonmalignant cells. Targeting of CD146 with AA98 substantially enhanced vorinostat-induced killing via the suppression of activation of AKT pathways in cancer cells. Moreover, AA98 in combination with vorinostat significantly inhibited angiogenesis. In vivo, AA98 synergized with vorinostat to inhibit tumor growth and metastasis.Conclusion: The present study provided the first evidence that an undesired induction of CD146 could serve as a protective response to offset the antitumor efficacy of vorinostat. On the other hand, targeting CD146 in combination with vorinostat could be exploited as a novel strategy to more effectively kill cancer cells. Clin Cancer Res; 16(21); 5165-76. ©2010 AACR.

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Immunization against MUC18/MCAM, a novel antigen that drives melanoma invasion and metastasis

Cited by 56 publications

References 28 publications

Quantitative Analysis of Surface Plasma Membrane Proteins of Primary and Metastatic Melanoma Cells

Quantitative Analysis of Surface Plasma Membrane Proteins of Primary and Metastatic Melanoma Cells

Silencing cAMP-response Element-binding Protein (CREB) Identifies CYR61 as a Tumor Suppressor Gene in Melanoma

Synergistic Killing Effect between Vorinostat and Target of CD146 in Malignant Cells

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