Melanoma-associated antigen genes – An update

Sang, Meixiang; Wang, Lifang; Ding, Chao; Zhou, Xin; Wang, Bin; Wang, Ling; Lian, Yishui; Shan, Baoen

doi:10.1016/j.canlet.2010.10.021

Cited by 119 publications

(87 citation statements)

References 48 publications

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“…Disease progression and development of metastasis require stepwise acquisition of aggressive characteristics (2), including resistance to the immune system (3), even though melanoma cells are frequently immunogenic (4). Immunomodulation with interleukin (IL)-2 yields an objective clinical response in approximately 20% of the patients, with 5% of them exhibiting a durable complete response (5).…”

Section: Introductionmentioning

confidence: 99%

Novel Immunotherapy for Malignant Melanoma with a Monoclonal Antibody That Blocks CEACAM1 Homophilic Interactions

Ortenberg

Sapir

Raz

et al. 2012

Molecular Cancer Therapeutics

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CEACAM1 (biliary glycoprotein-1, CD66a) was reported as a strong clinical predictor of poor prognosis in melanoma. We have previously identified CEACAM1 as a tumor escape mechanism from cytotoxic lymphocytes. Here, we present substantial evidence in vitro and in vivo that blocking of CEACAM1 function with a novel monoclonal antibody (MRG1) is a promising strategy for cancer immunotherapy. MRG1, a murine IgG1 monoclonal antibody, was raised against human CEACAM1. It recognizes the CEACAM1-specific N-domain with high affinity (K D $ 2 nmol/L). Furthermore, MRG1 is a potent inhibitor of CEACAM1 homophilic binding and does not induce any agonistic effect. We show using cytotoxicity assays that MRG1 renders multiple melanoma cell lines more vulnerable to T cells in a dose-dependent manner, only following antigen-restricted recognition. Accordingly, MRG1 significantly enhances the antitumor effect of adoptively transferred, melanoma-reactive human lymphocytes using human melanoma xenograft models in severe combined immunodeficient/nonobese diabetic (SCID/NOD) mice. A significant antibody-dependent cell cytotoxicity response was excluded. It is shown that MRG1 reaches the tumor and is cleared within a week. Importantly, approximately 90% of melanoma specimens are CEACAM1 þ , implying that the majority of patients with melanoma could be amenable to MRG1-based therapy. Normal human tissue microarray displays limited binding to luminal epithelial cells on some secretory ducts, which was weaker than the broad normal cell binding of other anticancer antibodies in clinical use. Importantly, MRG1 does not directly affect CEACAM1 þ cells. CEACAM1 blockade is different from other immunomodulatory approaches, as MRG1 targets inhibitory interactions between tumor cells and late effector lymphocytes, which is thus a more specific and compartmentalized immune stimulation with potentially superior safety profile.

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Section: Introductionmentioning

confidence: 99%

Novel Immunotherapy for Malignant Melanoma with a Monoclonal Antibody That Blocks CEACAM1 Homophilic Interactions

Ortenberg

Sapir

Raz

et al. 2012

Molecular Cancer Therapeutics

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“…2 Owing to their high sequence homology MAGE-A proteins have been considered functionally redundant, and have been largely exploited in the immunotherapy field through cancer vaccine development or as tumor markers. [3][4][5] Only during the last few years, their biological function has begun to be investigated. A growing body of evidence indicates that MAGE-A proteins could confer advantages to cancer cells by different mechanisms and with a certain degree of specificity.…”

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confidence: 99%

MageA2 restrains cellular senescence by targeting the function of PMLIV/p53 axis at the PML-NBs

et al. 2011

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MAGE-A genes are a subfamily of the melanoma antigen genes (MAGEs), whose expression is restricted to tumor cells of different origin and normal tissues of the human germline. Although the specific function of individual MAGE-A proteins is being currently explored, compelling evidence suggest their involvement in the regulation of different pathways during tumor progression. We have previously reported that MageA2 binds histone deacetylase (HDAC)3 and represses p53-dependent apoptosis in response to chemotherapeutic drugs. The promyelocytic leukemia (PML) tumor suppressor is a regulator of p53 acetylation and function in cellular senescence. Here, we demonstrate that MageA2 interferes with p53 acetylation at PMLnuclear bodies (NBs) and with PMLIV-dependent activation of p53. Moreover, a fraction of MageA2 colocalizes with PML-NBs through direct association with PML, and decreases PMLIV sumoylation through an HDAC-dependent mechanism. This reduction in PML post-translational modification promotes defects in PML-NBs formation. Remarkably, we show that in human fibroblasts expressing RasV12 oncogene, MageA2 expression decreases cellular senescence and increases proliferation. These results correlate with a reduction in NBs number and an impaired p53 response. All these data suggest that MageA2, in addition to its anti-apoptotic effect, could have a novel role in the early progression to malignancy by interfering with PML/p53 function, thereby blocking the senescence program, a critical barrier against cell transformation.

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“…Type I MAGE genes are expressed in tumors of various histological origins, but are completely silent in normal tissues, with the exception of male germ cells and placenta; thus, the corresponding proteins represent attractive targets for cancer immunotherapy (6 in somatic cells, both in tumors and normal adult tissues, which suggests that they may play an important role in biological processes (7). Although the activation and expression of MAGEs were reported in various human cancers including cholangiocarcinoma, the physiological function of MAGEs remains largely unknown (8,9). However, the involvement of MAGEs in the regulation of cell cycle progression (10) and apoptosis (11,12) has been suggested.…”

Section: Introductionmentioning

confidence: 99%

Apoptosis-related protein-1 acts as a tumor suppressor in cholangiocarcinoma cells by inducing cell cycle arrest via downregulation of cyclin-dependent kinase subunits

Zheng

Wang

et al. 2015

Oncology Reports

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Abstract. Cholangiocarcinoma, a malignancy arising from the biliary tract, is associated with high mortality due to the late diagnosis and lack of effective therapeutic approaches. Our knowledge of the molecular alterations during the carcinogenesis of cholangiocarcinoma is limited. Previous study suggests that apoptosis-related protein-1 (Apr-1) is involved in cancer cell proliferation and survival. In the present study, we first detected the expression pattern of Apr-1 in human cholangiocarcinoma tissues and the effects of forced Apr-1 expression on cell proliferation and cell cycle progression. Cell cycle gene array analysis was used to identify downstream molecules that were regulated by Apr-1, and their expression levels were further evaluated in human cholangiocarcinoma tissues. We showed that Apr-1 expression was downregulated in human cholangiocarcinoma tissues. Forced expression of Apr-1 inhibited cell proliferation of cholangiocarcinoma cell line QBC939 and induced G2/M phase arrest. Downregulation of cell cycle-related genes cyclin-dependent kinase (Cdk) 2, and cyclin-dependent kinase subunits (Cks) 1 and 2 was involved in Apr-1-induced cell cycle arrest. Furthermore, we found that Cdk2 and Cks1/2 expression levels were elevated in human cholangiocarcinoma tissues. Taken together, our data showed that Apr-1 plays a crucial role in cell proliferation by controlling cell cycle progression, implying a tumor-suppressor function of Apr-1 in cholangiocarcinoma carcinogenesis. Thus, the present study provides a rationale to further study the underlying mechanisms of Apr-1 downregulation in cholangiocarcinoma for exploring potential diagnostic and therapeutic targets.

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Melanoma-associated antigen genes – An update

Cited by 119 publications

References 48 publications

Novel Immunotherapy for Malignant Melanoma with a Monoclonal Antibody That Blocks CEACAM1 Homophilic Interactions

Novel Immunotherapy for Malignant Melanoma with a Monoclonal Antibody That Blocks CEACAM1 Homophilic Interactions

MageA2 restrains cellular senescence by targeting the function of PMLIV/p53 axis at the PML-NBs

Apoptosis-related protein-1 acts as a tumor suppressor in cholangiocarcinoma cells by inducing cell cycle arrest via downregulation of cyclin-dependent kinase subunits

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