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1.
Leukemia ; 30(10): 2011-2018, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27109509

RESUMO

CD49d, the alpha-chain of the integrin heterodimer α4ß1, was identified among the strongest predictors of overall survival (OS) in chronic lymphocytic leukemia (CLL), along with IGHV mutational status and deletion of the 17p chromosome involving TP53. In addition to TP53, the clinical relevance of NOTCH1, SF3B1 and BIRC3 gene mutations has been recently emphasized. By analyzing a cohort of 778 unselected CLL patients, we assessed the clinical relevance of CD49d as an OS predictor in subgroups defined by mutation/deletion of the TP53, NOTCH1, SF3B1 and BIRC3 genes. In this context, CD49d emerged as an independent predictor of OS in multivariate Cox analysis (Hazard ratio =1.88, P<0.0001). Consistently, high CD49d expression identified CLL subsets with inferior OS in the context of each category of a previously reported hierarchical risk stratification model. Moreover, by evaluating the relative importance of biological prognosticators by random survival forests, CD49d was selected among the top-ranked OS predictor (variable importance =0.0410), along with IGHV mutational status and TP53 abnormalities. These results confirmed CD49d as an independent negative OS prognosticator in CLL also in comprehensive models comprising the novel recurrent mutations. In this context, TP53 disruption and NOTCH1 mutations retained prognostic relevance, in keeping with their roles in CLL cell immuno-chemoresistance.


Assuntos
Integrina alfa4/fisiologia , Leucemia Linfocítica Crônica de Células B/mortalidade , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína 3 com Repetições IAP de Baculovírus , Humanos , Proteínas Inibidoras de Apoptose/genética , Leucemia Linfocítica Crônica de Células B/diagnóstico , Pessoa de Meia-Idade , Fosfoproteínas/genética , Prognóstico , Fatores de Processamento de RNA/genética , Receptores de Antígenos de Linfócitos B/genética , Taxa de Sobrevida , Proteína Supressora de Tumor p53/genética , Ubiquitina-Proteína Ligases/genética
2.
Int J Cancer ; 91(4): 500-7, 2001 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-11251973

RESUMO

Conflicting evidences suggested that levels of HLA-A and -B antigens expressed on normal and neoplastic cells of given individuals are genetically predetermined, or, on the other hand, regulated by molecular mechanisms generating the down-regulated expression of HLA-B antigens frequently observed on melanoma cells. In our study, we quantitated, both at the protein and mRNA level, the amounts of HLA-A and -B antigens constitutively expressed on 23 primary cultures of metastatic melanomas and on autologous peripheral blood mononuclear cells (PBMC). Flow cytometric analyses identified a significantly (p < 0.01) lower expression of HLA-B antigens on melanoma cell cultures but not on autologous PBMC. Consistently, lower amounts of HLA-B antigens mRNA were detected by RNase protection assay exclusively in neoplastic cells. This unbalanced expression of HLA-A and -B antigens was readily reverted by interferon (IFN)-gamma but not by the DNA hypomethylating agent 5-aza-2'-deoxycytidine in 4 melanoma cell cultures investigated. Significantly (p < 0.05) lower levels of HLA-B antigens were also detected on cells from solid malignancies of different histotypes but not on neoplastic cells from hemopoietic neoplasms; levels of HLA-B antigens were rapidly up-regulated by IFN-gamma exclusively on non-hemopoietic transformed cells. Together, these data strongly argue against a genetic predetermination of the amounts of HLA-A and -B antigens expressed on normal and neoplastic cells of distinct melanoma patients and suggest that constitutively low levels of HLA-B antigens are a specific feature of non-hemopoietic transformed cells that is controlled by common regulatory mechanism(s) and that is possibly shared by non-hemopoietic normal cells.


Assuntos
Azacitidina/análogos & derivados , Antígenos HLA-A/biossíntese , Antígenos HLA-B/biossíntese , Interferon gama/uso terapêutico , Melanoma/metabolismo , Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos/uso terapêutico , Azacitidina/uso terapêutico , Sequência de Bases , Células Cultivadas , DNA Complementar/metabolismo , Decitabina , Regulação para Baixo , Citometria de Fluxo , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Humanos , Leucócitos Mononucleares/metabolismo , Melanoma/genética , Dados de Sequência Molecular , Neoplasias/genética , Neoplasias/metabolismo , Fenótipo , RNA Mensageiro/metabolismo , Proteínas Recombinantes/metabolismo , Ribonucleases/metabolismo , Homologia de Sequência do Ácido Nucleico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Células Tumorais Cultivadas , Regulação para Cima
3.
J Immunother ; 22(1): 16-24, 1999 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9924695

RESUMO

The immunogenic potential of melanoma cells and their recognition by the host's cytotoxic cells depends on the presence and on the level of expression of human leukocyte antigen (HLA) class I antigens, costimulatory molecules and melanoma-associated antigens (MAA), on neoplastic cells. In this study, we demonstrate that the DNA hypomethylating agent 5-aza-2'-deoxycytidine (5-AZA-CdR), significantly (p < 0.05) enhanced the constitutive expression of HLA class I antigens, HLA-A1 and -A2 alleles, and of the costimulatory molecules intercellular adhesion molecule-1 and lymphocyte function-associated antigen-3, on a panel of 12 melanoma cells. This upregulation peaked at day 4, slowly decreased thereafter, and returned to baseline levels 32 days after the end of treatment. In addition, treatment with 5-AZA-CdR induced a persistent expression of MAGE-1 in Mel 275 melanoma cells; this was still detectable, by reverse transcriptase polymerase chain reaction, 60 days after the end of treatment. In contrast, 5-AZA-CdR did not affect the constitutive expression of the high molecular weight-MAA by the melanoma cells investigated. These observations, together with data obtained comparing the effect of 5-AZA-CdR with that of interferon-gamma, strongly suggest that 5-AZA-CdR may have prospective therapeutic implications in active and/or passive specific immunotherapy for human melanoma.


Assuntos
Azacitidina/análogos & derivados , Antígenos CD58/biossíntese , Antígenos de Histocompatibilidade Classe I/biossíntese , Molécula 1 de Adesão Intercelular/biossíntese , Melanoma/imunologia , Alelos , Antígenos de Neoplasias , Azacitidina/farmacologia , Western Blotting , Decitabina , Citometria de Fluxo , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Antígenos Específicos de Melanoma , Proteínas de Neoplasias/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Células Tumorais Cultivadas , Regulação para Cima/efeitos dos fármacos
4.
Breast Cancer Res Treat ; 58(1): 19-23, 1999 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-10634514

RESUMO

To date, no soluble markers can discriminate benign from malignant breast lesions; therefore, to assess the diagnostic potential of circulating intercellular adhesion molecule-1 (sICAM-1), serum concentrations of sICAM-1 were quantitated in 230 consecutive patients that underwent surgery for breast neoplasias, utilizing an enzyme-linked immunosorbent assay. Histological diagnosis revealed that 177 patients had breast cancer and 53 had a benign breast disease. In the cancer patient group, 90 subjects had pT1 tumors without (pT1N0M0, n = 46) or with (pT1N1M0, n = 41; pT1N2M0, n = 3) regional lymph node metastases. Mean levels of serum sICAM-1 of patients with pT1 breast cancer, without or with regional lymph node involvement, were significantly (P < 0.05) higher than those of patients with benign breast lesions and of 49 age-matched control subjects. Elevated levels of serum sICAM-1 were detected in 27/90 (30%) pT1 breast tumors and in 1/53 (2%) benign breast lesions; thus, among subjects with high levels of sICAM-1, 96% had breast cancer. No significant correlation was found between levels of serum sICAM-1 and breast cancer progression. These observations, altogether, suggest that in the presence of a suspicious breast neoplasm the quantitative analysis of serum sICAM-1 can orient clinical diagnosis towards malignancy.


Assuntos
Neoplasias da Mama/patologia , Molécula 1 de Adesão Intercelular/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Neoplasias da Mama/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Solubilidade
5.
J Clin Invest ; 100(5): 1248-55, 1997 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-9276743

RESUMO

Protectin (CD59), a glycosylphosphatidylinositol-anchored cell membrane glycoprotein, is differentially expressed on melanocytic cells and represents the main restriction factor of C-mediated lysis of melanoma cells. In this study, we report that CD59-positive melanoma cells constitutively release a soluble form of CD59 (sCD59), and that its levels directly correlate (r = 0.926; P < 0.05) with the amount of membrane-bound CD59. SDS-PAGE analysis showed that the molecular components of sCD59 are similar to those of cellular CD59 expressed by melanoma cells. Melanoma-released sCD59 is anchor positive since it inserts into cell membranes of homologous cells that transiently increase their expression of CD59. Moreover, sCD59 is functional: it blocks the binding of the anti-CD59 mAb YTH53.1 to melanoma cells and reverses its effects on C-mediated lysis. In fact, preincubation of mAb YTH53.1 with scalar doses of conditioned media of CD59-positive but not of CD59-negative melanoma cells reduced significantly (P < 0.05), and in a dose-dependent fashion, the enhancement of C-mediated lysis of anti-GD3-sensitized melanoma cells induced by the masking of cellular CD59 by mAb YTH53.1. Altogether, these data demonstrate that CD59-positive human melanoma cells release a soluble form of CD59 that is structurally similar to cellular CD59, retains its anchoring ability, is functional, and may impair the effectiveness of clinical approaches to humoral immunotherapy for human melanoma.


Assuntos
Antígenos CD59/fisiologia , Proteínas do Sistema Complemento/fisiologia , Citotoxicidade Imunológica , Melanoma/imunologia , Animais , Anticorpos Monoclonais/imunologia , Antígenos CD59/análise , Humanos , Melanoma/terapia , Camundongos , Ratos , Células Tumorais Cultivadas
6.
Br J Cancer ; 76(10): 1255-61, 1997.
Artigo em Inglês | MEDLINE | ID: mdl-9374368

RESUMO

Levels of circulating soluble intercellular adhesion molecule-1 (sICAM-1) are elevated in patients affected by solid malignancies; however, the cellular sources generating high levels of sICAM-1 remain to be characterized. Using conditioned media (CM) from seven ICAM-1-positive or -negative neoplastic cells, we demonstrate that tumour-derived interleukin 1alpha (IL-1alpha) significantly (P < 0.05) up-regulates the release of sICAM-1 by human umbilical vein endothelial cells. The intensity of the effect correlated with the amounts of IL-1alpha detectable in CM. Levels of ICAM-1 mRNA were also up-regulated by tumour-secreted IL-1alpha. The up-regulation of the shedding of sICAM-1 and of its expression at protein and mRNA level were completely reversed by the addition of anti-IL-1alpha neutralizing antibodies. Consistent with the in vitro data, tumour endothelia were strongly stained for ICAM-1 compared with autologous normal tissue endothelia. Taken altogether, our observations reveal an IL-1alpha-mediated tumour-endothelium relationship sustaining the shedding of sICAM-1 by endothelial cells. This is a general phenomenon in solid malignancies that correlates with the ability of neoplastic cells to secrete IL-1alpha rather than with their expression of ICAM-1 and/or histological origin. sICAM-1 has been previously shown to inhibit LFA-1/ICAM-1-mediated cell-cell interactions; therefore, the ability of neoplastic cells to secrete IL-1alpha is likely to represent a mechanism for their escape from immune interaction.


Assuntos
Endotélio Vascular/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-1/fisiologia , Neoplasias/imunologia , Células Cultivadas , Meios de Cultivo Condicionados , Humanos , Molécula 1 de Adesão Intercelular/análise , Regulação para Cima , Neoplasias da Bexiga Urinária/química
7.
Br J Cancer ; 74(10): 1586-91, 1996 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-8932339

RESUMO

Human endoglin (CD105) is a member of the transforming growth factor beta (TGF-beta) receptor family that binds TGF-beta1 and -beta3, but not TGF-beta2, on human endothelial cells. Immunohistochemical analyses demonstrated that CD105 is expressed on normal and neoplastic cells of the melanocytic lineage. The anti-CD105 MAb, MAEND3, stained 50, 25 and 34% of intradermal naevi, primary and metastatic melanomas investigated, respectively, and nine out of 12 melanoma cell lines. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis revealed that CD105 expressed by melanoma cells consists of a homodimeric protein with an apparent molecular weight of 180 and 95 kDa under non-reducing and reducing conditions. Cross-linking of 125I-labelled TGF-beta1 to melanoma cells, Mel 97, by disuccinimidyl suberate (DSS) demonstrated that CD105 expressed on pigmented cells binds TGF-beta1; the pattern of binding of TGF-beta1 to melanoma cells was found to be similar to that of human umbilical vein endothelial cells. The addition of exogenous, bioactive TGF-beta1 significantly (P<0.05) inhibited the growth of CD105-positive melanoma cells, Mel 97, but did not affect that of CD105-negative melanoma cells, F0-1. These data, altogether, demonstrate that CD105 is expressed on pigmented cells and might play a functionally relevant role in the biology of human melanoma cells by regulating their sensitivity to TGF-betas.


Assuntos
Melanoma/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Cutâneas/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , Animais , Antígenos CD , Divisão Celular/efeitos dos fármacos , Eletroforese em Gel de Poliacrilamida , Endoglina , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Imuno-Histoquímica , Radioisótopos do Iodo , Melanoma/patologia , Camundongos , Camundongos Endogâmicos BALB C , Nevo/metabolismo , Receptores de Superfície Celular , Dermatopatias/metabolismo , Neoplasias Cutâneas/patologia , Fator de Crescimento Transformador beta/farmacologia , Células Tumorais Cultivadas/efeitos dos fármacos , Molécula 1 de Adesão de Célula Vascular/química
8.
Lab Invest ; 74(1): 33-42, 1996 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-8569195

RESUMO

Normal and neoplastic cells are protected from autologous complement (C) attack by different cell-surface C-regulatory proteins including CD59 (protectin), CD46 (membrane cofactor protein) and CD55 (decay-accelerating factor). Indirect immunofluorescence (IIF) analysis showed a differential expression of CD59, CD46, and CD55 in nine human melanoma cell lines and that the expression of CD59 was highly heterogeneous compared with that of CD46 and CD55. Levels of cell membrane CD59 were found to regulate the differential sensitivity of melanoma cells investigated to homologous C-mediated lysis; in fact, an inverse correlation (r > 0.7, p < 0.05) was found between levels of cell membrane CD59, but not of CD46 and CD55, and extent of C-mediated lysis of melanoma cells sensitized with scalar concentrations of the anti-GD3 ganglioside mAb R24. Masking of CD59 by 2.5 micrograms/ml of the anti-CD59 mAb YTH53.1 induced or enhanced C-mediated lysis of melanoma cells sensitized with 2.5 micrograms/ml of mAb R24; the latter phenomenon was found to be directly correlated (r > 0.865, p < 0.01) with levels of cell membrane CD59. CD59 is bound to melanoma cells by a glycosylphosphatidylinositol anchor: treatment of C-resistant melanoma cells Mel 97, by increasing doses of phosphatidylinositol-specific phospholipase C (PI-PLC), progressively decreased cell-surface expression of CD59 and increased C-mediated lysis of cells sensitized with mAb R24. Staining of 38 benign and malignant lesions of melanocytic origin by mAb YTH53.1 demonstrated that CD59 is consistently expressed in vivo and confirmed the heterogeneous expression detected in vitro. Our data, altogether, demonstrate that CD59 is the main restriction factor of C-mediated lysis of melanoma cells and that levels of CD59 may account for their differential resistance to C-mediated lysis. The analysis of the levels of CD59 could represent an useful strategy in selecting melanoma patients who may benefit from immunotherapeutic treatment(s) that trigger C activation.


Assuntos
Antígenos CD59/farmacologia , Proteínas do Sistema Complemento/fisiologia , Citotoxicidade Imunológica , Melanoma/imunologia , Anticorpos Monoclonais/farmacologia , Antígenos CD/análise , Antígenos de Neoplasias/imunologia , Antígenos CD55/análise , Antígenos CD59/metabolismo , Citotoxicidade Imunológica/efeitos dos fármacos , Técnica Indireta de Fluorescência para Anticorpo , Gangliosídeos/imunologia , Humanos , Imuno-Histoquímica , Melanoma/metabolismo , Proteína Cofatora de Membrana , Glicoproteínas de Membrana/análise , Nevo/imunologia , Nevo/patologia , Fosfatidilinositol Diacilglicerol-Liase , Fosfoinositídeo Fosfolipase C , Diester Fosfórico Hidrolases/farmacologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/metabolismo , Células Tumorais Cultivadas
9.
Int J Cancer ; 61(4): 548-56, 1995 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-7538980

RESUMO

Immunohistochemical and/or indirect immunofluorescence analysis with monoclonal antibody (MAb) H19 demonstrated the expression of protectin (CD59) in 54 surgically removed metastatic melanoma lesions and on 8 out of 12 melanoma cell lines. CD59 expression had a low degree of intra- and intertumor heterogeneity. SDS-PAGE analysis showed that the molecular weight of CD59 expressed on melanoma cells is about 20 kDa. Treatment of melanoma cells with 5U/ml of phosphatidylinositol-specific phospholipase C completely abolished cell-surface expression of CD59. Interferon-gamma and/or tumor necrosis factor-alpha or phorbol 12-myristate 13-acetate neither modulated the expression of CD59 by melanoma cells nor influenced the amounts of CD59-specific mRNA. F(ab')2 fragments of anti-CD59 MAb YTH53. I did not inhibit the lysis of melanoma cells by allogeneic natural killer (NK) cells or lymphokine-activated killer (LAK) cells. In contrast, the whole Ig molecule of MAb HI9 or YTH53.I significantly (p < 0.05) enhanced NK-cell-mediated lysis of melanoma cells, suggesting the induction of antibody-dependent cell-mediated cytotoxicity. Lastly, masking of CD59 by MAb YTH53.I or its F(ab')2 fragments significantly (p < 0.05) enhanced, in a dose-dependent fashion, the lysis of anti-GD3-sensitized melanoma cells by homologous complement. These data demonstrate that CD59 expressed by human melanoma cells might regulate host-tumor interaction by protecting neoplastic cells from complement-mediated lysis.


Assuntos
Antígenos CD/imunologia , Proteínas Inativadoras do Complemento/imunologia , Citotoxicidade Imunológica/imunologia , Células Matadoras Ativadas por Linfocina/imunologia , Células Matadoras Naturais/imunologia , Melanoma/imunologia , Glicoproteínas de Membrana/imunologia , Anticorpos Monoclonais/farmacologia , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Antígenos CD/análise , Antígenos CD59 , Proteínas Inativadoras do Complemento/análise , Citocinas/farmacologia , Imunofluorescência , Humanos , Imunização , Fragmentos de Imunoglobulinas/farmacologia , Imuno-Histoquímica , Melanoma/química , Melanoma/secundário , Glicoproteínas de Membrana/análise , Fosfatidilinositol Diacilglicerol-Liase , Fosfoinositídeo Fosfolipase C , Diester Fosfórico Hidrolases/farmacologia , RNA Mensageiro/análise , Acetato de Tetradecanoilforbol/farmacologia
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