RESUMEN
The challenge in classical Hodgkin Lymphoma (cHL) management is the 30-40% of refractory/relapsed cases. AIMS: The aim of this work was to determine whether NIK and BCL-2 could be useful as prognosis biomarkers in cHL. In addition, we evaluated BCL-2 as a directed-therapy in cHL cell lines using venetoclax. MAIN METHODS: We evaluated NIK and BCL-2 expression in 112 untreated cHL patients' lymph-node biopsies by immunohistochemistry. cHL cell lines were treated with venetoclax alone or combined with vincristine or doxorubicin. Cell viability, metabolic activity and cell death were analyzed by trypan-blue exclusion method, MTS assay and FDA/IP staining respectively. KEY FINDINGS: No correlation between NIK or BCL-2 expression and the majority of the clinical parameters was found. Patients with ≥60% BCL-2+ HRS-cells had a shorter disease-free survival (DFS) and overall survival (OS) (p = 0.002, p = 0.02 respectively). A decision tree analysis, in a 30 patients subgroup, showed that patients with <60% NIK+ HRS-cells but with ≥60% BCL-2+ HRS-cells had a worse outcome in terms of DFS and OS. These parameters performed better as prognosis indicators as compared to the diagnosis bone marrow status. Human cHL cell lines U-H01, KM-H2, L1236, SUPHD1, L540 showed sensitivity to venetoclax. The co-treatment effect of venetoclax and vincristine or doxorubicin on cell viability was diverse depending on the cell line evaluated. SIGNIFICANCE: BCL-2 should be considered as a prognosis biomarker as well as a potential new therapeutic target in cHL. We report for the first time the cytotoxic effect of venetoclax in human cHL cell lines.
Asunto(s)
Antineoplásicos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Enfermedad de Hodgkin/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Sulfonamidas/farmacología , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/metabolismo , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Línea Celular Tumoral , Niño , Femenino , Enfermedad de Hodgkin/mortalidad , Enfermedad de Hodgkin/patología , Humanos , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida/métodos , Proteínas Serina-Treonina Quinasas/metabolismo , Sulfonamidas/administración & dosificación , Adulto Joven , Quinasa de Factor Nuclear kappa BRESUMEN
The Epstein-Barr virus (EBV), Kaposi sarcoma herpesvirus (KSHV) and human T-lymphotropic virus (HTLV-1) are lymphomagenic viruses with region-specific induced morbidity. The RIAL-CYTED aims to increase the knowledge of lymphoma in Latin America (LA), and, as such, we systematically analyzed the literature to better understand our risk for virus-induced lymphoma. We observed that high endemicity regions for certain lymphomas, e.g., Mexico and Peru, have a high incidence of EBV-positive lymphomas of T/NK cell origin. Peru also carries the highest frequency of EBV-positive classical Hodgkin lymphoma (HL) and EBV-positive diffuse large B cell lymphoma, not otherwise specified (NOS), than any other LA country. Adult T cell lymphoma is endemic to the North of Brazil and Chile. While only few cases of KSHV-positive lymphomas were found, in spite of the close correlation of Kaposi sarcoma and the prevalence of pathogenic types of KSHV. Both EBV-associated HL and Burkitt lymphoma mainly affect young children, unlike in developed countries, in which adolescents and young adults are the most affected, correlating with an early EBV seroconversion for LA population despite of lack of infectious mononucleosis symptoms. High endemicity of KSHV and HTLV infection was observed among Amerindian populations, with differences between Amazonian and Andean populations.
RESUMEN
PURPOSE: Despite considerable evidence that supports the NF-kB role in the immune system and lymphomagenesis, it is unclear whether specific NF-kB dimers control a particular set of genes that account for their biological functions. Our previous work showed that Hodgkin Lymphoma (HL) is unique, among germinal center (GC)-derived lymphomas, with respect to its dependency on Rel-B to survive. In contrast, diffuse large B-Cell lymphoma (DLBCL) including both Activated B-Cell-Like and Germinal Center B-Cell-Like, requires cREL and Rel-A to survive and it is not affected by Rel-B depletion. These findings highlighted the activity of specific NF-kB subunits in different GC-derived lymphomas. METHODS: Sequenced chromatin immunoprecipitated DNA fragments (ChIP-Seq) analysis revealed an extensive NF-kB DNA-binding network in DLBCL and HL. The ChIP-Seq data was merged with microarray analysis following the Rel-A, Rel-B or cRel knockdown to determine effectively regulated genes. RESULTS: Downstream target analysis showed enrichment for cell cycle control, among other signatures. Rel-B and cRel controlled different genes within the same signature in HL and DLBCL, respectively. BCL2 was exclusively controlled by Rel-B in HL. Both mRNA and protein levels decreased following Rel-B depletion meanwhile there was no change upon cRel knock-down. BCL2 exogenous expression partially rescued the death induced by decreased Rel-B in HL cells. CONCLUSION: The Rel-B hierarchical network defined HL and the cRel hierarchical network characterized DLBCL. Each Rel member performs specific functions in distinct GC-derived lymphomas. This result should be considered for the development of targeted therapies that are aimed to selectively inhibit individual NF-kB dimers.
Asunto(s)
ADN de Neoplasias/metabolismo , Enfermedad de Hodgkin/metabolismo , Linfoma de Células B Grandes Difuso/metabolismo , FN-kappa B/metabolismo , Apoptosis/genética , Linfocitos B/metabolismo , Linfocitos B/patología , Línea Celular Tumoral , ADN de Neoplasias/genética , Perfilación de la Expresión Génica , Células HEK293 , Enfermedad de Hodgkin/genética , Humanos , Linfoma de Células B Grandes Difuso/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-rel/genética , Proteínas Proto-Oncogénicas c-rel/metabolismo , Transducción de Señal , Factor de Transcripción ReIA/genética , Factor de Transcripción ReIA/metabolismo , Factor de Transcripción ReIB/genética , Factor de Transcripción ReIB/metabolismo , Transcripción GenéticaRESUMEN
Mice bearing LP07 lung adenocarcinoma present some characteristics similar to those shown in patients with several malignant diseases. LP07 tumor bearers develop paraneoplastic syndromes such as cachexia, leukocytosis, and hypercalcemia, partly due to a systemic inflammatory response. We analyzed some of the mechanisms involved in the effectiveness of the association of the appetite-stimulant medroxiprogesterone acetate (MPA) and the nonselective cyclooxigenase (COX) inhibitor indomethacin (INDO) in LP07 tumor bearing mice. INDO and INDO plus MPA treatments significantly inhibited tumor growth, which was not inhibited by MPA. The number of lung metastatic nodules was decreased with all treatments, being most effective INDO alone and INDO plus MPA. A significant decrease of plasmatic levels of the matrix metalloproteinases MMP-9 and MMP-2 correlated with these results. Paraneoplastic syndromes, leukocytosis, and cachexia were abolished by all treatments. We determined effects of the treatments on circulating cytokines shown to regulate cachexia and inflammation. Both treatments alone, and INDO plus MPA, reduced circulating IL-6 throughout tumor evolution. A pronounced increase in serum IL-1ss levels was detected in untreated tumor bearers. These levels decreased and were closer to normal serum values when LP07 mice were treated with INDO plus MPA. The combination of a nonsteroidal antiinflammatory drug as INDO and MPA showed to be effective in inhibiting tumor and metastatic growth and diminishing paraneoplastic symptoms and SIR. A variety of specific molecules are implicated as playing a role in cancer-induced cachexia and hematological alterations.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Pulmonares/tratamiento farmacológico , Síndromes Paraneoplásicos/prevención & control , Adenocarcinoma/complicaciones , Adenocarcinoma/patología , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antineoplásicos Hormonales/administración & dosificación , Estimulantes del Apetito/administración & dosificación , Caquexia/etiología , Caquexia/prevención & control , Ensayo de Inmunoadsorción Enzimática , Femenino , Hipercalcemia/etiología , Hipercalcemia/prevención & control , Indometacina/administración & dosificación , Interleucina-1/sangre , Interleucina-6/sangre , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/patología , Metaloproteinasa 2 de la Matriz/sangre , Metaloproteinasa 2 de la Matriz/efectos de los fármacos , Metaloproteinasa 9 de la Matriz/sangre , Metaloproteinasa 9 de la Matriz/efectos de los fármacos , Acetato de Medroxiprogesterona/administración & dosificación , Ratones , Ratones Endogámicos BALB CRESUMEN
BACKGROUND AND OBJECTIVES: Therapy of malignant glioma tumors is based on histology and clinical factors. However, comparable lesions may correspond with important prognostic differences. Our purpose was to analyze retrospectively the prognostic input of platelet-derived growth factor receptor (PDGF-R), epidermal growth factor (EGF-R), and bcl-2 expression in 103 malignant gliomas from uniformly treated patients. METHODS: The expression of the antigens was analyzed by immunohistochemistry (IHC). Prognostic evaluation was performed with the multivariate proportional hazards model. The follow-up period lasted 19 (5-122) months for survivors. RESULTS: We observed that almost 50% of gliomas showed high expression of PDGF-R, while a lower expression of EGF-R and bcl-2 was found. No association between the main prognostic factors in malignant glioma (sex, age, histological grade, and Karnofsky score) and the labeling index (LI) of these antigens was observed. We found that only PDGF-R and EGF-R overexpression were associated with a shorter survival in patients with World Health Organization (WHO) II astrocytomas, being both associations independent of known prognostic factors, as shown by Cox model. Besides, we confirmed other authors' results that high histological grade and low performance score were associated with worse prognosis. CONCLUSIONS: PDGF-R and EGF-R expression could be relevant in determining the prognosis of low-grade astrocytomas (LGAs) and in providing a more objective mechanism for their classification.
Asunto(s)
Astrocitoma/genética , Neoplasias Encefálicas/genética , Receptores ErbB/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Receptores del Factor de Crecimiento Derivado de Plaquetas/genética , Adolescente , Adulto , Anciano , Astrocitoma/metabolismo , Astrocitoma/mortalidad , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidad , Receptores ErbB/biosíntesis , Femenino , Expresión Génica , Glioma/genética , Glioma/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesis , Receptores del Factor de Crecimiento Derivado de Plaquetas/biosíntesis , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
Previously we determined that plasma MMP-9 activity was significantly elevated in breast cancer patients compared to benign mammary pathologies and healthy controls. Now we analyzed its potential usefulness in the follow-up and in the prognosis of these patients. MMP-9 activity was measured by gelatin quantitative zymography in the euglobulin plasma fraction of 46 breast cancer patients in a 38-month follow-up study. Blood samples were obtained before surgery (S1), 1 month after (S2) and every 3 months. The relapse-free survival (RFS) and overall survival (OS) analysis was performed along 56 months in 113 patients using the Kaplan-Meier curves and Cox analysis. In 63% of the S2 analyzed, MMP-9 decreased after surgery. In 44 patients evaluated during the adjuvant period who developed a complete response, MMP-9 decreased compared to their S1, whereas 2 patients showed an enhancement in correlation with lack of response. Further analysis indicated that in all patients who never showed evidence of recurrence, plasma MMP-9 activity remained low, but it increased 1 to 8 months preceding the clinical detection of progression in those patients who relapsed. Kaplan-Meier curves indicated that high levels of plasma MMP-9 activity at the moment of breast cancer diagnosis were associated with a worse OS rate. Cox analysis showed it was not associated with tumor stage or patient's age. Our results, which show a good correlation between plasma MMP-9 activity and the clinical status of each patient, suggest its usefulness as a marker both in the follow-up and in the prognosis of breast cancer patients.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/enzimología , Metaloproteinasa 9 de la Matriz/sangre , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/enzimología , Carcinoma Ductal de Mama/patología , Carcinoma Lobular/enzimología , Carcinoma Lobular/patología , Quimioterapia Adyuvante , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Gelatina/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Ganglios Linfáticos/patología , Persona de Mediana Edad , Recurrencia Local de Neoplasia/enzimología , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Pronóstico , Seroglobulinas/metabolismo , Tasa de SupervivenciaRESUMEN
BACKGROUND AND OBJECTIVES: Glioma invasiveness involves the attachment of tumor cells to the brain extracellular matrix, rich in hyaluronic acid (HA). CD44, the principal receptor for HA is found as a standard molecule (CD44s) or as variants (CD44v). We undertook a retrospective study to evaluate the expression pattern of CD44s, the isoforms CD44v3, v4/5 and v6 and to correlate their expression with clinical-anatomopathological parameters and survival rate. METHODS: The expression of these molecules was evaluated immunohistochemically in 84 gliomas. RESULTS: No expression of CD44v was detected in any tumors. CD44s staining of tumor cells was found in 70 of 84 (83.3%) of the gliomas. In 23 of 39 (59.0%) of the GBM more than the 70% of the cells were stained, while only 2 of 21 (9.5%) of LGA showed high expression. The association between CD44 and histological grade remained when the prognostic variables were considered in a multivariate analysis. Higher expression of CD44 was associated with worse overall survival rate; however, the Cox analysis indicated that survival was not associated with CD44. CONCLUSIONS: Our results suggest that overexpression of CD44s could be relevant in determining the highly invasive behaviour of gliomas, though it does not behave as an independent prognostic factor for survival.
Asunto(s)
Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Receptores de Hialuranos/metabolismo , Adolescente , Adulto , Anciano , Argentina , Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/mortalidad , Femenino , Glioma/mortalidad , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
The ability of tumor cells to adhere and detach from extracellular matrix and endothelial cells, is a crucial step in the metastatic process and may alter the clinical prognosis of some human tumors such as melanomas. CD44, the major cell surface receptor for hyaluronate, has been implicated in cell adhesion and in tumor progression. We studied the expression of standard CD44 molecule (CD44s) and its variants v3 and v6 in 57 human primary melanoma biopsies, without previous treatment. We analyzed the association between CD44 expression and the principal clinicopathological features, including survival. Fifty-six of 57 tumors expressed CD44s, associated to the cytoplasmic membrane. No expression of CD44v3 or CD44v6 was detected. No association between CD44s expression and prognostic factors such as tumor thickness, growth type, stage or anatomic site of the lesion was found. However, a positive correlation between CD44s expression and Clark level (Spearman, p<0.001) was found. While only 33.3% of melanomas Clark I + II showed high expression of CD44s (more than 50% of positive cells), 82.6% of melanomas Clark IV + V did so. Kaplan-Meier analysis revelead that patients whose melanomas had high expression of CD44s showed a reduced relapse free survival (RFS) rate, though without statistical significance. No difference between the level of CD44 expression and overall survival (OS) was found. We conclude that melanomas only expressed CD44s, and that its level was associated with Clark's stage. CD44s seems not to be useful as a tumor marker, because it does not predict either RFS or OS.