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1.
Clin Transl Oncol ; 22(11): 1976-1991, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-32418154

RESUMEN

In this update of the consensus of the Spanish Society of Medical Oncology (Sociedad Española de Oncología Médica-SEOM) and the Spanish Society of Pathology (Sociedad Española de Anatomía Patológica-SEAP), advances in the analysis of biomarkers in advanced colorectal cancer (CRC) as well as susceptibility markers of hereditary CRC and molecular biomarkers of localized CRC are reviewed. Recently published information on the essential determination of KRAS, NRAS and BRAF mutations and the convenience of determining the amplification of human epidermal growth factor receptor 2 (HER2), the expression of proteins in the DNA repair pathway and the study of NTRK fusions are also evaluated. From the pathological point of view, the importance of analysing the tumour budding and poorly differentiated clusters, and its prognostic value in CRC is reviewed, as well as the impact of molecular lymph node analysis on lymph node staging in CRC. The incorporation of pan-genomic technologies, such as next-generation sequencing (NGS) and liquid biopsy in the clinical management of patients with CRC is also outlined. All these aspects are developed in this guide, which, like the previous one, will remain open to any necessary revision in the future.


Asunto(s)
Biomarcadores de Tumor/análisis , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Consenso , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Biopsia Líquida , Oncología Médica , Mutación , Patología , Sociedades Médicas , España
2.
Oncogene ; 36(41): 5695-5708, 2017 10 12.
Artículo en Inglés | MEDLINE | ID: mdl-28581514

RESUMEN

Despite the promising targeted and immune-based interventions in melanoma treatment, long-lasting responses are limited. Melanoma cells present an aberrant redox state that leads to the production of toxic aldehydes that must be converted into less reactive molecules. Targeting the detoxification machinery constitutes a novel therapeutic avenue for melanoma. Here, using 56 cell lines representing nine different tumor types, we demonstrate that melanoma cells exhibit a strong correlation between reactive oxygen species amounts and aldehyde dehydrogenase 1 (ALDH1) activity. We found that ALDH1A3 is upregulated by epigenetic mechanisms in melanoma cells compared with normal melanocytes. Furthermore, it is highly expressed in a large percentage of human nevi and melanomas during melanocyte transformation, which is consistent with the data from the TCGA, CCLE and protein atlas databases. Melanoma treatment with the novel irreversible isoform-specific ALDH1 inhibitor [4-dimethylamino-4-methyl-pent-2-ynthioic acid-S methylester] di-methyl-ampal-thio-ester (DIMATE) or depletion of ALDH1A1 and/or ALDH1A3, promoted the accumulation of apoptogenic aldehydes leading to apoptosis and tumor growth inhibition in immunocompetent, immunosuppressed and patient-derived xenograft mouse models. Interestingly, DIMATE also targeted the slow cycling label-retaining tumor cell population containing the tumorigenic and chemoresistant cells. Our findings suggest that aldehyde detoxification is relevant metabolic mechanism in melanoma cells, which can be used as a novel approach for melanoma treatment.


Asunto(s)
Aldehído Oxidorreductasas/genética , Alquinos/administración & dosificación , Melanocitos/efectos de los fármacos , Melanoma/tratamiento farmacológico , Compuestos de Sulfhidrilo/administración & dosificación , Aldehído Oxidorreductasas/antagonistas & inhibidores , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/genética , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Humanos , Melanocitos/patología , Melanoma/genética , Melanoma/patología , Ratones , Células Madre Neoplásicas/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
4.
Histol Histopathol ; 29(6): 721-30, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24217963

RESUMEN

BACKGROUND: Schwannomas are benign nerve sheath tumors that only very rarely undergo malignant changes. Oncogenic-induced senescence is a defense mechanism against such malignant transformation. Different molecular pathways are involved in this process, such as RAS-RAF-MAPK. Based on the fact that the RAS-RAF-MAPK pathway is known to be activated in peripheral nerve sheath tumors, this study analyzes senescence markers in Schwannomas to demonstrate the possible role of senescence in their genesis. METHODS: A retrospective immunohistochemical study was done in 39 schwannoma and 18 malignant peripheral nerve sheath tumors (MPNST). Staining for p16INK4a, Ki67, p53 and CyclinD1 was performed in all the cases. Additionally, ß-galactosidase staining was done in those cases in which frozen tissue was available (n=8). RESULTS: Higher levels of p16INK4a (p=0.0001) and lower levels of Ki67 (p=0.0001) were found in Schwannomas. Beta-galactosidase activity was positive in 5/5 Schwannomas and negative in 3/3 MPNST. CONCLUSIONS: Our results support the senescence nature of Schwannomas and the absence of a senescence phenotype in MPNST.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias de Cabeza y Cuello/patología , Neurilemoma/patología , Neoplasias de los Tejidos Blandos/patología , Adulto , Anciano , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Femenino , Neoplasias de Cabeza y Cuello/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Neurilemoma/metabolismo , Fenotipo , Estudios Retrospectivos , Neoplasias de los Tejidos Blandos/metabolismo , Adulto Joven
5.
Int J Cancer ; 133(1): 235-46, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23292912

RESUMEN

In this work, we have analyzed the expression of different members of the ErbB family in human samples of testicular germ cell tumors (GCTs). We observed expression of ErbB1 or ErbB2 in different tumor subtypes, but we also found high expression of ErbB3 in all GCTs tested. This pattern of expression was maintained when primary tumors were orthotopically implanted in nude mice. We have chosen a choriocarcinoma model characterized by high levels of ErbB1, but also of ErbB2 and ErbB3, to assay the in vivo effect of ErbB inhibitors on tumoral growth. Our results showed a complete lack of effect (refractoriness) to the pure ErbB1 receptor inhibitors cetuximab and gefitinib. While these inhibitors blocked ErbB1 phosphorylation, ErbB2 phosphorylation was not affected, suggesting an ErbB1-independent activation of this receptor. To confirm the importance of ErbB2 activation, animals were treated with lapatinib, a dual ErbB1 and ErbB2 inhibitor. Lapatinib treatment caused a 50% inhibition in tumor growth, an effect correlated with a blockade of both ErbB1 and ErbB2 phosphorylation levels, and of downstream signaling pathways (Akt, ERKs and Stat3). ErbB2 activation could still occur due to the formation of ErbB2/ErbB3 heterodimers, and ErbB3 activation was completely inhibited by lapatinib. Finally, combined inhibition of ErbB1 (gefitinib) and ErbB3 activities (knockdown expression by shRNA) inhibited tumoral testicular cells proliferation in a similar way to lapatinib. Our results explain why lapatinib but not anti-ErbB1 agents might be effective for treatment of testicular GCT patients.


Asunto(s)
Antineoplásicos/farmacología , Receptores ErbB/antagonistas & inhibidores , Neoplasias de Células Germinales y Embrionarias/tratamiento farmacológico , Neoplasias de Células Germinales y Embrionarias/metabolismo , Quinazolinas/farmacología , Neoplasias Testiculares/tratamiento farmacológico , Neoplasias Testiculares/metabolismo , Animales , Anticuerpos Monoclonales Humanizados/farmacología , Western Blotting , Carcinoma Embrionario/tratamiento farmacológico , Carcinoma Embrionario/metabolismo , Supervivencia Celular/efectos de los fármacos , Cetuximab , Coriocarcinoma/tratamiento farmacológico , Coriocarcinoma/metabolismo , Tumor del Seno Endodérmico/tratamiento farmacológico , Tumor del Seno Endodérmico/metabolismo , Receptores ErbB/metabolismo , Gefitinib , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inmunoprecipitación , Lapatinib , Masculino , Ratones , Ratones Desnudos , Neoplasias Experimentales , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor ErbB-2/antagonistas & inhibidores , Receptor ErbB-3/antagonistas & inhibidores , Teratocarcinoma/tratamiento farmacológico , Teratocarcinoma/metabolismo , Trasplante Heterólogo
6.
Curr Med Chem ; 19(5): 661-74, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22204339

RESUMEN

Potassium channels (KCh) are a diverse group of membrane proteins that participate in the control of the membrane potential. More than eighty different KCh genes have been identified, which are expressed in virtually all living cells. In addition to nerve and cardiac action potentials, these proteins are involved in a number of physiological processes, including cell volume regulation, apoptosis, immunomodulation and differentiation. Furthermore, many KCh have been reported to play a role in proliferation and cell cycle progression in mammalian cells, and an important number of studies report the involvement of KCh in cancer progression. The voltage dependent potassium (Kv) channels, in turn, form the largest family of human KCh, which comprises about 40 genes. Because Kv1.3 and Kv1.5 channels modulate proliferation of different mammalian cells, these proteins have been analyzed in a number of tumors and cancer cells. In most cancers, the expression patterns of Kv1.3 and Kv1.5 are remodeled, and in some cases, a correlation has been established between protein abundance and grade of tumor malignancy. The list of cancers evaluated is constantly growing, indicating that these proteins may be future targets for treatment. The aim of this review is to provide an updated overview of Kv1.3 and Kv1.5 channels during cancer development. Unlike Kv1.5, Kv1.3 is characterized by a very selective and potent pharmacology, which could lead to specific pharmacological targeting. Because potassium channels may play a pivotal role in tumor cell proliferation, these proteins should be taken into account when designing new cancer treatment strategies.


Asunto(s)
Canal de Potasio Kv1.3/análisis , Canal de Potasio Kv1.5/análisis , Neoplasias/diagnóstico , Neoplasias/tratamiento farmacológico , Biomarcadores de Tumor , Proliferación Celular , Humanos , Terapia Molecular Dirigida , Neoplasias/patología , Neoplasias/prevención & control
8.
Curr Cancer Drug Targets ; 9(8): 904-14, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-20025600

RESUMEN

Membrane ion channels participate in cancerous processes such as proliferation, migration and invasion, which contribute to metastasis. Increasing evidence indicates that voltage-dependent K(+) (Kv) channels are involved in the proliferation of many types of cells, including tumor cells. Kv channels have generated immense interest as a promising tool for developing new anti-tumor therapies. Therefore, the identification of potential biomarkers and therapeutic targets in specific cancers is an important prerequisite for the treatment. Since Kv1.3 and Kv1.5 are involved in the proliferation of many mammalian cells, we aimed to study the expression of Kv1.3 and Kv1.5 in a plethora of human cancers. Thus, tissues from breast, stomach, kidney, bladder, lung, skin, colon, ovary, pancreas, brain, lymph node, skeletal muscle and some of their malignant counterparts have been analyzed. Whereas Kv1.3 expression was either decreased or did not change in most tumors, Kv1.5 was overexpressed. However, the presence of Kv1.3 was mostly associated with inflammatory lymphoplasmocytic cells. Independent of the suitability of individual channels as therapeutic targets, the identification of a Kv phenotype from tumor specimens could have a diagnostic value of its own. Our results demonstrate that Kv1.5, and to some extent Kv1.3, are aberrantly expressed in a number of human cancers. These channels could serve both as novel markers of the metastatic phenotype and as potential new therapeutic targets. The concept of Kv channels as therapeutic targets or prognostic biomarkers attracts increasing interest and warrants further investigation.


Asunto(s)
Canal de Potasio Kv1.3/metabolismo , Canal de Potasio Kv1.5/metabolismo , Neoplasias/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Western Blotting , Preescolar , Femenino , Humanos , Técnicas para Inmunoenzimas , Masculino , Persona de Mediana Edad , Neoplasias/patología , Pronóstico
9.
Carcinogenesis ; 29(11): 2089-95, 2008 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-18713839

RESUMEN

With the idea to discover novel genes involved in proliferation, we have performed a genome-wide loss-of-function genetic screen to identify additional putative tumor suppressor genes. We have previously identified five genes belonging to different biochemical families. In this report, we focused on the study of one of these genes designated S-adenosylhomocysteine hydrolase (SAHH), which has also been previously identified in an independent short hairpin RNA screening. SAHH inactivation confers resistance to both p53 and p16(INK4)-induced proliferation arrest. Interestingly, SAHH inactivation inhibits p53 transcriptional activity and impairs DNA damage-induced transcription of p21(Cip1). Given that SAHH downregulation modulates senescence in primary cells, we also studied SAHH expression in human tumors at the messenger RNA (mRNA) and protein levels. SAHH mRNA was lost in 50% of tumor tissues from 206 patients with different kinds of tumors in comparison with normal tissue counterparts. Moreover, SAHH protein was also affected in some colon cancers. Such findings may be of relevance to cancer research, suggesting that SAHH might be a largely unexplored tumor suppressor.


Asunto(s)
Adenosilhomocisteinasa/genética , Regulación hacia Abajo , Animales , División Celular , Femenino , Células HeLa , Humanos , Ratones , Células 3T3 NIH , Reacción en Cadena de la Polimerasa , Embarazo , ARN Interferente Pequeño , Proteína de Retinoblastoma/metabolismo , Proteína p53 Supresora de Tumor/metabolismo
10.
Oncología (Barc.) ; 28(8): 394-406, ago. 2005. graf
Artículo en Es | IBECS | ID: ibc-041163

RESUMEN

El efecto citotóxico de las drogas antitumorales es producido mediante la inducción de apoptosis. Esta observaciónimplica la posibilidad de que los factores que afecten la activación de caspasas pueden ser determinantesimportantes como sensibilizantes a los tratamientos antitumorales. Aquí, examinamos el efecto de la sobreexpresiónde caspasa-1 en la respuesta a la quimio y radioterapia. La expresión de la caspasa-1 mediada porun vector adenoviral fue capaz de matar directamente a las células y de sensibilizar las restantes a cisplatino oradiación gamma in vitro. En células HeLa transfectadas establemente con caspasa-1, la sensibilización a cisplatinofue debida a una amplificación en la vía mitocondrial de apoptosis inducida por cisplatino pero esteefecto es independiente del estado de p53, JNK o p38 en la célula


The cytotoxic effect of anticancer drugs has been shown to involve induction of apoptosis. This observationraises the possibility that factors affecting caspase activation might be important determinants as anticancerdrug sensitivity. Ectopic expression of caspase-1 has been shown to trigger apoptosis. Here, we examine theeffect of caspase-1 over-expression on the response to chemotherapy and radiotherapy. Caspase-1 expressionmediated by an adenoviral vector was able to kill directly cells and to sensitize the remaining cells to cisplatinor ã-radiation in vitro. In HeLa cells stably transfected with caspase-1, sensitisation to cisplatin was due to anamplification of the cisplatin-induced mitochondrial apoptotic pathway activation but this effect is independentof p53, JNK or p38 status


Asunto(s)
Humanos , Caspasa 1/farmacocinética , Cisplatino/farmacocinética , Antineoplásicos/farmacocinética , Tolerancia a Radiación , Tolerancia a Medicamentos , Apoptosis , Proteína p53 Supresora de Tumor/análisis
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