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3.
Ann Oncol ; 26(12): 2450-6, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26416897

RESUMEN

BACKGROUND: Tumor-associated macrophages (TAMs) with the M2-like phenotype are regulated by mainly NF-kB pathway including TBK1, which can influence tumor progression by secretion of proangiogenic factors such as vascular endothelial growth factor. The CCL2/CCR2 axis, histidine-rich glycoprotein (HRG), and placenta growth factor (PIGF) play a critical role in the polarization of M1/M2 phenotypes and the recruitment of TAMs to tumor microenvironment. We therefore hypothesized that variations in genes involved in regulating TAMs may predict clinical outcomes of bevacizumab treatment in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: We analyzed genomic DNA extracted from samples of patients receiving bevacizumab plus FOLFIRI as a first-line treatment using PCR-based direct sequencing. Twelve functional single-nucleotide polymorphisms in eight genes (CCL2, CCR2, HRG, PIGF, NFKB1, TBK1, CCL18, and IRF3) were tested for associations with clinical outcomes in a discovery cohort of 228 participants in TRIBE trial (NCT00719797), then validated in 248 KRAS exon2 (KRAS) wild-type participants in FIRE3 trial (NCT00433927). FIRE3-cetuximab cohort served as a negative control. RESULTS: TBK1 rs7486100 was significantly associated with overall survival in 95 KRAS wild-type patients of TRIBE cohort in univariate analysis and had a strong trend in multivariable analysis; furthermore, the association of the T allele was observed for progression-free survival (PFS) in both univariate and multivariable analyses in FIRE3-bevacizumab but not cetuximab cohort. CCL2 rs4586, CCL18 rs14304, and IRF3 rs2304205 had univariate and multivariable correlations with PFS in KRAS mutant patients of the TRIBE cohort, whereas they had no correlations in KRAS wild-type patients of the TRIBE cohort. No association was seen in control cohort. CONCLUSIONS: Our study demonstrates for the first time that variations in genes regulating TAMs-related functions are significantly associated with clinical outcomes in mCRC patients treated with bevacizumab-containing chemotherapy. These results also suggest that some TAM-related gene variations may predict outcomes of bevacizumab treatment in KRAS status-dependent manner.


Asunto(s)
Bevacizumab/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Variación Genética/genética , Macrófagos/fisiología , Adulto , Anciano , Estudios de Cohortes , Neoplasias Colorrectales/diagnóstico , Femenino , Variación Genética/efectos de los fármacos , Humanos , Macrófagos/efectos de los fármacos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Resultado del Tratamiento
4.
Pharmacogenomics J ; 15(1): 69-76, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25069475

RESUMEN

Pericytes are crucial for angiogenesis. The impact of pericyte function to bevacizumab efficacy in mCRC treatment has not been comprehensively examined. This retrospective study investigated germline polymorphisms in genes related to early pericyte maturation to predict bevacizumab efficacy in 424 patients of two clinical trials treated first line with FOLFIRI+bevacizumab. Eight single-nucleotide polymorphisms (SNPs) were tested for potential biomarker value: RGS5 (regulator of G-protein signaling 5; rs1056515, rs2661280), PDGFR-ß (platelet-derived growth factor receptor-ß; rs2229562, rs2302273), CSPG4 (chondroitin sulfate proteoglycan NG2; rs8023621, rs1127648) and RALBP1 (RalA binding protein 1; rs10989, rs329007). For progression-free survival (PFS), PDGFR-ß (rs2302273) was able to define significantly different patient cohorts in uni- and multivariate testing. RALPB1 (rs329007) showed predictive value for tumor response. The C allele in RGS5 (rs2661280) predicted longer overall survival and CSPG4 rs1127648 was associated with differences in PFS, but for both value was lost when multivariate analysis was applied. A comprehensive statistical analysis revealed that the biomarker value of the SNPs was dependent on primary tumor location. This is the first study to identify pericyte germline polymorphisms associated with clinical outcome in mCRC patients treated first line with FOLFIRI+bevacizumab. The differences seen with regard to primary tumor location may lead to further research to understand the clinical outcome differences seen in right- and left-sided colon cancer.


Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Camptotecina/análogos & derivados , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Pericitos/patología , Adulto , Anciano , Anciano de 80 o más Años , Bevacizumab , Camptotecina/administración & dosificación , Neoplasias Colorrectales/diagnóstico , Femenino , Fluorouracilo/administración & dosificación , Humanos , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Resultado del Tratamiento
5.
Br J Cancer ; 108(5): 1052-60, 2013 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-23422754

RESUMEN

BACKGROUND: Combining bevacizumab with first-line chemotherapy significantly improves progression-free survival (PFS) in HER2-negative metastatic breast cancer (mBC). However, identification of patients benefitting most from bevacizumab remains elusive. The AVADO trial included an extensive optional exploratory biomarker programme. METHODS: Patients with HER2-negative mBC were randomised to receive docetaxel with placebo or bevacizumab. The primary end point was PFS. Plasma samples were analysed using a multiplex ELISA. Blood mRNA expression was assessed using quantitative PCR. Tumour tissue samples were analysed by immunohistochemistry. Single-nucleotide polymorphisms (SNPs) involved in the VEGF pathway were analysed in germline DNA. RESULTS: Samples for biomarker analysis were available from 24-54% of the 736 treated patients (depending on specimen type). The most consistent potential predictive effect was observed with plasma VEGF-A and VEGFR-2; high baseline concentrations were associated with greater treatment effect. Blood mRNA analyses suggested a greater bevacizumab effect in patients with high VEGF121. No consistent predictive effect was seen for tumour neuropilin or other candidate tumour markers by immunohistochemistry, or for any of the SNPs investigated. CONCLUSION: Plasma VEGF-A and VEGFR-2 are potential predictive markers for bevacizumab efficacy, supporting findings in gastric and pancreatic cancers. Plasma VEGF-A is being evaluated prospectively in mBC in the MERiDiAN trial.


Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/sangre , Neoplasias de la Mama/tratamiento farmacológico , Receptor ErbB-2/metabolismo , Taxoides/administración & dosificación , Factor A de Crecimiento Endotelial Vascular/sangre , Receptor 2 de Factores de Crecimiento Endotelial Vascular/sangre , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab , Neoplasias de la Mama/sangre , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Supervivencia sin Enfermedad , Docetaxel , Femenino , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Polimorfismo de Nucleótido Simple , Valor Predictivo de las Pruebas
6.
J Cell Biochem ; 100(3): 679-92, 2007 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-16986113

RESUMEN

Cells experience a variety of physiological and non-physiological stresses and consequently have appropriate mechanisms to deal with such deviations from homeostasis. Particularly subject to mechanical stress and shear forces are the cells that make up the bones. Osteoblastic cells can interpret this stress as a stimulus for proliferation; however, the molecular mechanisms underlying this phenomenon are poorly understood. We have identified annexin II as being specifically upregulated in mechanically stressed osteoblasts and found that increased levels of this protein are necessary for 1[alpha],25-dihydroxyvitamin D(3) mediated augmentation of the proliferative response of osteoblasts after mechanical stress. Our data demonstrate a novel interaction between 1[alpha],25-dihydroxyvitamin D(3) and annexin II in the proliferative response of osteoblasts as well as a novel function for annexin II in the stress response. These findings may offer new therapeutic opportunities for conditions that require regenerative osteoblastic activity such as osteoporosis.


Asunto(s)
Anexina A2/fisiología , Calcitriol/farmacología , Proliferación Celular/efectos de los fármacos , Osteoblastos/efectos de los fármacos , Adulto , Anciano , Animales , Western Blotting , Línea Celular , Electroforesis en Gel Bidimensional , Humanos , Ratones , Persona de Mediana Edad , Osteoblastos/citología
7.
Biochem Soc Trans ; 33(Pt 4): 689-93, 2005 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-16042575

RESUMEN

Mutations in MMR (DNA mismatch repair) genes underlie HNPCC (hereditary non-polyposis colon cancer) and also a significant proportion of sporadic colorectal cancers. MMR maintains genome stability and suppresses tumour formation by correcting DNA replication errors and by mediating an apoptotic response to DNA damage. Analysis of mouse lines with MMR missense mutations demonstrates that these MMR functions can be separated and allows the assessment of their individual roles in tumour suppression. These studies in mice indicate that, although the increased mutation rates caused by MMR defects are sufficient to drive tumorigenesis, both functions co-operate in tumour suppression.


Asunto(s)
Disparidad de Par Base/genética , Neoplasias del Colon/genética , Reparación del ADN/genética , Predisposición Genética a la Enfermedad/genética , Mutación Missense , Animales , Daño del ADN , Modelos Animales de Enfermedad , Humanos , Ratones
8.
Gene ; 264(2): 197-203, 2001 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-11250074

RESUMEN

P53 is by far the most frequently altered gene in mammalian tumors. However, so far not a single p53 lesion has been reported in malignancies of cancer model systems in lower vertebrates. For analyzing the function of p53 in lower vertebrates, the gene was cloned from the medakafish (Oryzias latipes). Despite some differences in the genomic organization, the fish p53 amino acid sequence is highly conserved. Contrary to higher vertebrates, the level of p53 mRNA in medaka embryos gradually increases during embryogenesis. High expression of the p53 mRNA was detected in melanoma cells compared to undetectable expression of the gene in embryonic stem cells and fibroblasts. No effect of ultraviolet (UV) irradiation on the expression of p53 in cell cultures as well as in medaka fry was observed, indicating a possible difference in the function of p53 in lower vertebrates.


Asunto(s)
Oryzias/genética , Proteína p53 Supresora de Tumor/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Southern Blotting , Línea Celular , Clonación Molecular , ADN/química , ADN/genética , Exones , Dosificación de Gen , Regulación de la Expresión Génica/efectos de la radiación , Genes/genética , Genes Supresores de Tumor/genética , Intrones , Datos de Secuencia Molecular , Análisis de Secuencia de ADN , Células Tumorales Cultivadas , Rayos Ultravioleta
9.
J Biol Chem ; 275(48): 37469-73, 2000 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-10984493

RESUMEN

The tumor suppresser protein p53 is critical for guarding the genome from incorporation of damaged DNA (Lane, D. P. (1992) Nature 358, 15-16). A relevant stress that activates p53 function is UV light (Noda, A., Toma-Aiba, Y., and Fujiwara, Y. (2000) Oncogene 19, 21-31). Another well known component of the mammalian UV response is the transcription factor c-Jun (Angel, P., and Karin, M. (1991) Biochim. Biophys. Acta 1072, 129-157). We show here that upon UV irradiation p53 activates transcription of the human mismatch repair gene MSH2. Interestingly, this up-regulation critically depends on functional interaction with c-Jun. Hence, the synergistic interaction of a proto-oncogene with a tumor suppresser gene is required for the regulation of the mammalian stress response through activation of expression of MSH2.


Asunto(s)
Reparación del ADN/genética , Proteínas de Unión al ADN , Regulación de la Expresión Génica/efectos de la radiación , Proteínas Proto-Oncogénicas c-jun/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteína p53 Supresora de Tumor/metabolismo , Rayos Ultravioleta , Secuencia de Bases , Línea Celular , ADN , Humanos , Proteína 2 Homóloga a MutS , Regiones Promotoras Genéticas , Proto-Oncogenes Mas , Células Tumorales Cultivadas
10.
Biochem Biophys Res Commun ; 221(3): 722-8, 1996 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-8630028

RESUMEN

MSH2 is one of the genes involved in DNA-mismatch repair. Mutations in the coding region of the human gene (hMSH2) have been shown to be directly involved in microsatellite instability in hereditary nonpolyposis colorectal tumors. Examination of the promoter region of hMHS2 revealed a site with homology to the p53 consensus binding sequence. Using gel mobility shift experiments we were able to show that purified p53 has at least in vitro the potential to specifically bind the hMSH2-p53 motif. This binding activity was even stronger than the binding activity measured with the p53-consensus site. These data identify the hMSH2 gene as a possible novel p53-regulated target gene and indicate a direct involvement of p53 in repair mechanisms via DNA binding of a mismatch repair gene.


Asunto(s)
Reparación del ADN/genética , Proteínas de Unión al ADN/genética , Proteínas Fúngicas , Regiones Promotoras Genéticas , Proteína p53 Supresora de Tumor/metabolismo , Animales , Baculoviridae/genética , Secuencia de Bases , Sitios de Unión , Línea Celular , ADN Recombinante , Proteínas de Unión al ADN/metabolismo , Humanos , Insectos , Datos de Secuencia Molecular , Proteína 2 Homóloga a MutS , Unión Proteica , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Homología de Secuencia de Ácido Nucleico , Proteína p53 Supresora de Tumor/genética
11.
Hum Genet ; 97(1): 114-6, 1996 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-8557250

RESUMEN

Hereditary nonpolyposis colorectal cancer (HN-PCC) is one of man's commonest hereditary diseases. Several studies have identified four responsible genes that are involved in a process known as DNA mismatch repair; hMSH2 is the most important of these four genes. In addition to mutational analysis of these genes, investigations of transcriptional regulatory mechanisms are important. Therefore, our purpose has been to isolate the hMSH2 promoter region. Using direct sequencing of P1 recombinant DNA we have characterized 1100 bp of the hMSH2 promoter.


Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Reparación del ADN/genética , Proteínas de Unión al ADN/genética , Proteínas Fúngicas , Regiones Promotoras Genéticas , Secuencia de Bases , Cartilla de ADN , Exones , Femenino , Biblioteca Genómica , Humanos , Datos de Secuencia Molecular , Proteína 2 Homóloga a MutS , Placenta/metabolismo , Reacción en Cadena de la Polimerasa , Embarazo
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