RESUMEN
Chromosome 18q is lost a high proportion of colorectal and pancreatic cancers. Three candidate tumor suppressor genes, DCC, Smad4 and Smad2 have been identified in this chromosome region. DCC and Smad4 aberrations have been previously identified in pancreatic and colorectal tumors. The aim of this study was to compare the presence of concurrent genetic aberrations in DCC and neighboring Smad4 and Smad2 genes during colorectal and pancreatic distal dissemination. We have used a panel of orthotopically implanted colorectal and pancreatic xenografts and corresponding metastases. We have shown that while LOH at DCC locus occurred at a similar frequency in both tumors, diminished DCC protein expression was exclusively present in colorectal tumors harboring intragenic DCC LOH. In contrast, in pancreatic xenografts loss of DCC protein and mRNA expression was restricted to metastases. Smad4 gene aberrations were detected at a similar frequency in both tumors and were selected for during distal dissemination. Acquisition of alterations in both genes occurred independently. Our results suggest that both DCC and Smad4 contribute to pancreatic and colorectal distal dissemination. However, the role of DCC may differ between both tumor types.
Asunto(s)
Adenocarcinoma/genética , Cromosomas Humanos Par 18/genética , Neoplasias Colorrectales/genética , Proteínas de Unión al ADN/genética , Genes DCC , Pérdida de Heterocigocidad , Metástasis de la Neoplasia/genética , Proteínas de Neoplasias/genética , Oncogenes , Neoplasias Pancreáticas/genética , Transactivadores/genética , Adenocarcinoma/patología , Adulto , Anciano , Animales , Ascitis/genética , Ascitis/patología , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Neoplasias Colorrectales/patología , Análisis Mutacional de ADN , ADN de Neoplasias/genética , Proteínas de Unión al ADN/fisiología , Progresión de la Enfermedad , Humanos , Metástasis Linfática , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Proteínas de Neoplasias/fisiología , Trasplante de Neoplasias , Células Neoplásicas Circulantes , Neoplasias Pancreáticas/patología , Neoplasias Peritoneales/genética , Neoplasias Peritoneales/patología , Neoplasias Peritoneales/secundario , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/genética , Proteína Smad2 , Proteína Smad4 , Transactivadores/fisiología , Trasplante HeterólogoRESUMEN
Resistance to TGF-beta1 occurred in pancreatic cancer cells suggesting that inactivation of TGF-beta inhibitory signaling pathways may play an important role in human pancreatic cancer. The aim of our study was to determine the presence of alterations in the main putative components of the TGF-beta inhibitory signaling pathways (p15, Smad4, Smad2, TGFbeta-RII, CDC25A). A panel of human carcinomas of the exocrine pancreas orthotopically implanted and perpetuated in nude mice and pancreatic cancer cell lines were studied. p15 gene alterations, mainly homozygous deletions that involved exons 1 and/or 2, were found in the 62.5% (5 of 8) of pancreatic xenografts whereas Smad4 gene aberrations were found in one of eight xenografts and in two of seven cell lines. Additional aberrations in these genes were acquired during in vivo perpetuation and distal dissemination. Paradoxically, TGFbeta-RII overexpression and a decrease in CDC25A protein levels were found in all tumors and cell lines. In one cell line, resistance to TGF-beta1 occurred in the absence of alterations in the genes analysed so far. We conclude that all human pancreatic tumor cells analysed herein have non-functional TGF-beta pathways. The majority of cells harbor alterations in at least one of the putative components of TGF-beta pathways, mainly in p15 and Smad4 genes. These results suggest that inactivation of TGF-beta signaling pathways plays an important role in human pancreatic tumorigenesis.