Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / genetics*
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Adenocarcinoma / pathology
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Adult
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Aged
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Animals
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Ascites / genetics
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Ascites / pathology
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Chromosomes, Human, Pair 18 / genetics*
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Colonic Neoplasms / genetics
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Colonic Neoplasms / pathology
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Colorectal Neoplasms / genetics*
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Colorectal Neoplasms / pathology
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DNA Mutational Analysis
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DNA, Neoplasm / genetics
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / physiology
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Disease Progression
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Genes, DCC*
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Humans
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Loss of Heterozygosity*
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Lymphatic Metastasis
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Male
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Mice
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Mice, Nude
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Middle Aged
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Neoplasm Metastasis / genetics*
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Neoplasm Proteins / genetics*
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Neoplasm Proteins / physiology
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Neoplasm Transplantation
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Neoplastic Cells, Circulating
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Oncogenes*
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Pancreatic Neoplasms / genetics*
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Pancreatic Neoplasms / pathology
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Peritoneal Neoplasms / genetics
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Peritoneal Neoplasms / pathology
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Peritoneal Neoplasms / secondary
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / genetics
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Smad2 Protein
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Smad4 Protein
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Trans-Activators / genetics*
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Trans-Activators / physiology
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Transplantation, Heterologous
Substances
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DNA, Neoplasm
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DNA-Binding Proteins
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Neoplasm Proteins
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SMAD2 protein, human
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SMAD4 protein, human
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Smad2 Protein
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Smad2 protein, mouse
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Smad4 Protein
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Smad4 protein, mouse
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Trans-Activators