High Thymidylate Synthase Expression in Colorectal Cancer with Microsatellite Instability: Implications for Chemotherapeutic Strategies
| Autor: | Luigi Ricciardiello, Guido Biasco, Pasquale Chieco, Paola Paterini, Franco Bazzoli, Claudio Ceccarelli, M. Pariali, Graziella Angiolini, Giuseppe Martinelli, Enrico Roda |
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| Přispěvatelé: | RICCIARDIELLO L., CECCARELLI C., ANGIOLINI G., PARIALI M., CHIECO P., PATERINI P., BIASCO G., MARTINELLI GN., RODA E., BAZZOLI F. |
| Rok vydání: | 2005 |
| Předmět: |
Male
Vascular Endothelial Growth Factor A Cancer Research Pathology Colorectal cancer Cell Cycle Proteins Thymidylate synthase chemistry.chemical_compound Gene expression Promoter Regions Genetic beta Catenin Aged 80 and over biology Nuclear Proteins Proto-Oncogene Proteins c-mdm2 Methylation Middle Aged Immunohistochemistry Neoplasm Proteins DNA-Binding Proteins Vascular endothelial growth factor MutS Homolog 2 Protein Oncology Mdm2 Female DNA mismatch repair Colorectal Neoplasms MutL Protein Homolog 1 Adult Cyclin-Dependent Kinase Inhibitor p21 congenital hereditary and neonatal diseases and abnormalities medicine.medical_specialty Colon cancer microsatellite instability 5-fluorouracil thymidylate synthase p53 Drug Therapy Proto-Oncogene Proteins medicine Humans neoplasms Adaptor Proteins Signal Transducing Aged nutritional and metabolic diseases Microsatellite instability Thymidylate Synthase DNA Methylation medicine.disease digestive system diseases Cytoskeletal Proteins chemistry Trans-Activators Cancer research biology.protein Tumor Suppressor Protein p53 Carrier Proteins Microsatellite Repeats |
| Zdroj: | Clinical Cancer Research. 11:4234-4240 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-05-0141 |
| Popis: | Colon cancers displaying microsatellite instability (MSI) are clinically less aggressive. Based on in vitro studies and recent clinical data, cancers displaying MSI do not respond to 5-fluorouracil (5-FU). The reasons why MSI tumors are clinically less aggressive and do not respond to 5-FU–based therapies have not been fully elucidated. Purpose: We investigated biomolecular markers in an attempt to explain the different clinical behavior and chemotherapeutic responses of MSI and non-MSI colon cancers. Experimental Design: One hundred ninety-two sporadic colon cancers were tested for MSI with five mononucleotide markers and methylation of the hMLH1 promoter. Slides were stained for thymidylate synthase (TS), p53, MDM2, p21WAF1/CIP1, β-catenin, vascular endothelial growth factor, hMLH1, hMSH2, and hMSH6. Tumors were regarded as having wild-type, functional p53 (Fp53) if reduced expression of p53 and positive MDM2 and p21WAF1/CIP1 expressions were found. Results: Of the cases, 12.5% were MSI-H (at least two markers mutated). Of MSI-H cases, 83.3% were characterized by a complete loss of at least one of the mismatch repair proteins, in particular loss of hMLH1 by promoter hypermethylation. MSI-H colon cancers showed higher expression of TS compared with MSS (no mutated markers)/MSI-L (one mutated marker) colon cancers (66.6% for MSI-H versus 14.8% MSS/MSI-L; P < 0.0001); 20.8% of MSI-H cases showed high expression of the vascular endothelial growth factor, compared with 45.8% MSS/MSI-L colon cancers (P = 0.0005); 45.8% MSI-H cases had Fp53 compared 11.9% MSS/MSI-L cases (P < 0.0001). Conclusions: About 12% of colon cancers display MSI mostly due to lack of hMLH1 resulting from promoter hypermethylation. These tumors have high expression of TS and retain fully functional p53 system. Thus, these data suggest why sporadic hMLH1-defective colon cancers often do not respond to 5-FU. |
| Databáze: | OpenAIRE |
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