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High thymidylate synthase expression in colorectal cancer with microsatellite instability: implications for
Luigi Ricciardiello1, Claudio Ceccarelli, Graziella Angiolini
1Department of Internal Medicine and Gastroenterology, University of Bologna, Italy.
Unlabelled:
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, p21(WAF1/CIP1), beta-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 p21(WAF1/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.
Insights
Colon cancers with microsatellite instability (MSI) are less aggressive and do not respond to 5-fluorouracil (5-FU). This is linked to high thymidylate synthase expression and functional p53 in MSI tumors, explaining their resistance to 5-FU therapy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Colon cancers with microsatellite instability (MSI) exhibit distinct clinical behaviors, often being less aggressive.
- Existing evidence suggests MSI-positive tumors do not respond effectively to 5-fluorouracil (5-FU)-based chemotherapy.
- The underlying molecular mechanisms for these differences remain incompletely understood.
Purpose of the Study:
- To investigate specific biomolecular markers that differentiate the clinical behavior and chemosensitivity of MSI versus non-MSI colon cancers.
- To elucidate the molecular basis for the observed differences in therapeutic response.
Main Methods:
- Assessed microsatellite instability (MSI) in 192 sporadic colon cancers using five mononucleotide markers and hMLH1 promoter methylation analysis.
- Performed immunohistochemical staining for thymidylate synthase (TS), p53, MDM2, p21(WAF1/CIP1), beta-catenin, vascular endothelial growth factor (VEGF), hMLH1, hMSH2, and hMSH6.
- Defined tumors with functional p53 (Fp53) based on reduced p53 expression and positive MDM2 and p21(WAF1/CIP1) staining.
Main Results:
- Approximately 12.5% of colon cancers were classified as MSI-High (MSI-H), predominantly due to hMLH1 promoter hypermethylation and loss of mismatch repair proteins.
- MSI-H colon cancers demonstrated significantly higher thymidylate synthase (TS) expression (66.6%) compared to MSS/MSI-Low tumors (14.8%).
- MSI-H tumors showed a higher prevalence of functional p53 (Fp53) (45.8%) and lower vascular endothelial growth factor (VEGF) expression (20.8%) compared to MSS/MSI-L cancers.
Conclusions:
- Microsatellite instability (MSI) in sporadic colon cancers, often caused by hMLH1 promoter hypermethylation, is associated with high TS expression and a functional p53 system.
- These molecular characteristics, particularly elevated TS and intact p53, provide a rationale for the observed lack of response to 5-fluorouracil (5-FU) in MSI-H colon cancers.
- Understanding these markers is crucial for predicting treatment outcomes and developing targeted therapies for MSI-defective colon cancers.
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