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Nuclear thymidylate synthase expression, p53 expression and 5FU response in colorectal carcinoma
1Department of Pathology, University of Edinburgh Medical School, Teviot Place, Edinburgh, EH8 9AG.
Abstract:
Thymidylate synthase (TS) is a key enzyme in DNA synthesis and is inhibited by metabolites of the chemotherapeutic agent 5-fluorouracil (5FU). Nuclear expression of TS in human tissue in vivo has not been characterised and its clinicopathological correlates in malignancy are unknown. 52 cases of primary colorectal carcinoma (CRC) and 24 cases of matched metastatic carcinoma were studied immunohistochemically using the monoclonal antibody TS106. The degree of nuclear TS immunostaining correlated closely with levels of TS mRNA expression amongst 10 CRCs studied. Strong nuclear immunostaining was seen in normal basal crypt colonocytes and germinal centre cells, and in a varying proportion of adenocarcinoma cells. Amongst the primary carcinomas, higher TS nuclear expression was associated with prominent extracellular mucin production and right-sided location. Higher TS nuclear expression also showed a significant association with poorer response to protracted venous infusional 5FU therapy. There was no clear association between TS nuclear expression and Ki67 or p53 expression assessed immunohistochemically. There was a strong positive correlation between TS nuclear expression in primary and metastatic CRC but the latter generally showed higher expression than matched primary tumour tissue. These findings confirm the nuclear expression of TS protein in human cells in vivo and provide new insight into how such expression may relate to the behaviour of CRCs.
Insights
Nuclear thymidylate synthase (TS) expression in colorectal cancer (CRC) correlates with tumor characteristics and 5-fluorouracil (5FU) treatment response. This study characterized TS nuclear expression in vivo, revealing its association with poorer treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Thymidylate synthase (TS) is crucial for DNA synthesis and a target for 5-fluorouracil (5FU) chemotherapy.
- Nuclear expression of TS in human tissues in vivo and its clinical significance in malignancy remain largely uncharacterized.
Purpose of the Study:
- To characterize nuclear TS protein expression in primary and metastatic colorectal carcinoma (CRC) in vivo.
- To investigate the clinicopathological correlates of nuclear TS expression in CRC.
- To assess the relationship between nuclear TS expression and response to 5FU-based chemotherapy.
Main Methods:
- Immunohistochemistry using the monoclonal antibody TS106 was performed on 52 primary and 24 matched metastatic colorectal carcinomas.
- TS nuclear immunostaining was correlated with TS mRNA levels, clinicopathological features, and patient response to 5FU therapy.
- Expression levels of Ki67 and p53 were also assessed.
Main Results:
- Nuclear TS expression was observed in normal colonocytes and a variable proportion of CRC cells.
- Higher nuclear TS expression in primary tumors correlated with extracellular mucin production and right-sided location.
- Increased nuclear TS expression was associated with a poorer response to protracted venous infusional 5FU therapy and higher expression in metastatic versus primary tumors.
Conclusions:
- This study confirms nuclear TS protein expression in human CRC in vivo.
- Nuclear TS expression is a potential predictive biomarker for 5FU chemotherapy response in CRC patients.
- Further research into the role of nuclear TS in CRC progression and treatment is warranted.
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