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Int. J. Mol. Sci. 2014, 15(9), 15767-15777; doi:10.3390/ijms150915767

CES2, ABCG2, TS and Topo-I Primary and Synchronous Metastasis Expression and Clinical Outcome in Metastatic Colorectal Cancer Patients Treated with First-Line FOLFIRI Regimen

1
Medical Oncology Unit, National Cancer Research Centre—Istituto Tumori "Giovanni Paolo II", Viale Orazio Flacco 65, 70124 Bari, Italy
2
Pathology Department, National Cancer Research Centre—Istituto Tumori "Giovanni Paolo II", Viale Orazio Flacco 65, 70124 Bari, Italy
3
Functional Biomorphology Laboratory, National Cancer Research Centre—Istituto Tumori "Giovanni Paolo II", Viale Orazio Flacco 65, 70124 Bari, Italy
4
IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), 47014 Meldola, Italy
5
Oncology Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Viale Cappuccini 1, 71013 San Giovanni Rotondo, Italy
6
Experimental Medical Oncology, National Cancer Research Centre—Istituto Tumori "Giovanni Paolo II", Viale Orazio Flacco 65, 70124 Bari, Italy
*
Author to whom correspondence should be addressed.
Received: 14 July 2014 / Revised: 22 August 2014 / Accepted: 2 September 2014 / Published: 5 September 2014
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Abstract

Enzymatic activation of irinotecan (CPT-11) is due to carboxylesterase (CES), and its pharmacological behavior is influenced by drug resistance-related proteins. We previously reported that the clinical response and prognosis of metastatic colorectal cancer (mCRC) patients did not differ in tumors with different thymidylate synthase (TS) or topoisomerase-I (Topo-I) expression. Using immunohistochemistry (IHC), we evaluated the biological role of CES2 and the expression of breast cancer resistance protein (BCRP/ABCG2) in 58 consecutive mCRC patients, who had undergone a first-line CPT-11/5-FU/leucovirin (FOLFIRI) regimen. The expression of these proteins was also examined in a group of synchronous lymph nodes and liver metastases. Furthermore, all samples were revaluated for TS and Topo-I expression. High expression of CES2, ABCG2, TS and Topo-I was observed in 55%, 56%, 38% and 49% of patients, respectively. There was a significant association between high TS and high ABCG2 expression (p = 0.049). Univariate analysis showed that only TS expression significantly impacted on time to progression (p = 0.005). Moreover, Cox’ multivariate analysis revealed that TS expression was significantly associated with overall survival (p = 0.01). No significant correlation was found between investigated markers expression and clinical response. Topo-I expression resulted in being significantly higher in liver metastases with respect to the corresponding primary tumors (p < 0.0001), emphasizing the role of Topo-I expression in metastatic cancer biology. In primary tumor tissues, CES2 expression tended to be higher than that observed in liver metastasis tissues (p = 0.05). These preliminary data may suggest CES2 over-expression as a potential marker of malignant phenotype. In light of these findings, we suggest that Topo-I expression together with TS expression could be associated with metastatic progression of CRC. Further studies are warranted with the aim of evaluating the potential predictive and prognostic role of CES2 and ABCG2 in larger series of patients. View Full-Text
Keywords: irinotecan; leucovorin; 5-fluorouracil; carboxylesterase 2 (CES2); breast cancer resistance protein 2 (ABCG2); immunohistochemistry irinotecan; leucovorin; 5-fluorouracil; carboxylesterase 2 (CES2); breast cancer resistance protein 2 (ABCG2); immunohistochemistry
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Silvestris, N.; Simone, G.; Partipilo, G.; Scarpi, E.; Lorusso, V.; Brunetti, A.E.; Maiello, E.; Paradiso, A.; Mangia, A. CES2, ABCG2, TS and Topo-I Primary and Synchronous Metastasis Expression and Clinical Outcome in Metastatic Colorectal Cancer Patients Treated with First-Line FOLFIRI Regimen. Int. J. Mol. Sci. 2014, 15, 15767-15777.

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