Clinical relevance of thymidylate synthase expression in the signet ring cell histotype component of colorectal carcinoma

Abstract

Thymidylate Synthase (TS) is the key enzyme for DNA synthesis pathways and is inhibited by 5-fluorouracil (5FU). The aim of this work was to study TS expression and the proliferation rate in the different histological types of colorectal carcinoma (CRC). 50 patients with CRC were included in this study and evaluated immunohistochemically using the monoclonal antibodies, TS106 and Ki67. 20 tumours were of the intestinal type, 15 cases were signet ring cell carcinoma (SRCCs) and 15 cases were "mixed-type", with at least two different histological components. Intestinal and mucinous histotypes were positive for TS and Ki67, while "signet ring cell" samples were negative or showed only weak and focal positivity for both the TS and Ki67 antibodies. Our results show that signet ring cells (that are also often present in intestinal and mucinous carcinomas), are in the post-mitotic phase of the cell cycle and show a low proliferation index and TS expression. As TS is the key enzyme for DNA synthesis pathways and is inhibited by 5-fluorouracil (5FU), we can hypothesise that TS expression levels in the different histotypes of CRC could affect the potential responsiveness of these tumours to fluoropyrimidine chemotherapy, with a low efficacy being expected in signet ring cell areas.

Primary signet ring cell carcinoma of the colon and rectum

“…Surgical management has a key role in the treatment of localized tumors. [42,46]. The effectiveness of targeted therapies including angiogenesis inhibitors and EGFR inhibitors is not established.…”

“…The aim of the treatment is to improve symptoms, maintain quality of life, and stop tumor progression. Published series showed that these SRCC are less sensitive to commonly used chemotherapy drugs, including 5FU, oxaliplatin, and irinotecan[7,46,47].Cabibi et al have demonstrated that this drug resistance may be due to a low proliferative activity of tumor cells, as the analysis of 15 SRCC samples showed very low levels of Ki-67 expression (a proliferation marker) and weak positivity for thymidylate synthase (key enzyme for DNA synthesis pathways targeted by 5FU)…”

Role of Claudin-4 and Matrix Metalloproteinase-2 in Tumor Invasion of Colorectal Adenocarcinoma

“…MMP-9 which located on cell surface is needed for tumor invasion and angiogenesis 19 . The increasing of MMP-2 could degrade extracellular matrix and destroy protein on basalis membrane; thus, tumor cell could enter the stroma and adjacent tissue easier 20 . MT1-MMP (membrane-type MMPs) activate pro-MMP-2 and break type I, II, III collagens, gelatine, fibronectin, laminin-1, vitronectin, cartilage proteoglycans, and fibrillin-1, which expressed by epithelial cell 21 .…”

The value of adjuvant chemotherapy in stage II/III colorectal signet ring cell carcinoma

“…Therefore, the application of other therapeutic approaches has been increasing, including chemotherapy 10 . However, relevant researches have shown that colorectal SRCC is relatively insensitive to the commonly applied chemotherapeutics, such as irinotecan, oxaliplatin as well as 5-fluorouracil 13 , 14 , 23 . Cabibi et al have demonstrated that such drug resistance may be due to a low proliferative activity of tumor cells, as the analysis of 15 SRCC samples showed very low levels of Ki-67 expression (a proliferation marker) and weak positivity for thymidylate synthase (key enzyme for DNA synthesis pathways targeted by 5-FU) 13 , 23 , 24 .…”