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Thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) are 5-fluorouracil (5-FU) metabolizing enzymes and are involved in the sensitivity of carcinoma patients to 5-FU. Although 5-FU is often used for the treatment of oral carcinoma, there has not been any investigation into the expression of these enzymes in metastatic lymph nodes or of their roles in the effectiveness of 5-FU in treating lymph node-metastatic cancer. Oral squamous cell carcinoma (OSCC) often metastasizes to the lymph nodes, and these enzymes may be significant in the survival of patients with this disease. This study investigated the expression of TS and DPD in cervical lymph node metastases and its relationship with primary OSCC, as well as the interaction between these enzymes and Kangai 1(KAI1/CD82) which is a metastasis suppressor protein. Surgical specimens from 20 cases of OSCC with lymph node metastasis, 20 cases of OSCC without lymph node metastasis, and 10 cases of normal mucosa were examined by immunohistochemistry. The relationship between TS and DPD expression and clinicopathological data was analyzed. TS and DPD proteins were overexpressed in primary OSCC compared to that in normal mucosa. TS expression of the primary oral cancer cells in the group with lymph node metastasis was higher than that of those without. DPD expression did not significantly correlate with the occurrence of lymph node metastasis, nor was it different between primary oral cancer cells and cervical metastases. CD82 expression was significantly reduced in lymph node metastases. These findings indicate that TS and CD82 may be of great value in assessing lymph node metastasis of OSCC, and could be taken as new targets for therapy of metastatic OSCC.

We have been investigating various molecules correlated with the malignancy of esophageal squamous cell carcinoma and, in the present study, we examined the correlation of four of them (KAI1, FAK, EphA2, Ki-67 labeling index) with the prognosis of affected patients. Furthermore, the use of biopsy samples was studied to evaluate whether the grade of tumor malignancy can be determined before treatment in a clinical setting.Tissue specimens that had been surgically removed from 91 patients with thoracic esophageal cancer and 247 biopsy samples were examined. The malignancy index (MI) was defined in terms of the KAI1, FAK and EphA2 scores and the Ki-67 labeling index, and the reliability and utility of the correlation between MI and prognosis was evaluated.The mean 5-year survival rate of patients with MI=0 was 100%, while that of patients with MI=1, 2 and 3 was 70%, 48% and 10%, respectively. Patients with MI=4 all died, with the exception of one who has been observed for 3 years. The rate of concordance between the biopsy samples and surgical specimens was 79.4% for KAI1, 88.2% for FAK and 73.5% for EphA2, and the rates of concordance for 1, 2, 3, 4, 5, 6, 7 and 8 biopsy samples were 66.7%, 64.1%, 74.5%, 90.7%, 91.7%, 83.3%, 100% and 100%, respectively.It may be feasible to evaluate the malignancy of tumor cells and to predict patient outcome by using multiple marker molecules. It is anticipated that such data will accelerate the development of "tailor-made" therapy.

The importance of KAI1 to colorectal cancer (CRC) progression is unclear, with conflicting data regarding changes in KAI1 expression during tumour progression.In situ hybridisation and immunohistochemistry, with a semiquantitative scoring system, were used to assess KAI1 mRNA and protein levels, respectively, in normal colon samples (43), and non-metastatic (24) or metastatic (33) primary cancers, and liver metastases (48).There was significant loss of KAI1 mRNA and protein staining in non-metastatic primary tumours versus normal tissues (Bonferroni, p0.05) but levels recovered to near normal in metastatic primary tumours and liver metastases. Increased KAI1 expression significantly correlated with distant metastases (Mann-Whitney, p = 0.0001, mRNA; p = 0.033, protein), cancer-specific survival (Cox regression analysis p = 0.0002, mRNA; 0.0493, protein) and overall patient survival (p = 0.0001, mRNA). Multivariate analysis (Cox proportional hazards model) confirmed high KAI1 mRNA expression was an independent prognostic indicator of distant metastasis (p0.0001), cancer-specific survival (p0.0001) and overall patient survival (p0.0001).These data indicate a complex relationship between KAI1 and progression of human CRC, in which expression is reduced in localised primary tumours, but regained in disease associated with metastasis.

Since its identification as a suppressor gene for prostate cancer metastasis, down-regulation of KAI1/CD82 in a variety of malignancies has been reported.Using immunohistochemistry, we examined KAI1/CD82 expression in surgical specimens obtained from 70 patients with advanced colorectal cancer and its correlation with clinicopathological factors, to clarify their prognostic significance.KAI1/CD82 expression was positive in 55% of the 70 colorectal cancers. There were statistically significant correlations between KAI1/CD82 expression and Dukes' stage, venous invasion, lymph node metastasis, tumor differentiation and liver metastasis. The significant correlation between KAI1/CD82 expression and outcome among patients with Dukes' C cancer (p=0.024) is particularly noteworthy. On multivariate analysis, KAI1/CD82 expression and Dukes' stage were identified as significant and independent prognostic factors (p=0.006 and 0.045, respectively).KAI1/CD82 expression closely correlates with clinicopathological factors for colorectal cancers. KAI1/CD82 expression appears to be a useful prognostic marker.

Loss of KAI1 protein is a frequent event in various types of cancer and has been reported to be associated with increased rate of metastasis and shorter survival time.Expression of KAI1 and p53 was immunohistochemically determined in 75 biopsy specimens from patients with primary irradiated, invasive squamous cell cervical cancer and 30 cases with CIN I-III.In invasive cancer, 22 cases showed strong expression, 42 cases down-regulation, and 11 cases no expression of KAI1. All specimens with CIN I showed strong KAI1 expression, while in CIN II and III down-regulation was observed in 45% of cases. There was no significant correlation of KAI1 expression with clinical and histopathological parameters. No influence of KAI1 expression on prognosis was observed.KAI1-down-regulation is a frequent event in cervical cancer occurring early in carcinogenesis. KAI1 expression did not influence the prognosis of patients with primary irradiated cervical cancer.