| Budget Amount *help |
¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 1996: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1995: ¥1,000,000 (Direct Cost: ¥1,000,000)
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| Research Abstract |
Splice variants of CD44 are overexpressed in human cancer cell lines, such as those from breast, lung, stomach, and colorectal cancers. It is thought that splice variants of CD44 may play an important role in tumor growth and metastasis. This study was conducted to clarify the association between the expression of variant CD44 containing exons 8-10 and metastatic potential in human colorectal cancer.
We found that the expression of a CD44 splice variant exons 8-10 was increased in all of 60 colorectal cancer specimens examined compared with matched normal colorectal mucosa, as determined by Northern blotting. The level of CD44 variant exon 8-10 expression was significantly higher in carcinomas associated with liver metastasis than in those without liver metastasis. In addition, expression of CD44 variants exons 8-10 in liver metastases was more intense than that in the primary colorectal cancers. We have established a murine monoclonal antibody (mAb 44-1V) that is reactive with an epito
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pe in a CD44 variant exon 9 product, and demonstrated that CD44v8-10 with molecular weight of 130 kD was expressed in colorectal cancers, and not in normal counterparts. We analyzed the expression of the CD44 variant exon 8 to 10 product in colorectal cancer immunohistochemically using this mAb 44-1V,and evaluate its prognostic value. There were significant correlations between CD44v8-10 immunoreactivity and both lymph node and hematogenous metastasis. Patients with CD44v8-10-positive tumors had a greater relative risk of death compared with those tumors were CD44v8-10-negative. In multivariate analysis using Cox regression model, CD44v8-10 expression emerged as an independent prognostic indicator. These results suggested that CD44v8-10 plays a role in metastasis of colorectal cancer, and that CD44v8-10 expression may be a biologic marker of prognostic significance. We used an enzymed linked immunosorbent assay (ELISA) system to detect the soluble CD44v8-10 level. We report that the expression of serum CD44v8-10 concentration is elevated in colorectal cancer patients with positive immunostaining, suggesting its usefulness as an indicator or predictor of hematogenous metastasis in clorectal cancer patients.
In addition, we examined the role of the variant CD44v8-10 in the metastasis of the human colon cancer cell line HT29 using mAb 44-1V.All of the control mice developed massive liver metastases, while only one mouse (11.1%) in the group pretreated with mAb 44-1v developed liver metastasis. However, the intravenous administration of mAb 44-1V did not reduce the rate of liver metastasis. These results support the hypothesis that CD44v8-10 plays an important role in the metastatic process after migration from the primary cancer, especially in the adhesion to the capillaries of distant organ. Less
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