CD44v6 down-regulation is an independent prognostic factor for poor outcome of colorectal carcinoma

Abstract

We aim to investigate the variation of CD44v6 expression in the normal-adenoma-primary carcinoma-liver metastasis sequence and its prognostic impact on colorectal carcinomas. The difference in CD44v6 expression between the tumor center and invasive front was also assessed. Immunohistochemistry was performed for CD44v6 on two cohorts. The first was tissue microarrays including 402 primary CRCs sampled from the tumor center and the invasive margin. The second was whole-tissue sections, consisting of 217 adenomas, 72 primary carcinomas, and the corresponding metastatic carcinomas. In the first cohort, we found that CD44v6 down-regulation was inclined to lymph node metastasis and perineural invasion, and had an unfavorable prognosis compared with CD44v6 up-regulation. In the second cohort, CD44v6 expression was predominant in adenoma over primary carcinoma and liver metastasis in multiple steps (normal < adenoma > primary carcinoma and liver metastasis). In addition, our analysis showed that CD44v6 expression was decreased at the invasion front of the CRC compared with the center of the tumor. In conclusion, the maximal expression of CD44v6 in adenoma plays a crucial role in colorectal carcinogenesis, while loss of CD44v6 expression on the cell surface of the tumor edge enhances the progression of metastasis. CD44v6 down-regulation is an independent prognostic factor for strikingly worse disease-specific survival.

Keywords: CD44v6; adenoma; colorectal carcinoma; immunohistochemistry; metastasis.

Figure 1

Expression of CD44v6 in the normal, adenoma, primary carcinoma, and liver metastasis sequence. CD44v6 immunoreactivity was minimal in normal tissue (A), maximal in adenoma (B), and moderate in primary carcinoma (C) and liver metastasis (D). There was no difference between primary carcinoma and liver metastasis (magnification, 10×).

Figure 2

Kaplan-Meier analysis for DSS according to CD44v6 expression. Patients with negative CD44v6 expression tended to have a unfavorable prognosis compared with those with positive expression, although the difference was not statistically significant.

Figure 3

Immunohistochemical analysis of CD44v6 and E-cadherin (membranous) expression in CRC tissues. Positive and corresponding negative staining for CD44v6 (A and B) and E-cadherin (C and D) (magnification, 10×). (A and C) is the same tissue, (B and D) is the same tissue.

Figure 4

Immunohistochemical analysis of CD44v6 expression in the center and the invasive front ofCRC tissues. A. Whole-tissue scan (NanoZoomer Digital Pathology Scan, Hamamatsu, Japan) (magnification, 0.42×). B. Higher CD44v6 expression in the center of the tissue (magnification, 10×). C. Lower CD44v6 expression in the invasion front of the tissue (magnification, 10×).