Cancer Res Treat.  2016 Jan;48(1):142-152. 10.4143/crt.2014.227.

CD44 Variant 9 Serves as a Poor Prognostic Marker in Early Gastric Cancer, But Not in Advanced Gastric Cancer

• Go SI
• Ko GH
• Lee WS
• Kim RB
• Lee JH
• Jeong SH
• Lee YJ
• Hong SC
• Ha WS

• KMID: 2152270
• DOI: http://doi.org/10.4143/crt.2014.227

Abstract

PURPOSE
The present study is to investigate the significance of CD44 variant 9 (CD44v9) expression as a biomarker in primary gastric cancer.
MATERIALS AND METHODS
With various gastric tissues, we performed immunohistochemical staining for CD44v9.
RESULTS
The positive expression rates for CD44v9 in tumor, including adenoma, early gastric cancer (EGC), and advanced gastric cancer (AGC), were higher than those in non-tumor tissues (p=0.003). In addition, the higher expression for CD44v9 was observed as the tissue becomes malignant. In the analysis of 333 gastric cancer tissues, we found that positive expression rates for CD44v9 were higher in the intestinal type or well differentiated gastric cancer than in the diffuse type or poorly differentiated gastric cancer. Interestingly, the positive expression indicated poor prognosis in EGC (5-year survival rate [5-YSR] in stage I, 81.7% vs. 95.2%; p=0.013), but not in AGC (5-YSR in stage II, 66.9% vs. 62.2%; p=0.821; 5-YSR in stage III, 34.5% vs. 32.0%; p=0.929). Moreover, strong positive expression (3+) showed a trend suggesting worse prognosis only in EGC, and it appeared to be associated with lymph node metastasis.
CONCLUSION
This study suggests that CD44v9 may be a good biomarker for prognosis prediction and for chemoprevention or biomarker-driven therapies only for EGC.

Keyword

CD44 variant; Biological markers; Stomach neoplasms; Survival; Prognosis

MeSH Terms

Adenoma
Biological Markers
Chemoprevention
Lymph Nodes
Neoplasm Metastasis
Prognosis
Stomach Neoplasms*
Survival Rate
Biological Markers

Figure

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  Fig. 1. Representative figures of immunohistochemical staining for CD44 variant 9 (CD44v9) expression on the basis of positive criteria. Membranous reactions were scored in accordance to the percentage of CD44v9-positive cells as follows: (A) immunonegativity (0%-4%), (B) 1+ reactivity intensity (5%-19%), (C) 2+ reactivity intensity (20%-49%), (D) 3+ reactivity intensity (50%-100%) (A-D, ×200).

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  Fig. 2. Representative findings of immunohistochemical staining for CD44 variant 9 (CD44v9) in various gastric tissues. (A) Foveolar and fundic gland cells in normal tissue. Most of the foveolar and fundic gland cells were negative for CD44v9. (B) Antral gland cells in normal tissue. Some of the neck cells and antral gland cells were positive for CD44v9. (C) Antral gland cells in Helicobacter pylori–infected gastritis mucosa. Some of the antral gland cells in this H. pylori–infected gastric mucosa were positive for CD44v9. (D) Intestinal metaplastic cells. Some of the intestinal metaplastic cells were positive for CD44v9. (E) Low-grade tubular adenoma. (F) High-grade tubular adenoma. Many tumor cells are positive in a high-grade tubular adenoma. (G) Early gastric cancer cells. Many tumor cells were positive in an early gastric cancer confined within mucosa. (H) Advanced gastric cancer cells (A-H, ×200).

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  Fig. 3. CD44 variant 9 (CD44v9)–positive rates various gastric cancer tissues. Positive criteria for CD44v9 were defined as follows: immunohistochemical staining (IHC) score more than 0 (A, B), IHC score more than 1+ (C), and IHC score of 3+ (D) (*p < 0.05 and **p < 0.01, vs. control). EGC, early gastric cancer; AGC, advanced gastric cancer.

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  Fig. 4. Kaplan-Meier curves for overall survival according to CD44 variant 9 (CD44v9) status in the whole patients.

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  Fig. 5. Kaplan-Meier curves for overall survival according to CD44 variant 9 (CD44v9) status in patients with each TNM stage: stage I (A), stage II (B), stage III (C). The overall survival by immunoexpression intensities (0, 1+/2+, and 3+) at each early gastric cancer and advanced gastric cancer: stage I (D), stage II or III (E).

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  Fig. 6. The positive expression of CD44 variants and prognosis in a meta-analysis of the previous studies (n=5). a)Hirata et al. [12] studied with early gastric cancer alone and the end point was recurrence. Diamonds are the summary estimate from the pooled studies with 95% confidence interval (CI).

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  Fig. 7. The positive expression of CD44 variants and the risk of lymph node metastasis in a meta-analysis of the previous studies (n=5). a)CD44v5: Muller et al. [17] studied both CD44v5 and CD44v6 in the same paper. The values were different, so we analyzed the data separately. Diamonds are the summary estimate from the pooled studies with 95% confidence interval (CI).

Reference

References

1. Jung KW, Won YJ, Kong HJ, Oh CM, Lee DH, Lee JS. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2011. Cancer Res Treat. 2014; 46:109–23.

2. Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010; 376:687–97.

3. Aruffo A, Stamenkovic I, Melnick M, Underhill CB, Seed B. CD44 is the principal cell surface receptor for hyaluronate. Cell. 1990; 61:1303–13.

4. Culty M, Miyake K, Kincade PW, Sikorski E, Butcher EC, Underhill C. The hyaluronate receptor is a member of the CD44 (H-CAM) family of cell surface glycoproteins. J Cell Biol. 1990; 111(6 Pt 1):2765–74.

5. Thomas L, Byers HR, Vink J, Stamenkovic I. CD44H regulates tumor cell migration on hyaluronate-coated substrate. J Cell Biol. 1992; 118:971–7.

6. Gunthert U, Hofmann M, Rudy W, Reber S, Zoller M, Haussmann I, et al. A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells. Cell. 1991; 65:13–24.

7. Dalerba P, Dylla SJ, Park IK, Liu R, Wang X, Cho RW, et al. Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci U S A. 2007; 104:10158–63.

8. Ishimoto T, Oshima H, Oshima M, Kai K, Torii R, Masuko T, et al. CD44+ slow-cycling tumor cell expansion is triggered by cooperative actions of Wnt and prostaglandin E2 in gastric tumorigenesis. Cancer Sci. 2010; 101:673–8.

9. Ishimoto T, Nagano O, Yae T, Tamada M, Motohara T, Oshima H, et al. CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc(-) and thereby promotes tumor growth. Cancer Cell. 2011; 19:387–400.

10. Yasui W, Kudo Y, Naka K, Fujimoto J, Ue T, Yokozaki H, et al. Expression of CD44 containing variant exon 9 (CD44v9) in gastric adenomas and adenocarcinomas: relation to the proliferation and progression. Int J Oncol. 1998; 12:1253–8.

11. Yamaguchi A, Urano T, Goi T, Saito M, Takeuchi K, Hirose K, et al. Expression of a CD44 variant containing exons 8 to 10 is a useful independent factor for the prediction of prognosis in colorectal cancer patients. J Clin Oncol. 1996; 14:1122–7.

12. Hirata K, Suzuki H, Imaeda H, Matsuzaki J, Tsugawa H, Nagano O, et al. CD44 variant 9 expression in primary early gastric cancer as a predictive marker for recurrence. Br J Cancer. 2013; 109:379–86.

13. Yamamichi K, Uehara Y, Kitamura N, Nakane Y, Hioki K. Increased expression of CD44v6 mRNA significantly correlates with distant metastasis and poor prognosis in gastric cancer. Int J Cancer. 1998; 79:256–62.

14. Yamaguchi A, Goi T, Yu J, Hirono Y, Ishida M, Iida A, et al. Expression of CD44v6 in advanced gastric cancer and its relationship to hematogenous metastasis and long-term prognosis. J Surg Oncol. 2002; 79:230–5.

15. Mulder JW, Kruyt PM, Sewnath M, Oosting J, Seldenrijk CA, Weidema WF, et al. Colorectal cancer prognosis and expression of exon-v6-containing CD44 proteins. Lancet. 1994; 344:1470–2.

16. Kim YS, Chi SG, Kim YW, Park YK, Yoon C. Molecular genetic characterization of alternatively spliced CD44 transcripts in human stomach carcinoma. J Korean Med Sci. 1997; 12:505–13.

17. Muller W, Schneiders A, Heider KH, Meier S, Hommel G, Gabbert HE. Expression and prognostic value of the CD44 splicing variants v5 and v6 in gastric cancer. J Pathol. 1997; 183:222–7.