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The Significance of CD44 Variant 9 in Resected Lung Adenocarcinoma: Correlation with Pathological Early-Stage and EGFR Mutation

  • Translational Research and Biomarkers
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Abstract

Background

CD44 isoforms serve as a marker for cancer stem cells. CD44 variant 9 (CD44v9) contributes to the defense against reactive oxygen species, resulting in resistance to chemoradiotherapy. However, the significance of CD44v9 in patients with lung adenocarcinoma is unknown.

Methods

We used immunohistochemical analysis to retrospectively analyze CD44v9 expression in 268 surgically resected lung adenocarcinomas and investigated the association between CD44v9 expression and patients’ clinicopathological features.

Results

The expression of CD44v9 in 193 of 268 (72.0%) patients was significantly associated with early-stage cancer, low-grade tumors, absence of vessel and pleural invasion, and a mutated epidermal growth factor receptor (EGFR) gene. Multivariate logistic analysis revealed that CD44v9 expression was significantly associated with early-stage disease [odds ratio (OR) 0.29, 95% confidence interval (CI) 0.14–0.59; p < 0.001] and mutant EGFR (OR 2.53, 95% CI 1.06–6.04; p = 0.036). The percentage of CD44v9-positive tumors was higher in the earlier stages of disease; however, there was no significant difference in the survival of patients in each stage of disease who had positive or negative CD44v9 expression.

Conclusion

CD44v9 was highly expressed in EGFR-mutant tumors, particularly in early-stage lung adenocarcinoma, suggesting that CD44v9 expression may play an important role in EGFR-mutant tumors.

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References

  1. Oxnard GR, Binder A, Janne PA. New targetable oncogenes in non-small-cell lung cancer. J Clin Oncol. 2013;31(8):1097–04.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Takada K, Toyokawa G, Shoji F, Okamoto T, Maehara Y. The significance of the PD-L1 expression in non-small-cell lung cancer: trenchant double swords as predictive and prognostic markers. Clin Lung Cancer. 2018;19(2):120–29.

    Article  CAS  PubMed  Google Scholar 

  3. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375(19):1823–33.

    Article  CAS  Google Scholar 

  4. Codd AS, Kanaseki T, Torigo T, Tabi Z. Cancer stem cells as targets for immunotherapy. Immunology. 2018;153(3):304–14.

    Article  CAS  PubMed  Google Scholar 

  5. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414(6859):105–11.

    Article  CAS  Google Scholar 

  6. Ponta H, Sherman L, Herrlich PA. CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol. 2003;4(1):33–45.

    Article  CAS  PubMed  Google Scholar 

  7. Zoller M. CD44: can a cancer-initiating cell profit from an abundantly expressed molecule? Nature reviews. Cancer. 2011;11(4):254–67.

    Article  CAS  PubMed  Google Scholar 

  8. Ishii H, Saitoh M, Sakamoto K, et al. Epithelial splicing regulatory proteins 1 (ESRP1) and 2 (ESRP2) suppress cancer cell motility via different mechanisms. J Biol Chem. 2014;289(40):27386–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ishimoto T, Nagano O, Yae T, 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(3):387–400.

    Article  CAS  PubMed  Google Scholar 

  10. Diehn M, Cho RW, Lobo NA, et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature. 2009;458(7239):780–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Sosulski A, Horn H, Zhang L, et al. CD44 splice variant v8-10 as a marker of serous ovarian cancer prognosis. PLoS ONE. 2016;11(6):e0156595.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hirata K, Suzuki H, Imaeda H, et al. CD44 variant 9 expression in primary early gastric cancer as a predictive marker for recurrence. Br J Cancer. 2013;109(2):379–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Aso T, Matsuo M, Kiyohara H, et al. Induction of CD44 variant 9-expressing cancer stem cells might attenuate the efficacy of chemoradioselection and worsens the prognosis of patients with advanced head and neck cancer. PLoS ONE. 2015;10(3):e0116596.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kobayashi K, Matsumoto H, Matsuyama H, et al. Clinical significance of CD44 variant 9 expression as a prognostic indicator in bladder cancer. Oncol Rep. 2016;36(5):2852–60.

    Article  CAS  PubMed  Google Scholar 

  15. Shitara K, Doi T, Nagano O, et al. Phase 1 study of sulfasalazine and cisplatin for patients with CD44v-positive gastric cancer refractory to cisplatin (EPOC1407). Gastric cancer. 2017;20(6):1004–09.

    Article  CAS  PubMed  Google Scholar 

  16. Otsubo K, Nosaki K, Imamura CK, et al. Phase I study of salazosulfapyridine in combination with cisplatin and pemetrexed for advanced non-small-cell lung cancer. Cancer Sci. 2017;108(9):1843–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kohno M, Okamoto T, Suda K, et al. Prognostic and therapeutic implications of aromatase expression in lung adenocarcinomas with EGFR mutations. Clin Cancer Res. 2014;20(13):3613–22.

    Article  CAS  PubMed  Google Scholar 

  18. Allred DC, Harvey JM, Berardo M, Clark GM. Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol. 1998;11(2):155–68.

    CAS  PubMed  Google Scholar 

  19. Yamaguchi A, Urano T, Goi T, 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(4):1122–27.

    Article  CAS  PubMed  Google Scholar 

  20. Sato S, Miyauchi M, Takekoshi T, et al. Reduced expression of CD44 variant 9 is related to lymph node metastasis and poor survival in squamous cell carcinoma of tongue. Oral Oncol. 2000;36(6):545–49.

    Article  CAS  PubMed  Google Scholar 

  21. Go SI, Ko GH, Lee WS, et al. CD44 variant 9 serves as a poor prognostic marker in early gastric cancer, but not in advanced gastric cancer. Cancer Res Treat. 2016;48(1):142–52.

    Article  CAS  PubMed  Google Scholar 

  22. Brown RL, Reinke LM, Damerow MS, et al. CD44 splice isoform switching in human and mouse epithelium is essential for epithelial-mesenchymal transition and breast cancer progression. J Clin Invest. 2011;121(3):1064–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Mashita N, Yamada S, Nakayama G, et al. Epithelial to mesenchymal transition might be induced via CD44 isoform switching in colorectal cancer. J Surg Oncol. 2014;110(6):745–51.

    Article  CAS  PubMed  Google Scholar 

  24. Larsen JE, Nathan V, Osborne JK, et al. ZEB1 drives epithelial-to-mesenchymal transition in lung cancer. J Clin Invest. 2016;126(9):3219–35.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Kawano Y, Iwama E, Tsuchihashi K, et al. CD44 variant-dependent regulation of redox balance in EGFR mutation-positive non-small cell lung cancer: a target for treatment. Lung Cancer. 2017;113:72–78.

    Article  PubMed  Google Scholar 

  26. Suda K, Murakami I, Yu H, et al. CD44 facilitates epithelial to mesenchymal transition phenotypic change at acquisition of resistance to EGFR kinase inhibitors in lung cancer. Mol Cancer Ther. 2018;17(10):2257–65.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors thank Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.

Funding

This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka-shi, Fukuoka, 812-8582, Japan

    Takaki Akamine MD, Tetsuzo Tagawa MD, PhD, Gouji Toyokawa MD, PhD, Shinkichi Takamori MD, PhD, Fumihiko Hirai MD, PhD, Tatsuro Okamoto MD, PhD & Yoshihiko Maehara MD, PhD

  2. Pathophysiological and Experimental Pathology, Department of Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka-shi, Fukuoka, 812-8582, Japan

    Kayo Ijichi MD

  3. Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka-shi, Fukuoka, 812-8582, Japan

    Yoshinao Oda MD, PhD

Authors
  1. Takaki Akamine MD
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  2. Tetsuzo Tagawa MD, PhD
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  3. Kayo Ijichi MD
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  4. Gouji Toyokawa MD, PhD
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  5. Shinkichi Takamori MD, PhD
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  6. Fumihiko Hirai MD, PhD
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  7. Tatsuro Okamoto MD, PhD
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  8. Yoshinao Oda MD, PhD
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  9. Yoshihiko Maehara MD, PhD
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Corresponding author

Correspondence to Tetsuzo Tagawa MD, PhD.

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Fig. 1

Expression of CD44 in lung adenocarcinoma demonstrating representative (a) negative and (b) positive cases (TIFF 480 kb)

Fig. 2

Mosaic plot of data for a proportion of CD44v9 Allred scores at each stage (TIFF 70 kb)

Fig. 3

Kaplan–Meier analysis of association of stage-specific CD44v9 expression in relation to progression-free and overall survival (TIFF 94 kb)

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Akamine, T., Tagawa, T., Ijichi, K. et al. The Significance of CD44 Variant 9 in Resected Lung Adenocarcinoma: Correlation with Pathological Early-Stage and EGFR Mutation. Ann Surg Oncol 26, 1544–1551 (2019). https://doi.org/10.1245/s10434-018-07137-2

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  • DOI: https://doi.org/10.1245/s10434-018-07137-2

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