Expression of the cancer stem cell markers CD44v6 and ABCG2 in tongue cancer: Effect of neoadjuvant chemotherapy on local recurrence

Yanamoto,Souichi; Yamada,Shin-Ichi; Takahashi,Hidenori; Naruse,Tomofumi; Matsushita,Yuki; Ikeda,Hisazumi; Shiraishi,Takeshi; Seki,Sachiko; Fujita,Shuichi; Ikeda,Tohru; Asahina,Izumi; Umeda,Masahiro

doi:10.3892/ijo.2014.2289

Expression of the cancer stem cell markers CD44v6 and ABCG2 in tongue cancer: Effect of neoadjuvant chemotherapy on local recurrence

Authors:
- Souichi Yanamoto
- Shin-Ichi Yamada
- Hidenori Takahashi
- Tomofumi Naruse
- Yuki Matsushita
- Hisazumi Ikeda
- Takeshi Shiraishi
- Sachiko Seki
- Shuichi Fujita
- Tohru Ikeda
- Izumi Asahina
- Masahiro Umeda
View Affiliations

Affiliations: Department of Clinical Oral Oncology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8588, Japan, Department of Regenerative Oral Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8588, Japan, Department of Oral Pathology and Bone Metabolism, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8588, Japan
Published online on: February 4, 2014 https://doi.org/10.3892/ijo.2014.2289
Pages: 1153-1162

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The efficacy of neoadjuvant chemotherapy (NAC) is controversial, and no report supports NAC with a high evidence level. Recently, we showed that a deep surgical margin was resected very close to the tumor site in many NAC-treated oral squamous cell carcinoma patients, suggesting that NAC may lead to local recurrence and poor outcomes. The purpose of this study was to evaluate the effect of NAC on tumor local recurrence using cancer stem cell marker immunohistochemistry. We retrospectively analyzed 89 patients who underwent radical surgery for tongue cancer, and examined the effect of NAC on tumor local recurrence. Cancer stem cell marker (CD44v6 and ABCG2) expression was detected by immunohistochemistry. In our study, the local recurrence rate was 12.4%. CD44v6 and ABCG2 expression was significantly associated with regional lymph node metastasis, pattern of invasion, depth of invasion, perineural invasion and local recurrence, respectively. Tumor local recurrence was a significant independent predictive factor of the 5-year disease specific survival. CD44v6 or ABCG2 positivity in NAC-treated patients was significantly associated with tumor local recurrence. It was suggested that local recurrence in NAC-treated cases is associated with cancer stem-like cells. We propose that NAC leads to the selection and/or residue of more aggressive cancer stem-like cells.

View Figures

View References

1.	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global Cancer Statistics 2011. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar
2.	Warnakulasuriya S: Global epidemiology of oral and oropharyngeal cancer. Oral Oncol. 45:309–316. 2009. View Article : Google Scholar
3.	Rogers SN, Brown JS, Woolgar JA, et al: Survival following primary surgery for oral cancer. Oral Oncol. 45:201–211. 2009. View Article : Google Scholar : PubMed/NCBI
4.	Brandwein-Gensler M, Teixeira MS, Lewis CM, et al: Oral squamous cell carcinoma. Histologic risk assessment, but not margin status, is strongly predictive of local disease-free and overall survival. Am J Surg Pathol. 29:167–178. 2005.
5.	Kernohan MD, Clark JR, Gao K, Ebrahimi A and Milross CG: Predicting the prognosis of oral squamous cell carcinoma after first recurrence. Arch Otolaryngol Head Neck Surg. 136:1235–1239. 2010. View Article : Google Scholar : PubMed/NCBI
6.	Yanamoto S, Yamada S, Takahashi H, et al: Clinicopathological risk factors for local recurrence in oral squamous cell carcinoma. Int J Oral Maxillofac Surg. 41:1195–1200. 2012. View Article : Google Scholar : PubMed/NCBI
7.	Liao CT, Chang JTC, Wang HM, et al: Analysis of risk factors of predictive local tumor control in oral cavity cancer. Ann Surg Oncol. 15:915–922. 2008. View Article : Google Scholar : PubMed/NCBI
8.	Ord RA, Kolokythas A and Reynolds MA: Surgical salvage for local and regional recurrence in oral cancer. J Oral Maxillofac Surg. 64:1409–1414. 2006. View Article : Google Scholar : PubMed/NCBI
9.	Braakhuis BJM, Bloemena E, Leemans CR and Brakenhoff RH: Molecular analysis of surgical margins in head and neck cancer: more than a marginal issue. Oral Oncol. 46:485–491. 2010. View Article : Google Scholar : PubMed/NCBI
10.	Partridge M, Li SR, Pateromichelakis S, et al: Detection of minimal residual cancer to investigate why oral tumors recur despiteseemingly adequate treatment. Clin Cancer Res. 6:2718–2725. 2000.PubMed/NCBI
11.	van Houten VMM, Leemans CR, Kummer JA, et al: Molecular diagnosis of surgical margins and local recurrence in head and neck cancer patients: a prospective study. Clin Cancer Res. 10:3614–3620. 2004.PubMed/NCBI
12.	Bilde A, von Buchwald C, Dabelsteen E, Therkildsen MH and Dabelsteen S: Molecular markers in the surgical margin of oral carcinomas. J Oral Pathol Med. 38:72–78. 2009. View Article : Google Scholar : PubMed/NCBI
13.	Yanamoto S, Yamada S, Takahashi H, et al: Predictors of locoregional recurrence in T1-2N0 tongue cancer patients. Pathol Oncol Res. 19:795–803. 2013. View Article : Google Scholar : PubMed/NCBI
14.	Kim JJ and Tannock IF: Repopulation of cancer cells during therapy: an important cause of treatment failure. Nat Rev Cancer. 5:516–525. 2005. View Article : Google Scholar : PubMed/NCBI
15.	Yoshikawa M, Tsuchihashi K, Ishimoto T, et al: xCT-expressing tumor cells that are resistant to EGFR-targeted therapy in head and neck squamous cell carcinoma. Cancer Res. 73:1855–1866. 2013. View Article : Google Scholar : PubMed/NCBI
16.	Naor D, Sionov RV and Ish-Shalom D: CD44: structure, function, and association with the malignant process. Adv Cancer Res. 71:241–319. 1997. View Article : Google Scholar : PubMed/NCBI
17.	Nagano O, Okazaki S and Saya H: Redox regulation in stem-like cancer cells by CD44 variant isoforms. Oncogene. 32:5191–5198. 2013. View Article : Google Scholar : PubMed/NCBI
18.	Jijiwa M, Demir H, Gupta S, et al: CD44v6 regulates growth of brain tumor stem cells partially through the AKT-mediated pathway. PLoS One. 6:e242172011. View Article : Google Scholar : PubMed/NCBI
19.	Lee HJ, Eom DW, Kang GH, et al: Colorectal micropapillary carcinomas are associated with poor prognosis and enriched in markers of stem cells. Mod Pathol. 26:1123–1131. 2013. View Article : Google Scholar : PubMed/NCBI
20.	Gaviraghi M, Tunici P, Valensin S, et al: Pancreatic cancer spheres are more than just aggregates of stem marker-positive cells. Biosci Rep. 31:45–55. 2011. View Article : Google Scholar : PubMed/NCBI
21.	Mack B and Gires O: CD44s and CD44v6 expression in head and neck epithelia. PLoS One. 3:e33602008. View Article : Google Scholar : PubMed/NCBI
22.	Zhou S, Schuetz JD, Bunting KD, et al: The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat Med. 67:1028–1034. 2001. View Article : Google Scholar : PubMed/NCBI
23.	Zhang P, Zhang Y, Mao L, Zhang Z and Chen W: Side population in oral squamous cell carcinoma possesses tumor stem cell phenotypes. Cancer Lett. 277:227–234. 2009. View Article : Google Scholar : PubMed/NCBI
24.	Yanamoto S, Kawasaki G, Yamada S, et al: Isolation and characterization of cancer stem-like side population cells in human oral cancer cells. Oral Oncol. 47:855–860. 2011. View Article : Google Scholar : PubMed/NCBI
25.	Bryne M, Koppang HS, Lilleng R and Kjaerheim A: Malignancy grading of the deep invasive margins of oral squamous cell carcinoma has high prognostic value. J Pathol. 166:375–381. 1992. View Article : Google Scholar : PubMed/NCBI
26.	Asakage T, Yokose T, Mukai K, et al: Tumor thickness predicts cervical metastasis in patients with stage I/II carcinoma of the tongue. Cancer. 82:1443–1448. 1998. View Article : Google Scholar : PubMed/NCBI
27.	Kurokawa H, Yamashita Y, Takeda S, Zhang M, Fukuyama H and Takahashi T: Risk factors for late cervical lymph node metastases in patients with stage I or II carcinoma of the tongue. Head Neck. 24:731–736. 2002. View Article : Google Scholar : PubMed/NCBI
28.	Lim SC, Zhang S, Ishii G, et al: Predictive markers for late cervical metastasis in stage I and II invasive squamous cell carcinoma of the oral tongue. Clin Cancer Res. 10:166–172. 2004. View Article : Google Scholar : PubMed/NCBI
29.	Sparano A, Weinstein G, Chalian A, Yodul M and Weber R: Multivariate predictors of occult neck metastasis in early oral tongue cancer. Otolaryngol Head Neck Surg. 131:472–476. 2004. View Article : Google Scholar : PubMed/NCBI
30.	Huang SH, Hwang D, Lockwood G, Goldstein DP and O’Sullivan B: Predictive value of tumor thickness for cervical lymph-node involvement in squamous cell carcinoma of the oral cavity. A meta-analysis of reported studies Cancer. 115:1489–1497. 2009.PubMed/NCBI
31.	Fan KH, Wang HM, Kang CJ, et al: Treatment results of postoperative radiotherapy on squamous cell carcinoma of the oral cavity: coexistence of multiple minor risk factors results in higher recurrence rates. Int J Radiat Oncol Biol Phys. 77:1024–1029. 2010. View Article : Google Scholar
32.	Schneider PM, Baldus SE, Metzger R, et al: Histomorphologic tumor regression and lymph node metastases determine prognosis following neoadjuvant radiochemotherapy for esophageal cancer. Ann Surg. 242:684–692. 2005. View Article : Google Scholar
33.	Bollschweiler E, Besch S, Drebber U, et al: Influence of neoadjuvant chemoradiation on the number and size of analyzed lymph nodes in esophageal cancer. Ann Surg Oncol. 17:3187–3194. 2010. View Article : Google Scholar : PubMed/NCBI
34.	Ota S, Ishii G, Goto K, et al: Immunohistochemical expression of BCRP and ERCC1 in biopsy specimen predicts survival in advanced non-small-cell lung cancer treated with cisplatin-based chemotherapy. Lung Cancer. 64:98–104. 2009. View Article : Google Scholar
35.	Hang D, Dong HC, Ning T, Dong B, Hou DL and Xu WG: Prognostic value of the stem cell markers CD133 and ABCG2 expression in esophageal squamous cell carcinoma. Dis Esophagus. 25:638–644. 2012. View Article : Google Scholar : PubMed/NCBI
36.	Zhao H, Ren J, Zhuo X, Ye H, Zou J and Liu S: Prognostic significance of surviving and CD44v6 in laryngeal cancer surgical margins. J Cancer Res Clin Oncol. 134:1051–1058. 2008. View Article : Google Scholar : PubMed/NCBI
37.	Dalerba P, Cho RW and Clarke MF: Cancer stem cells: models and concepts. Annu Rev Med. 58:267–284. 2007. View Article : Google Scholar : PubMed/NCBI
38.	Visvader JE and Lindeman GJ: Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer. 8:755–768. 2008. View Article : Google Scholar : PubMed/NCBI
39.	Graziano A, d’Aquino R, Tirino V, Desiderio V, Rossi A and Pirozzi G: The stem cell hypothesis in head and neck cancer. J Cell Biochem. 103:408–412. 2008. View Article : Google Scholar : PubMed/NCBI
40.	Prince ME and Ailles LE: Cancer stem cells in head and neck squamous cell cancer. J Clin Oncol. 26:2871–2875. 2008. View Article : Google Scholar : PubMed/NCBI
41.	Sinha N, Mukhopadhyay S, Das DN, Panda PK and Bhutia SK: Relevance of cancer initiating/stem cells in carcinogenesis and therapy resistance in oral cancer. Oral Oncol. 49:854–862. 2013. View Article : Google Scholar : PubMed/NCBI
42.	Screaton GR, Bell MV, Jackson DG, Cornelis FB, Gerth U and Bell JI: Genomic structure of DNA encoding the lymphocyte homing receptor CD44 reveals at least 12 alternatively spliced exons. Proc Natl Acad Sci USA. 89:12160–12164. 1992. View Article : Google Scholar
43.	Goodison S, Urquidi V and Tarin D: CD44 cell adhesion molecules. Mol Pathol. 52:189–196. 1999. View Article : Google Scholar
44.	Wang SJ, Wong G, de Heer AM, Xia W and Bourguignon LY: CD44 variant isoforms in head and neck squamous cell carcinoma progression. Laryngoscope. 119:1518–1530. 2009. View Article : Google Scholar : PubMed/NCBI
45.	Yang YM and Chang JW: Bladder cancer initiating cells (BCICs) are among (initiating) cells. Cancer Invest. 26:725–733. 2008. View Article : Google Scholar : PubMed/NCBI
46.	Shi J, Zhou Z, Di W and Li N: Correlation of CD44v6 expression with ovarian cancer progression and recurrence. BMC Cancer. 13:1822013. View Article : Google Scholar : PubMed/NCBI
47.	Shen B, Dong P, Li D and Gao S: Expression and function of ABCG2 in head and neck squamous cell carcinoma and cell lines. Exp Ther Med. 2:1151–1157. 2011.PubMed/NCBI
48.	Lore JM, Diaz-Ordaz E, Spaulding M, et al: Improved survival with preoperative chemotherapy followed by tumor response for advanced squamous cell carcinoma of the head and neck. Am J Surg. 170:506–511. 1995. View Article : Google Scholar
49.	Pignon JP, Bourhis J, Domenge C and Designe L: Chemotherapy added to locoregional treatment for head and neck squamous cell carcinoma: three meta-analyses of updated individual data. Lancet. 355:949–955. 2000. View Article : Google Scholar : PubMed/NCBI
50.	Licitra L, Grandi C, Guzzo M, et al: Primary chemotherapy in resectable oral cavity squamous cell carcinoma: a randomized controlled trial. J Clin Oncol. 21:327–333. 2003. View Article : Google Scholar : PubMed/NCBI
51.	Olasz L, Szalma J, Orsi E, Tornoczky T, Marko T and Nyarady Z: Neoadjuvant chemotherapy: does it have benefits for surgeon in the treatment of advanced squamous cell cancer of the oral cavity? Pathol Oncol Res. 16:207–212. 2010. View Article : Google Scholar : PubMed/NCBI
52.	Costa S, Terzano P, Bovicelli A, et al: CD44 isoform 6 (CD44v6) is a prognostic indicator of the response to neoadjuvant chemo-therapy in cervical carcinoma. Gynecol Oncol. 80:67–73. 2001. View Article : Google Scholar : PubMed/NCBI
53.	Saigusa S, Tanaka K, Toiyama Y, et al: Clinical significance of CD133 and hypoxia inducible factor-1α gene expression in rectal cancer after preoperative chemotherapy. Clin Oncol. 23:323–332. 2011.PubMed/NCBI
54.	Kawamoto A, Tanaka K, Saigusa S, et al: Clinical significance of radiation-induced CD133 expression in residual rectal cancer cells after chemoradiotherapy. Exp Ther Med. 3:403–409. 2012.
55.	Sprenger T, Conradi L, Beissbarth T, et al: Enrichment of CD133-expressing cells in rectal cancers treated with preoperative radiochemotherapy is an independent marker for metastasis and survival. Cancer. 119:26–35. 2013. View Article : Google Scholar