Abstract
Purpose
Expression of CD44 and its variants has been shown to be relevant to tumor progression in various human malignancies. We evaluated the expression of CD44v6 in the primary lesions of stage I non-small cell lung cancer (NSCLC) and correlated the expression level to its prognosis.
Methods
The expression of CD44v6, measured by immunohistochemistry, was assessed in the tumor specimens from 190 patients with stage I NSCLC. Each slide was assigned a score: the average of the score of tumor cells staining multiplied by the score of staining intensity. And depending on the cut-off score based on receiver operating characteristic (ROC) curve analysis, the CD44v6 expression was categorized into high- and low-level groups, which were then correlated directly with the clinical outcomes.
Results
The high expression of CD44v6 was detected more frequently in the squamous cell carcinoma (38 of 71 patients, 53.5%) than in the other types of carcinoma (p < 0.05). The Kaplan–Meier survival curves showed that high level expression of CD44v6 indicated a better post-operative survival (p = 0.006), especially for stage IB disease (p = 0.049) and squamous cell carcinoma (p = 0.029). The multivariate analysis also confirmed that the expression of CD44v6 was an independent prognostic indicator (p = 0.011).
Conclusions
CD44v6 might be correlated with histogenesis of NSCLC, and its decreased expression may be an adverse prognostic indicator for the patients with stage I NSCLC, especially for those with stage IB diseases. Patients of this subgroup might need adjuvant therapy additionally.
Similar content being viewed by others
References
ASCO (1997) Clinical practice guidelines for the treatment of unresectable non-small-cell lung cancer. Adopted on May 16, by the American Society of Clinical Oncology. J Clin Oncol 15(8):2996–3018
Bains MS (1991) Surgical treatment of lung cancer. Chest 100(3):826–837
Carter WG, Wayner EA (1988) Characterization of the class III collagen receptor, a phosphorylated, transmembrane glycoprotein expressed in nucleated human cells. J Biol Chem 263(9):4193–4201
Coradini D, Zorzet S, Rossin R et al (2004) Inhibition of hepatocellular carcinomas in vitro and hepatic metastases in vivo in mice by the histone deacetylase inhibitor HA-But. Clin Cancer Res 10(14):4822–4830
Dong WG, Sun XM, Yu BP, Luo HS, Yu JP (2003) Role of VEGF and CD44v6 in differentiating benign from malignant ascites. World J Gastroenterol 9(11):2596–2600
Fasano M, Sabatini MT, Wieczorek R, Sidhu G, Goswami S, Jagirdar J (1997) CD44 and its v6 spliced variant in lung tumors: a role in histogenesis. Cancer 80(1):34–41
Gunthert U, Hofmann M, Rudy W et al (1991) A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells. Cell 65(1):13–24
Hanley JA (1989) Receiver operating characteristic (ROC) methodology: the state of the art. Crit Rev Diagn Imaging 29(3):307–335
Harn HJ, Ho LI, Shyu RY et al (1996) Soluble CD44 isoforms in serum as potential markers of metastatic gastric carcinoma. J Clin Gastroenterol 22(2):107–110
Hirata T, Fukuse T, Naiki H, Hitomi S, Wada H (1998) Expression of CD44 variant exon 6 in stage I non-small cell lung carcinoma as a prognostic factor. Cancer Res 58(6):1108–1110
Kaufmann M, Heider KH, Sinn HP, von MG, Ponta H, Herrlich P (1995) CD44 variant exon epitopes in primary breast cancer and length of survival. Lancet 345(8950):615–619
Kuhn S, Koch M, Nubel T et al (2007) A complex of EpCAM, claudin-7, CD44 variant isoforms, and tetraspanins promotes colorectal cancer progression. Mol Cancer Res 5(6):553–567
Manten-Horst E, Danen EH, Smit L et al (1995) Expression of CD44 splice variants in human cutaneous melanoma and melanoma cell lines is related to tumor progression and metastatic potential. Int J Cancer 64(3):182–188
Marhaba R, Zoller M (2004) CD44 in cancer progression: adhesion, migration and growth regulation. J Mol Histol 35(3):211–231
Miwa T, Watanabe A, Yamada Y et al (1996) Progression in gastric carcinoma relative to the ratio of CD44 epithelial variant transcript to CD44 hematopoietic variant transcript. Cancer 77(1):25–29
Miyoshi T, Kondo K, Hino N, Uyama T, Monden Y (1997) The expression of the CD44 variant exon 6 is associated with lymph node metastasis in non-small cell lung cancer. Clin Cancer Res 3(8):1289–1297
Mulder JW, Kruyt PM, Sewnath M et al (1994) Colorectal cancer prognosis and expression of exon-v6-containing CD44 proteins. Lancet 344(8935):1470–1472
Naor D, Sionov RV, Ish-Shalom D (1997) CD44: structure, function, and association with the malignant process. Adv Cancer Res 71:241–319
Ramasami S, Kerr KM, Chapman AD, King G, Cockburn JS, Jeffrey RR (2000) Expression of CD44v6 but not E-cadherin or beta-catenin influences prognosis in primary pulmonary adenocarcinoma. J Pathol 192(4):427–432
Rudzki Z, Jothy S (1997) CD44 and the adhesion of neoplastic cells. Mol Pathol 50(2):57–71
Spira A, Ettinger DS (2004) Multidisciplinary management of lung cancer. N Engl J Med 350(4):379–392
St JT, Meyer J, Idzerda R, Gallatin WM (1990) Expression of CD44 confers a new adhesive phenotype on transfected cells. Cell 60(1):45–52
Stamenkovic I, Amiot M, Pesando JM, Seed B (1989) A lymphocyte molecule implicated in lymph node homing is a member of the cartilage link protein family. Cell 56(6):1057–1062
Stauder R, Eisterer W, Thaler J, Gunthert U (1995) CD44 variant isoforms in non-Hodgkin’s lymphoma: a new independent prognostic factor. Blood 85(10):2885–2899
Suzuki H, Yamashiro K (2002) Reduced expression of CD44 v3 and v6 is related to invasion in lung adenocarcinoma. Lung Cancer 38(2):137–141
Tran TA, Kallakury BV, Sheehan CE, Ross JS (1997) Expression of CD44 standard form and variant isoforms in non-small cell lung carcinomas. Hum Pathol 28(7):809–814
Wielenga VJ, Heider KH, Offerhaus GJ et al (1993) Expression of CD44 variant proteins in human colorectal cancer is related to tumor progression. Cancer Res 53(20):4754–4756
Wimmel A, Schilli M, Kaiser U et al (1997) Preferential histiotypic expression of CD44-isoforms in human lung cancer. Lung Cancer 16(2–3):151–172
Zhu ZH, Sun BY, Ma Y et al (2009) Three immunomarker support vector machines-based prognostic classifiers for stage IB non-small-cell lung cancer. J Clin Oncol 27(7):1091–1099
Zlobec I, Steele R, Terracciano L, Jass JR, Lugli A (2007) Selecting immunohistochemical cut-off scores for novel biomarkers of progression and survival in colorectal cancer. J Clin Pathol 60(10):1112–1116
Acknowledgments
This work was supported by the grant from Sun Yat-sen University Clinical Research 5010 plan ChiCTR-TRC-00000142.
Conflict of interest statement
We declare that we have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Additional information
D. Situ, H. Long, P. Lin and Z. Zhu contributed equally to this work.
Rights and permissions
About this article
Cite this article
Situ, D., Long, H., Lin, P. et al. Expression and prognostic relevance of CD44v6 in stage I non-small cell lung carcinoma. J Cancer Res Clin Oncol 136, 1213–1219 (2010). https://doi.org/10.1007/s00432-010-0771-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-010-0771-5