Original Article · Originalarbeit Onkologie 2013;36:629–634 DOI: 10.1159/000356041

Published online: October 14, 2013

Clinical Significance of Joint Detection of CD44v6 and CD62P in Nasopharyngeal Carcinoma Jie Yanga*  Lei Lia*  Yanxin Rena   Xiaojiang Lia  Yanling Tub  Jing Mac  Ruimei Suna  Liufang Zhaoa a

Head and Neck Tumor Research Center, 3rd Affiliated Hospital of Kunming Medical University, Yunnan, Department of Medical Oncology of Nanjing Red Cross Hospital, Nanjing, Jiangsu, c ENT Department of Kunming City Children’s Hospital, Kunming, Yunnan, China

Keywords Nasopharyngeal carcinoma · Adhesion molecules · Flow cytometry

Schlüsselwörter Nasopharynxkarzinom · Adhesionsmoleküle · Durchflusszytometrie

Summary Aim: The aim of this study was to investigate the expression and clinical prognostic significance of adhesion molecules in nasopharyngeal carcinoma (NPC) tissues and peripheral blood. Materials and Methods: Flow ­cytometry assays for the expression levels of CD44v6 and CD62P protein in peripheral blood and tissues from controls and NPC patients were performed. Clinical ­ and pathological features were reported and analyzed, and a survival study was carried out. Results: The ­expression of CD44v6 and CD62P in NPC tissues and peripheral blood was higher than that of the control ­ group (p < 0.05). Expression levels in peripheral blood of stage III/IV NPC patients was markedly higher than that of patients in stage I/II (p < 0.05), while it had no statistically significant difference in tissues (p > 0.05). The expression levels of CD44v6 and CD62P in the lymph gland metastasis and distant metastasis group were higher than groups without such metastasis (p < 0.05), and there was no statistical difference in NPC tissues (p > 0.05). The survival rates of NPC groups with low expression in the peripheral blood were higher than those of high-expression groups (p < 0.05). Conclusion: Joint detection of CD44v6 and CD62P in the peripheral blood or tissues of NPC patients has diagnostic and prognostic value as a marker of poor clinical outcome.

Zusammenfassung Ziel: Ziel dieser Studie war es, die Expression und klinisch-prognostische Signifikanz von Adhesionsmole­ külen im Gewebe und peripheren Blut von Patienten mit einem Nasopharynxkarzinom (NPC) zu untersuchen. ­Material und Methoden: Es wurden durchflusszytometrische Assays zur Bestimmung des Expressionsspiegels der CD44v6- und CD62P-Proteine im peripheren Blut und Gewebe von Kontrollen und NPC-Patienten durchgeführt. Klinische und pathologische Merkmale wurden aufgenommen und analysiert, und eine Überlebens­ studie wurde durchgeführt. Ergebnisse: Die Expression von CD44v6 und CD62P im Gewebe und peripheren Blut von NPC-Patienten war höher als in der Kontrollgruppe (p < 0,05). Die Expression im peripheren Blut von NPCPatienten im Stadium III/IVs war deutlich höher als bei Patienten im Stadium I/II (p < 0,05); im Gewebe bestanden dagegen keine statistisch signifikanten Unterschiede (p > 0,05). Die Expressionsspiegel von CD44v6 und CD62P in der Patientengruppe mit Lymphknoten- und Fernmetastasen waren höher als bei Patienten ohne derartige Metastasen (p < 0,05); im NPC-Gewebe bestanden keine statistisch signifikanten Unterschiede (p > 0,05). Die Überlebensrate war bei NPC-Patienten mit niedrigem ­Expressionsspiegel im peripheren Blut höher als bei Patienten mit hoher Expression (p < 0,05). Schlussfolgerung: Die gemeinsame Detektion von CD44v6 und CD62P im peripheren Blut bzw. Gewebe von NPC-Patienten hat diagnostische und prognostische Bedeutung als ein ­Marker schlechten klinischen Outcomes.

*These authors contributed equally to this work. © 2013 S. Karger GmbH, Freiburg 0378-584X/13/3611-0629$38.00/0 Fax +49 761 4 52 07 14 [email protected] www.karger.com

Accessible online at: www.karger.com/onk

Prof. Xiaojiang Li Head and Neck Tumor Research Center of Yunnan Province 3rd Affiliated Hospital of Kunming Medical University 650118 Kunming, China [email protected]

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b

Introduction Nasopharyngeal carcinoma (NPC) is a common malignant tumor in South China and Southeast Asia. According to statistics, the incidence of NPC is 30/100,000 in men and 13/100,000 in women [1]. NPC lesions are hidden and difficult to detect in the early stages. Furthermore, NPC may trigger lymph node and blood metastasis due to its high grade of malignancy and fast progressing nature; hence, tumors may reach an advanced stage in a short period of time before any symptoms emerge [2]. With improvements in chemoradiotherapy, the current 5-year survival rate is more than 50%, and patients of earlier stages may enjoy a greater than 80% 5-year survival rate [3– 5]. However, local recurrence and distant metastasis remain as main reasons for treatment failure. CD44v6 and CD62P play a key role in malignant tumor metastasis [6, 7]. The present study applied flow cytometry (FCM) to detect the expression rates of CD44v6 and CD62P in the tissues and peripheral blood of NPC patients, and analyzed their correlation with clinical indices and influence on survival rates.

Materials and Methods

­ ccording to the NPC TNM stage classification jointly proposed by A UICC and AJCC in 1997, 2 cases were stage I, 13 stage II, 21 stage III, and 9 stage IV. The control group comprised 12 healthy persons (7 male and 5 female) who underwent an examination of the nasopharynx due to discomfort in 10 cases and in 2 cases had chronic inflammation of the nasopharyngeal mucosa. NPC was ruled out based on pathological examination with the consent of the patients and their families. The mean age was 45.36 years (range 31–60 years). The tissue specimen and pathological specimen were derived from the same specimen; in order to avoid interference with clinical diagnosis, the experimental specimen was only a small part of the pathological specimen (diameter about 5 mm). The ­tissue specimen was placed in liquid nitrogen for storage and future use. 2 ml of peripheral blood were taken from every person and placed into a heparinized bottle. Consent was acquired from all patients before specimens were taken.

Methods Experiment Reagent Reagent CD44v6-FITC/CD45-PC and negative control IgG-FITC/ CD45-PC as well as reagent CD61-FITC/CD62P-PE and negative control CD61-FITC /IgG-PE were purchased from Beckman Coulter Inc., Brea, CA, USA; an EPICS-XL flow cytometer was also purchased from Beckman Coulter. FCM Detection

Specimens Nasopharyngeal Tissue Tissues were cut into pieces, digested for 2 h at 37 °C (with 1 mg/ml collagenase, 25 u/ml hyaluronidase, and 0.1 mg/ml DNase), and then filtered with a 300 mesh screen. Then, 10 µl of 2-tone fluorescently labeled antibody were added. All samples were mixed well and stored away from light at room temperature for 15–20 min. Peripheral Blood To prepare for FCM, 100 µl whole blood were mixed with 10 µl of 2-tone fluorescently labeled antibody, then stored away from light at

Fig. 1. Expression rates of CD44v6 in the peripheral blood of A the control group (2.7%) and B the nasopharyngeal carcinoma (NPC) group (15.9%); expression rates of CD44v6 in the tissue of C the control group (3.8%) and D the NPC group (71.9%).

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We collected 45 specimens (25 from male and 20 from female patients) of tissue and peripheral blood of first-visit patients of the 3rd ­Affiliated Hospital of Kunming Medical University from 2003 to 2006. NPC was proven by pathologic analysis (including 43 low differentiated squamous cell carcinoma cases and 2 medium and high differentiated squamous cell carcinoma cases); none of the patients received any treatment outside of the hospital, had any immune disorder, or took medication affecting the immune system. The mean age was 49.23 years (range 19–68 years). 38 patients had lymph node metastasis, and 7 had not.

Statistical Methods The SPSS12.0 statistical software package (IBM Inc., Armonk, NY, USA) was used for analysis. t was used for data detection, and the ­Kaplan-Meier method was adopted for survival rate analysis. The longrank method was used for survival rate comparison between groups. The difference had statistical meaning when p < 0.05.

Results High Expression of CD44v6 and CD62P in NPC Tissue and Peripheral Blood In 45 NPC tissue specimens, CD44v6 was 21.65 ± 12.39% and CD62P was 11.02 ± 5.83%, higher than CD44v6 (6.60 ± 1.43%) and CD62P (3.58 ± 0.83%) in the control groups; the difference was significant (p < 0.05). In the peripheral blood of NPC patients, CD44v6 was 8.41 ± 5.60% and CD62P was 5.46 ± 4.26%, higher than CD44v6 (3.88 ± 1.01%) and CD62P (1.45 ± 0.26%) in the control groups; the difference was significant (p < 0.05) (figs. 1 and 2) (table 1). Correlation between CD44v6 and CD62P Expression and Clinical Stage The expression of CD44v6 and CD62P was not statistically different in patients of different ages and sexes. We divided

the NPC patients into an early stage (stage I/II) group and a moderate to advanced group (stage III/IV) according to the NPC TNM stage classification jointly proposed by UICC and AJCC in 1997. In NPC tissues, the expression of CD44v6 in stage III/IV was higher than that in stage I/II (23.91 ± 12.25% vs. 18.53 ± 9.75%), but the difference was not statistically ­significant (p > 0.05). The expression of CD62P in stage III/IV patients was higher than that in the stage I/II group (11.12 ± 5.53% vs. 10.42 ± 3.81%), but there was no statistically significant difference (p > 0.05). In the peripheral blood of NPC patients, the expression of CD44v6 in stage III/IV patients was higher than that in the stage I/II group (11.61 ± 7.03% vs. 5.61 ± 2.64%), and this difference had statistical significance (p < 0.05). The expression of CD62P in stage III/IV patients was higher than that in the stage I/II group (8.30 ± 4.44% vs. 2.96 ± 1.91%); this difference also had statistical significance (p < 0.05). The 45 NPC patients were further divided into a lymph node metastasis group and a group without lymph node ­metastasis, according to the clinical data. In NPC tissue, the expression of CD44v6 in the lymph node metastasis group was higher than that in the group without lymph node metastasis (16.59 ± 10.54 vs. 10.56 ± 4.32%), but the difference was of no statistical meaning (p > 0.05). The expression of CD62P in patients with lymph node metastasis was higher than that in the group without lymph node metastasis (12.18 ± 5.05% vs. 7.98 ± 2.43%), but the difference was of no statistical meaning either (p > 0.05). In the peripheral blood of NPC patients, the expression of CD44v6 in the lymph node metastasis group was higher than that in the group without lymph node metastasis (10.24 ± 6.44% vs. 5.32 ± 3.29%), and the difference had statistical significance (p < 0.05). The expression of CD44v6 in the lymph node metastasis group was higher than that in

Fig. 2. Expression rates of CD62P in the peripheral blood of A the control group (0.8%) and B the nasopharyngeal carcinoma (NPC) group (7.9%); expression rates of CD62P in the tissue of C the control group (1.2%) and D the NPC group (17.8%).

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room temperature for 20 min. Q-prep was used for autohemolysis, and online detection was conducted after 30 min. Expression of CD44v6 and CD62P was analyzed (CD45+: lymphocyte cell, CD61+: platelet). The positive percentage of CD44v6 was calculated with the following formula: number of white blood cells with CD44v6 expression/the number of white blood cells with CD45 expression × 100%. The positive percentage of CD62P was calculated with the formula: number of platelets with CD62P expression/total number of platelets with CD61 expression × 100%.

the group without lymph node metastasis (6.88 ± 4.45% vs. 3.06 ± 2.57%), and the difference had statistical significance (p < 0.05). The 45 NPC patients were also divided into a distant metastasis group and a group without distant metastasis, according to clinical data. In NPC tissue, the expression of CD44v6 in the distant metastasis group was higher than that in the group without distant metastasis (23.50 ± 9.12 vs. 14.25 ± 7.34%), but the difference was of no statistical meaning (p > 0.05). The expression of CD62P in patients with distant metastasis was higher than that in the group without distant metastasis (13.88 ± 5.41% vs. 7.99 ± 3.68%), but the difference was also of no statistical meaning (p > 0.05). In the peripheral blood of NPC patients, the expression of CD44v6 in the Table 1. Expression of CD44v6 and CD62P in the tissue and peripheral blood of nasopharyngeal carcinoma (NPC) patients and controls Expression level, mean ± SD, % tissue NPC Controls p value

blood

CD44v6

CD62P

CD44v6

CD62P

21.65 ± 12.39   6.60 ± 1.43  0.0034

11.02 ± 5.83   3.58 ± 0.83  0.0046

8.41 ± 5.60 3.88 ± 1.01 0.0098

5.46 ± 4.26 1.45 ± 0.26 0.012

­ istant metastasis group was higher than that in the group d without distant metastasis (6.88 ± 4.45% vs. 3.06 ± 2.57%), and the difference was of statistical significance (p < 0.05). The expression of CD62 in the distant metastasis group was higher than that in the group without distant organ metastasis (9.31 ± 4.25% vs. 3.19 ± 2.11%), and the difference was also of statistical significance (p < 0.05) (table 2). Correlation between CD44v6 and CD62P Expression and Disease Recurrence All NPC patients received treatment according to the NCCN guidelines after a definitive pathological diagnosis was made. Stage I patients received radical radiotherapy, patients of stage II–IV without distant metastasis received 4–6 cycles of TP chemotherapy and radical radiotherapy, and patients of stage IV with distant metastasis received 6 cycles of TP chemotherapy and palliative radiotherapy. Based on the ­ ­average levels of indices in the peripheral blood, the 45 NPC patients were divided into 3 groups: low expression group A (CD44v6 ≤ 5.78%, CD62P ≤ 1.95%), high expression group B (CD44v6 > 5.78%, CD62P > 1.95%), and group C with 1 low expression index (CD44v6 ≤ 5.78% or CD62P ≤ 1.95%). The Kaplan-Meier method was applied to analyze 1-year,

Table 2. Clinical factors and CD44v6 and CD62P in patients with nasopharyngeal carcinoma (n = 45) Clinical factor

Patients, n

Expression, mean ± SD, % CD44v6

Age, years ≤ 43 > 43 p value Sex Male Female p value TNM stage I/II I/II III/VI p value Cervical lymph node metastasis Available Not available p value Distant metastasis Available Not available p value

CD62P

peripheral blood

tissue

peripheral blood

tissue

17 28

  8.71 ± 7.08   8.30 ± 5.56  0.175

19.71 ± 13.45 22.37 ± 12.28  0.828

4.94 ± 3.77 5.66 ± 4.46 0.783

10.57 ± 5.90 11.19 ± 5.95  0.789

25 20

  7.05 ±5.08 11.29 ± 6.74  0.107

19.73 ± 12.50 29.74 ± 8.73  0.199

5.02 ± 4.16 6.40 ± 4.42 0.333

10.15 ± 5.50 14.70 ± 6.30  0.869

15 30

  5.61 ± 2.64 11.61 ± 7.03  0.000

18.53 ± 9.75 23.91 ± 12.25  0.423

2.96 ± 1.91 8.30 ± 4.44 0.000

10.42 ± 3.81 11.12 ± 5.53  0.295

38 7

10.24 ± 6.44   5.32 ± 3.29  0.000

16.59 ± 10.54 10.56 ± 4.32  0.116

6.88 ± 4.45 3.06 ± 2.57 0.001

12.18 ± 5.05 7.98 ± 2.43  0.080

9 36

13.56 ± 6.45   5.38 ± 2.71  0,000

23.50 ± 9.12 14.25 ± 7.34  0.601

9.31 ± 4.25 3.19 ± 2.11 0.000

13.88 ± 5.41 7.99 ± 3.68  0.218

Group A B C

632

Cases, n 20 14 11

3 years

5 years

Survival time, medium ± SD, months

95% confidence interval, months

1 year

Survival rate, % 95.00 85.71 90.91

85.00 64.29 63.64

75.00 21.43 54.55

70.00 ± 2.24 41.00 ± 6.55 62.00 ± 15.41

62–74.38 17–53.83 31.79–92.21

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Table 3. Correlation between joint expression of CD44v6 and CD62P and survival in patients with nasopharyngeal carcinoma (A = low expression of 2 indices; B = high expression of 2 indices; C = low expression of 1 index)

3-year, and 5-year survival rates of the 3 groups (table 3), and the log-rank test showed that the difference in the survival rates of the 3 groups had statistical significance (p = 0.0015) (fig. 3).

Discussion As some studies have revealed, CD44v6 and CD62P are expressed in human malignant cells and tissues. Their mechanism of action remains unclear but has been reported to be associated with the progression and metastasis of malignancies [8, 9]. The present study explored the relationship between the expression of adhesion molecules in tissues and ­peripheral blood of NPC patients and clinical prognosis. The cell surface adhesion molecule CD44 is a single membrane surface glycoprotein family member encoded by single genes with high heterogeneity. CD44v6 is a new CD44 variant found by Gunthert et al. [10] in 1989 in the rat metastatic pancreatic cancer cell line BSp73ASML. Its coded protein is a segment containing a 162 amino acid sequence inserted ­between the 223rd amino acid and 247th amino acid of the CD44s protein of the rat. CD44v6 associates with its ligands (mainly including hyaluronic acid, fibronectin, collagen, integrin) and has involvement in cell-cell adhesion, fibronectin in the ground substance, and type IV collagen E. Furthermore, CD44v6 enables interaction between CD44 protein and cytoskeletal proteins through linking with the ligand ankyrin at the inner side of the cell membrane, allowing cancer cells to grow, infiltrate, and transfer to distant sites for implantation. CD44v6 is closely associated with prognosis of several tumors [11, 12]. CD62P, also called GMP140, P-selectin or PADGEM, is a member of a newly discovered cell adhesion molecule selectin family. It is expressed by activated platelets and endothelial cells, and it is rapidly expressed on the cell membrane surface

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Fig. 3. Kaplan-Meier survival curve of nasopharyngeal carcinoma (NPC) patients separated into 3 groups according to expression levels.

and partly released into the blood after stimulation of thrombin, histamine, and leukotrienes. Research indicates that s­everal tumor surfaces have CD62P receptors (S-Lewis x, S-Lewis α, and PSGLE-1), and these receptors may combine with CD62P to mediate adhesion of tumor cells to platelets and endo­ thelial cells and then promote transfer of tumor cells [5]. Our study showed that the expression of CD44v6 and CD62P in tissues and peripheral blood of NPC patients was higher than that of the control group. This is consistent with other studies and indicates that NPC cells secret high levels of CD44v6 and CD62P which promote tumor growth and development. The expression levels of CD44v6 and CD62P in the peripheral blood of NPC patients of stage III/IV was markedly higher than that of stage I/II patients (p < 0.05). We ­divided the NPC patients into groups with or without lymph node metastasis, and with or without distant metastasis, ­according to the patient data. In the peripheral blood, the ­expression of CD44v6 and CD62P was higher in the lymph node metastasis and distant metastasis groups than in the groups without lymph node metastasis and distant metastasis (p < 0.05); however, the expression difference was of no statistical significance (p > 0.05). As the disease progresses, CD44v6 and CD62P expression gradually increases. Adhesion molecules under physiological conditions get involved in the in vivo lymphocyte ‘homing’ process. Tumor cell transfer has steps similar to lymphocyte ‘homing’; transferred cancer cells combine with lymph cells through CD44v6, so CD44v6 remains in the lymph gland for growth and differentiation. On the other hand, CD44v6 expressed by some tumor cells may enable tumor cells in the blood to combine with fibronectin or collagen in the vascular endothelium, adhere to the endothelial cells, and cause hematogenous metastasis. CD62P receptors on the surface of tumor cells combine with CD62P, ­mediate the adhesion between tumor cells and platelets and endothelial cells, and form microemboli and small cancer ­emboli. These emboli adhere to vascular endothelial cells and remain in vessels of remote organs, pass through the vascular wall, and form a metastatic focus. The expression and release of CD62P increases with cancer stage, and at the same time, CD62P is under ­activating condition [13]. Because of the higher expression of CD44v6 and CD62P and their increased release into the peripheral blood by cells which have the ­tendency to metastasize in the moderate to advanced stages of disease, we considered it to be more significant to detect CD44v6 and CD62P in the peripheral blood rather than the tissue of NPC patients. The 45 NPC patients received standard treatments according to the NCCN guidelines and attended regular follow-up visits. We divided the patients into 3 groups: low expression group A (CD44v6 ≤ 5.78%, CD62P ≤ 1.95%), high expression group B (CD44v6 > 5.78%, CD62P > 1.95%), and group C with 1 low expression index (CD44v6 ≤ 5.78% or CD62P ≤ 1.95%). The 1-year survival rates of Group A, B, and C were 75, 21.43, and 54.55%, respectively; the 3-year survival rates

were 85, 64.29, and 63.64%, respectively; and the 5-year survival rates were 75, 21.43, and 54.55%, respectively. The survival rate difference between the 3 groups had statistical ­significance (p < 0.05). The results show that the higher the CD44v6 and CD62P level in the peripheral blood, the poorer the NPC patient’s prognosis will be. However, due to the small sample size in this study, it cannot be ruled out that the poorer prognosis has in fact no association with CD44v6 and CD62P levels. Research indicates that tumor cells which express CD44v6 link with some ligands in remote lymph and blood vessel; hence, tumor cells that are transferred to these locations attach themselves and grow more steadily, thus promoting recurrence and tumor transfer [14]. The adhesion of CD62P-mediated tumor cells to cells such as erythrocytes, platelets, or neutrophil granulocytes is an indispensable step for malignant tumors to transfer via blood vessels, stay in target organs, invade blood vessels, and form distant foci [15]. According to our findings, we conjecture that the high expression of both CD44v6 and CD62 may be correlated with poor prognosis in NPC patients, and the joint detection of CD44v6 and CD62P in the peripheral blood may serve as an important diagnostic and prognostic index. The high expression of CD44v6 and CD62P in NPC cells promotes transfer of tumor cells and affects the prognosis. ­According to reports by Shi et al. [16], lower expression of

CD44v6 could reduce the growth of the NPC cell line CEN2L2, preventing cancer cells to progress from stage G0–G1 to stage S. In animal experiments using CD44 antibody, soluble CD44 protein, or antisense technology, restrained tumor growth and transfer has been shown, and bivatuzumab – a monoclonal antibody directed against CD44v6 – has undergone stage I clinical testing in advanced head and neck squamous cell carcinoma [17]. Currently there are no reports about CD62P blocking tumor growth and transfer. However, as high expression of CD44v6 and CD62P in the peripheral blood of NPC patients related to a poorer prognosis, we believe that the joint detection of CD44v6 and CD62P in the blood may indeed be useful in predicting patients’ prognosis. In order to prevent malignant tumor spread, we will aim to target the molecular biological behavior of metastatic cells or change their configuration to lower CD44v6 and CD62P ­expression in the blood in future studies. Targeted therapy ­directed at CD44v6 and CD62P has the potential to further improve survival in patients with NPC.

Disclosure Statement The authors declare no conflicts of interests.

References

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  6 Yasui W, Oue N, Aung PP, et al.: Molecular-pathological prognostic factors of gastric cancer: a review. Gastric Cancer 2005;8:86–94.   7 Chen M, Geng JG: P-selectin mediates adhesion of leukocytes, platelets, and cancer cells in inflammation, thrombosis, and cancer growth and metastasis. Arch Immunol Ther Exp (Warsz) 2006;54:75–84.   8 Schadendorf D, Heidel J, Gawlik C, et al.: Association with clinical outcome of expression of VLA-4 in primary cutaneous malignant melanoma as well as P-selectin and E-selectin on intratumoral vessels. J Natl Cancer Inst 1995;87:366–371.   9 Kawano T, Yanoma S, Nakamura Y, et al.: Evaluation of soluble adhesion molecules CD44 (CD44st, CD44v5, CD44v6), ICAM-1, and VCAM-1 as tumor markers in head and neck cancer. Am J Otolaryngol 2005;26:308–313. 10 Gunther U, Hofmann M, Rudy W, et al.: A new variant of glycoprotein CD44 confer metastatic potential to rat carcinoma a cells. Cell 1991;65:13–24. 11 Orian-Rousseau V: CD44, a therapeutic target for metastasising tumours. Eur J Cancer 2010;46:1271– 1277. 12 Shen W D, Ji Y, Liu P F, et al.: Correlation of E-cadherin and CD44v6 expression with clinical

pathology in esophageal carcinoma. Mol Med Rep 2012;5:817–821. 13 Fox SB, Turner GD, Gatter KC, et al.: The increased expression of adhesion molecules ICAM1, E-and P-selectin on breast cancer endothelium. J Pathol 1995;177:369–376. 14 Hanlay WD, Napier SL, Burdich MM, et al.: ­Variant isoforms of CD44 are P- and L-selectin ligands on colon carcinoma cells. FASEB J 2006; 20:337–339. 15 Maulas M, Luukkaa M, Grenman R, et al.: Intratumoral lymphatics are essential for the metastatic spread and prognosis in squamous cell carcinomas of the head and neck region. Cancer Res 2003; 63:1920–1926. 16 Shi Y, Tian Y, Zhou YQ, et al.: Reduction of CD44 standard expression is associated with tumour ­recurrence and unfavourable outcome in differentiated thyroid carcinoma. J Pathol 2000;192:321– 327. 17 Tijink BM, Buter J, de Bree R, et al.: A phase I dose escalation study with anti-CD44v6 bivatuzumab mertansine in patients with incurable squamous cell carcinoma of the head and neck or ­esophagus. Clin Cancer Res 2006;12:6064–6072.

Yang/Li/Ren/Li/Tu/Ma/Sun/Zhao

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 1 Ng Y K, Wong E Y L, Lau C P Y, et al.: K252a ­induces anoikis-sensitization with suppression of cellular migration in Epstein-Barr virus (EBV)-­ associated nasopharyngeal carcinoma cells. Invest New Drugs 2012;30:48–58.  2 Chua D T T, Nicholls J M, Sham J S T, et al.: ­Prognostic value of epidermal growth factor receptor expression in patients with advanced stage ­nasopharyngeal carcinoma treated with induction chemotherapy and radiotherapy. Int J Radiat Oncol Biol Phys 2004;59:11–20.   3 Au JS, Law CK, Foo W, et al.: In-depth evaluation of the AJCC/UICC 1997 staging system of nasopharyngeal carcinoma: prognostic homogeneity and proposed refinements. Int J Radiat Oncol Biol Phys 2003;6:413–426.  4 Lee AW, Tung SY, Chua DT, et al.: Randomized trial of radiotherapy plus concurrent-adjuvant chemotherapy vs. radiotherapy alone for regionally advanced nasopharyngeal carcinoma. J Natl Cancer Inst 2010;102:1188–1198.   5 Lee AW, Sze WM, Au JS, et al.: Treatment results for nasopharyngeal carcinoma in the modern era: the Hong Kong experience. Int J Radiat Oncol Biol Phys 2005;61:1107–1116.

Clinical significance of joint detection of CD44v6 and CD62P in nasopharyngeal carcinoma.

The aim of this study was to investigate the expression and clinical prognostic significance of adhesion molecules in nasopharyngeal carcinoma (NPC) t...
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