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CD146 Is a Potential Marker for the Diagnosis of Malignancy in Cervical and Endometrial Cancer

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CD146 Is a Potential Marker for the Diagnosis of Malignancy in Cervical and Endometrial Cancer ONCOLOGY LETTERS 5: 1189-1194, 2013 CD146 is a potential marker for the diagnosis of malignancy in cervical and endometrial cancer HAOFENG ZHANG1, JUN ZHANG1, ZHAOQING WANG2, DI LU2, JING FENG2, DONGLING YANG2, XIUQIN CHEN3 and XIYUN YAN2 1Department of Obstetrics and Gynecology, Capital Medical University Affiliated Beijing Anzhen Hospital, Institute of Beijing Heart, Lung and Blood Vessel Diseases, Chaoyang, Beijing 100029; 2Protein and Peptide Pharmaceutical Laboratory, Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang, Beijing 100101; 3Department of Obstetrics and Gynecology, The Fifth Affiliated Hospital of Zhengzhou University, Erqi, Zhengzhou 450000, P.R. China Received October 30, 2012; Accepted January 14, 2013 DOI: 10.3892/ol.2013.1147 Abstract. Cluster of differentiation 146 (CD146) is an endothe- positively and significantly correlated with the pathological lial cell adhesion molecule which is overexpressed in various subtype of cervical cancer and with the histological grade and types of malignant cancer, including ovarian cancer. However, depth of myometrial invasion in endometrial cancer. In addi- whether CD146 is overexpressed in another two types of tion, we confirmed that CD146 is present in the majority of gynecological cancer, cervical cancer and endometrial cancer, blood vessels in cervical and endometrial cancer, suggesting remains unclear. In the present study, we showed that CD146 that CD146 may be actively implicated in the metastasis of expression levels were higher in cells from cervical cancer cervical and endometrial cancer via the vascular system. Thus, and endometrial cancer compared with their corresponding this study provides insights for further development of CD146 normal tissues, using anti-CD146 mouse antibody AA4 (mAb mAb in the detection of gynecological malignant cancer types AA4) and that mAb AA4 exhibited a high performance for and implies that a combined treatment strategy of anti-CD146 specificity, sensitivity and positive predictive value in the immunotherapy with other traditional chemo- or radiotherapy detection of these two types of cancer. CD146 expression was treatments may be a promising approach against cervical and endometrial cancer. Introduction Correspondence to: Professor Xiyun Yan, Protein and Peptide Pharmaceutical Laboratory, Chinese Academy of Sciences- Cluster of differentiation 146 (CD146) is a cell adhesion University of Tokyo Joint Laboratory of Structural Virology and molecule (CAM) which belongs to the immunoglobulin Immunology, Institute of Biophysics, Chinese Academy of Sciences, superfamily (IgSF) (1). Human CD146 has previously been 15 Datun Road, Chaoyang, Beijing 100101, P.R. China designated several synonyms, including MUC18 (1,2), A32 E-mail: [email protected] antigen (3,4), S-Endo-1 (5), melanoma CAM (MCAM or Professor Jun Zhang, Department of Obstetrics and Gynecology, Mel-CAM) (4,6,7), metastasis CAM (MET-CAM) (8) and Captial Medical University Affiliated Beijing Anzhen Hospital, hemopoietic CAM (HEMCAM) (9). The avian homolog of Institute of Beijing Heart, Lung and Blood Vessel Diseases, CD146 has been named gicerin (10). CD146 was originally 2 Anzhen Road, Chaoyang, Beijing 100029, P.R. China identified as a marker for melanoma (MCAM), due to its Email: [email protected] overexpression in metastatic lesions and advanced primary tumors, yet not in benign lesions (1,3,4). Increasing amounts Abbreviations: CD146, cluster of differentiation 146; mAb, mouse of evidence have demonstrated that CD146 is overexpressed antibody; CAM, cell adhesion molecule; MET-CAM, metastasis in a variety of carcinomas, in addition to melanomas (11-14). CAM; HEMCAM, hemopoietic CAM; V set, variable region; As a result of this characteristic, CD146 has attracted attention C-2 set, constant region; IgSF, immunoglobulin superfamily; and is considered to be a potential marker for tumor diagnosis, PPV, positive predictive value; NPV, negative predictive value; prognosis and treatment. The majority of studies support the FIGO, International Federation of Gynecology and Obstetrics systems; EECs, endometrioid adenocarcinomas; NEECs, theory that CD146 promotes tumor growth, angiogenesis and non-endometrioid adenocarcinomas metastasis (15), therefore, CD146 is a promising target for tumor therapy (16,17). Key words: CD146, marker, diagnostic testing, anti-CD146 mAb CD146 is a 113-kDa integral membrane glycoprotein, AA4, cervical cancer, endometrial cancer whose sequence of amino acids consists of a signal peptide, an extracellular fragment structure of five immunoglob- 1190 ZHANG et al: CD146 IS A MARKER FOR CERVICAL AND ENDOMETRIAL CANCER ulin-like domains (V-V-C2-C2-C2), a transmembrane and eosin (H&E) solution. Following deparaffinization, region and a short cytoplasmic tail (2,18). The Protein and tissue sections were stained with a CD146- or CD31-specific Peptide Pharmaceutical Laboratory, Chinese Academy of antibody, then with biotin-conjugated secondary antibodies Sciences-University of Tokyo, Tokyo, raised an array of (1:1000), followed by HRP-conjugated streptavidin (Dianova). mouse antibodies (mAbs) against CD146, among which AA4 The sections were counterstained with hematoxylin to visu- recognizes the epitope located at the second IgC2 domain (19). alize the nuclei. AA4 is able to specifically detect CD146 in tumor specimens from various organs, including breast tumors (14). CD146 Double-staining immunohistofluorescence analysis. Sections overexpression has been revealed in ovarian cancer and may (5 µm) were fixed in 4% paraformaldehyde (pH 7.4) for 15 min be a marker for poor prognosis in ovarian cancer patients (11). at room temperature. Following the general procedure, which Thus, CD146 Abs may be a useful marker in the detection of included permeabilization and blocking, the slides were gynecological malignancies. However, CD146 expression and co-incubated with antibodies for CD146 (mAb) and CD31 detection in two other types of gynecological cancer, cervical (rAb, rabbit Ab) overnight at 4˚C. After washing with PBS and endometrial cancer, has not been investigated. three times, the slides were incubated with a mixture of the two This study aimed to evaluate the distribution of CD146 secondary antibodies (anti-rabbit Alexa Fluor® 488 and anti- in cervical and endometrial cancer; the diagnostic use of mouse Alexa Fluor® 555) in the dark for 1 h. The nuclei were CD146 Abs in cervical and endometrial cancer was evaluated stained with DAPI. Fluorescent images were acquired using by calculating the correlation between clinical pathological a confocal microscope (FV1000, Olympus, Tokyo, Japan). parameters and the extent of immunohistochemical CD146 expression in tumor tissues. Statistical analysis. Statistical analysis was conducted using SPSS software. The significant differences between the groups Materials and methods and the association between CD146 expression and different clinicopathological parameters were evaluated using the Antibody and reagents. The anti-CD146 monoclonal antibody Chi-square test or Fisher's exact test. P<0.05 was considered to AA4 was generated in the Protein and Peptide Pharmaceutical indicate a statistically significant difference. Laboratory (Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Results Beijing, China). A CD31-specific antibody was purchased from Abcam (Cambridge, MA, USA). Biotin-conjugated secondary Classification of cervical cancer specimens into categories. antibodies (goat anti-rabbit or -mouse) and HRP-conjugated The collected specimens were divided into normal tissue and streptavidin were purchased from Dianova (Rodeo, CA, USA). cancerous tissue groups. The mean age of the patients with Goat anti-rabbit Alexa Fluor® 488 and goat anti-mouse Alexa normal and cancerous uterine cervical tissue was 44.12±10.61 Fluor® 555 were purchased from Invitrogen (San Diego, CA, and 48.25±9.86 years, respectively. The cervical samples USA). DAPI was purchased from Roche (Indianapolis, IN, consisted of 16 normal (control) and 256 malignant specimens USA). Normal goat serum and a 3,3'-diaminobenzidine (DAB) (Table I). Cervical cancer is a malignant neoplasm originating staining kit were purchased from ZSGB-BIO (China). from cells in the cervix uteri and consists of two histological subtypes. The majority of cervical cancer types are squamous Ethics statement. Informed consent was obtained from all cell carcinomas, arising in the squamous epithelial cells participants in this study. All procedures have been approved that line the cervix. Adenocarcinomas, arising in glandular by the Ethics Committee of Capital Medical University epithelial cells, are the second most common type of cervical Affiliated Beijing Anzhen Hospital, Institute of Beijing Heart, cancer (20). Cancer rarely occurs in other types of cells in Lung and Blood Vessel Diseases and Institute of Biophysics, the cervix. In this study, 241 of the cancer samples had the Chinese Academy of Sciences. squamous carcinoma subtype and only 15 samples had the adenocarcinoma subtype. Cervical cancer tissue was further Clinical sampling. Malignant specimens were obtained classified into categories following the review of existing from patients with gynecological cancer, including cervical patient medical records. With regard to the histological grade, carcinoma and endometrial carcinoma, by surgical excision,
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