恶性脑肿瘤中Her-2与CD44的表达及意义
摘要
恶性脑肿瘤的诊治在中枢神经系统疾病中仍是一个难点,临床治疗效果不佳。目前医务工作者在不断改良原有治疗方法的同时,正积极探索新的治疗手段。生物靶向治疗作为一种新的治疗手段有望成为恶性肿瘤治疗的有效方法,开展靶向治疗研究的前提就是要有行之有效的生物靶点。人类表皮生长因子受体2型(human epithelial receptor type 2,Her-2)是一种癌基因受体,在多种恶性肿瘤中有所表达。鉴别簇44号(cluster of differentiation 44,CD44)是细胞表面粘附分子中的一种,现已作为多种肿瘤研究及临床诊断的标志物。本研究目的:探讨人类表皮因子受体2型(Her-2)及CD44在常见恶性脑肿瘤中的表达情况及与肿瘤预后的关系。方法:采用免疫组织化学SP法和间接免疫荧光标记法检测胶质母细胞瘤、胶质肉瘤、髓母细胞瘤、间变性少突胶质细胞瘤共120例及10例正常脑组织标本中Her-2、CD44的表达,对数据进行统计学分析。结果: Her-2表达的阳性率在胶质母细胞瘤、胶质肉瘤、髓母细胞瘤和间变性少突胶质细胞瘤中分别是80.0%,73.3%,66.7%和33.3%。CD44表达的阳性率在上述四种肿瘤中分别为86.7%,80.0%,90.0%,73.3%。Her-2在正常脑组织中无表达,CD44在正常脑组织中表达阳性率为20.0%。Her-2与CD44在恶性脑肿瘤中的表达无相关性(P>0.05),但两者均与肿瘤预后关系密切。免疫荧光标记显示两者存在共定位现象。结论: Her-2在胶质母细胞瘤、胶质肉瘤、髓母细胞瘤中高表达,而在间变性少突胶质细胞瘤中相对低表达,CD44则普遍高表达。未发现两者在恶性脑肿瘤中表达具有相关性,但二者均与肿瘤的预后有密切关系,具有协同作用。因此Her-2与CD44有望成为脑肿瘤联合免疫治疗的联合靶位,在脑肿瘤诊治中发挥重要作用。
The diagnosis and treatment of malignant brain tumors in the central nervous system diseases are difficulty all the way, the effect of clinical treatment is not very well. At present the medical workers refine original treatments constantly and explore new treatments actively. Biological targeted therapy as a new treatment method is expected to become effective method to malignant tumors. the premise to carry out the targeting therapy research is having effective biological targets. Human epidermal growth factor receptor type 2 (Her-2) is a cancer gene receptor, in a variety of malignant tumor, to express. CD44 is a sort of cell surface adhesion molecules. Now it are, in variety of tumor, the research and clinical diagnostic markers.Objective To detect and analyze human epidermal growth factor receptor(HER-2) and CD44 in different malignant brain tumors, and to evaluate their prognostic significance.Methods Using immunohistochemistry and indirect immunofluorescence to detect the expression of Her-2 and CD44 in malignant brain tumors and analyzing the experimental data. The specimens contain 10 normal brain tumors and 120 malignant brain tumors that are glioblastoma, gliosarcoma, medulloblastoma and anaplastic oligodendroglioma.Results The positive rate of Her-2 in the glioblastoma, gliosarcoma, medulloblastoma, and anaplastic oligodendroglioma respectively were 80.0%, 73.3%, 66.7% and 33.3%. The positive rate of CD44 in these four tumors respectively were 86.7%, 80.0%, 90.0%, 73.3%. The expression of Her-2 in normal brain tissue was none, but CD44 was 20.0% . The expression in malignant brain tumor had no correlation between Her-2 and CD44 (P>0.05), but they both correlate with tumor prognosis. Conclusions The expressions of Her-2 were not same in malignant brain tumors, the expressions of CD44 were generally high. No correlation between Her-2 and CD44, but they have synergistic effect with the prognosis of tumors. Her-2 and CD44 are expected to be combined target site for target therapies of brain tumor. They will play an important role in the brain tumor diagnosis and treatment.
The diagnosis and treatment of malignant brain tumors in the central nervous system diseases are difficulty all the way, the effect of clinical treatment is not very well. At present the medical workers refine original treatments constantly and explore new treatments actively. Biological targeted therapy as a new treatment method is expected to become effective method to malignant tumors. the premise to carry out the targeting therapy research is having effective biological targets. Human epidermal growth factor receptor type 2 (Her-2) is a cancer gene receptor, in a variety of malignant tumor, to express. CD44 is a sort of cell surface adhesion molecules. Now it are, in variety of tumor, the research and clinical diagnostic markers.Objective To detect and analyze human epidermal growth factor receptor(HER-2) and CD44 in different malignant brain tumors, and to evaluate their prognostic significance.Methods Using immunohistochemistry and indirect immunofluorescence to detect the expression of Her-2 and CD44 in malignant brain tumors and analyzing the experimental data. The specimens contain 10 normal brain tumors and 120 malignant brain tumors that are glioblastoma, gliosarcoma, medulloblastoma and anaplastic oligodendroglioma.Results The positive rate of Her-2 in the glioblastoma, gliosarcoma, medulloblastoma, and anaplastic oligodendroglioma respectively were 80.0%, 73.3%, 66.7% and 33.3%. The positive rate of CD44 in these four tumors respectively were 86.7%, 80.0%, 90.0%, 73.3%. The expression of Her-2 in normal brain tissue was none, but CD44 was 20.0% . The expression in malignant brain tumor had no correlation between Her-2 and CD44 (P>0.05), but they both correlate with tumor prognosis. Conclusions The expressions of Her-2 were not same in malignant brain tumors, the expressions of CD44 were generally high. No correlation between Her-2 and CD44, but they have synergistic effect with the prognosis of tumors. Her-2 and CD44 are expected to be combined target site for target therapies of brain tumor. They will play an important role in the brain tumor diagnosis and treatment.
引文
[1] Freudenberg JA, Wang Q, Katsumata M, et al. The role of HER2 in early breast cancer metastasis and the origins of resistance to HER2-targeted therapies[J]. Exp Mol Pathol, 2009, 87(1): 1-11..
[2] Orian-Rousseau V. CD44, a therapeutic target for metastasising tumours[J]. European Journal of Cancer,2010,46(7):1271-1277.
[3]杨树源,只达石.神经外科学[M].北京:人民卫生出版社,2008.467.
[4] Freudenberg J A, Wang Q, Katsumata M, Drebin J, Nagatomo I, Greene M I. The role of HER2 in early breast cancer metastasis and the origins of resistance to HER2-targeted therapies[J]. Experimental and Molecular Pathology,2009,87(1):1-11.
[5] Wickremesekera A, Hovens C M, Kaye A H. Expression of ErbB-1 and 2 in vestibular schwannomas[J]. Journal of Clinical Neuroscience,2007,14 (12):1199-1206.
[6] Fuller S J, Sivarajah K, Sugden P H. ErbB receptors, their ligands, and the consequences of their activation and inhibition in the myocardium[J]. Journal of Molecular and Cellular Cardiology,2008,44(5):831-854.
[7] Cai Z, Zhang H, Liu J, Berezov A, Murali R, Wang Q, Greene M I. Targeting erbB receptors[J]. Seminars in Cell & Developmental Biology, 2010,21(9):961-966.
[8] Vazquez-Martin A, Colomer R, Menendez J A. Protein array technology to detect HER2 (erbB-2)-induced `cytokine signature' in breast cancer[J]. European Journal of Cancer,2007,43(7):1117-1124.
[9] Hynes N E, Macdonald G. ErbB receptors and signaling pathways in cancer[J]. Current Opinion in Cell Biology,2009,21(2):177-184.
[10] Gilbertson R J, Bentley L, Hernan R, Junttila T T, Frank A J, Haapasalo H, Connelly M, Wetmore C, Curran T, Elenius K, Ellison D W. ERBBreceptor signaling promotes ependymoma cell proliferation and represents a potential novel therapeutic target for this disease.[J]. Clin Cancer Res,2002,8(10):3054-3064.
[11] Hernan R, Fasheh R, Calabrese C, Frank A J, Maclean K H, Allard D, Barraclough R, Gilbertson R J. ERBB2 up-regulates S100A4 and several other prometastatic genes in medulloblastoma.[J]. Cancer Res,2003,63 (1):140-148.
[12] Park I H, Ro J, Lee K S, Nam B H, Kwon Y, Shin K H. Trastuzumab treatment beyond brain progression in HER2-positive metastatic breast cancer.[J]. Ann Oncol,2009,20(1):56-62.
[13] Bravo M J. Treatment of brain metastases in patients with HER2+ breast cancer.[J]. Adv Ther,2009,26 Suppl 1:S18-S26.
[14] Ahmed N, Ratnayake M, Savoldo B, Perlaky L, Dotti G, Wels W S, Bhattacharjee M B, Gilbertson R J, Shine H D, Weiss H L, Rooney C M, Heslop H E, Gottschalk S. Regression of experimental medulloblastoma following transfer of HER2-specific T cells.[J]. Cancer Res,2007,67 (12):5957-5964.
[15] Ahmed N, Salsman V S, Kew Y, Shaffer D, Powell S, Zhang Y J, Grossman R G, Heslop H E, Gottschalk S. HER2-specific T cells target primary glioblastoma stem cells and induce regression of autologous experimental tumors.[J]. Clin Cancer Res,2010,16(2):474-485.
[16] Polkinghorn W R, Tarbell N J. Medulloblastoma: tumorigenesis, current clinical paradigm, and efforts to improve risk stratification.[J]. Nat Clin Pract Oncol,2007,4(5):295-304.
[17] Emanuel S L, Hughes T V, Adams M, Rugg C A, Fuentes-Pesquera A, Connolly P J, Pandey N, Moreno-Mazza S, Butler J, Borowski V, Middleton S A, Gruninger R H, Story J R, Napier C, Hollister B, Greenberger L M. Cellular and in vivo activity of JNJ-28871063, a nonquinazoline pan-ErbB kinase inhibitor that crosses the blood-brainbarrier and displays efficacy against intracranial tumors.[J]. Mol Pharmacol,2008,73(2):338-348.
[18] Ponta H, Sherman L, Herrlich P A. CD44: from adhesion molecules to signalling regulators[J]. Nat Rev Mol Cell Biol,2003,4(1):33-45.
[19] Lokeshwar V B, Bourguignon L Y. Post-translational protein modification and expression of ankyrin-binding site(s) in GP85 (Pgp-1/CD44) and its biosynthetic precursors during T-lymphoma membrane biosynthesis[J]. J Biol Chem,1991,266(27):17983-17989.
[20] Orian-Rousseau V. CD44, a therapeutic target for metastasising tumours [J]. Eur J Cancer,2010,46(7):1271-1277.
[21] Gunthert U, Hofmann M, Rudy W, Reber S, Zoller M, Haussmann I, Matzku S, Wenzel A, Ponta H, Herrlich P. A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells[J]. Cell,1991, 65(1):13-24.
[22] Seiter S, Arch R, Reber S, Komitowski D, Hofmann M, Ponta H, Herrlich P, Matzku S, Zoller M. Prevention of tumor metastasis formation by anti-variant CD44[J]. J Exp Med,1993,177(2):443-455.
[23] Stauder R, Eisterer W, Thaler J, Gunthert U. CD44 variant isoforms in non-Hodgkin's lymphoma: a new independent prognostic factor[J]. Blood,1995,85(10):2885-2899.
[24] Wielenga V J, van der Neut R, Offerhaus G J, Pals S T. CD44 glycoproteins in colorectal cancer: expression, function, and prognostic value[J]. Adv Cancer Res,2000,77:169-187.
[25] Kainz C, Kohlberger P, Tempfer C, Sliutz G, Gitsch G, Reinthaller A, Breitenecker G. Prognostic value of CD44 splice variants in human stage III cervical cancer[J]. Eur J Cancer,1995,31A(10):1706-1709.
[26] Hsieh H F, Yu J C, Ho L I, Chiu S C, Harn H J. Molecular studies into the role of CD44 variants in metastasis in gastric cancer[J]. Mol Pathol,1999, 52(1):25-28.
[27] Gotte M, Yip G W. Heparanase, hyaluronan, and CD44 in cancers: a breast carcinoma perspective[J]. Cancer Res,2006,66(21):10233-10237.
[28] Heider K H, Kuthan H, Stehle G, Munzert G. CD44v6: a target for antibody-based cancer therapy[J]. Cancer Immunol Immunother,2004, 53(7):567-579.
[29] Colnot D R, Wilhelm A J, Cloos J, Roos J C, de Bree R, Quak J J, Snow G B, van Dongen G A. Evaluation of limited blood sampling in a preceding 99mTc-labeled diagnostic study to predict the pharmacokinetics and myelotoxicity of 186Re-cMAb U36 radioimmunotherapy[J]. J Nucl Med,2001,42(9):1364-1367.
[30] de Bree R, Roos J C, Quak J J, den Hollander W, Snow G B, van Dongen G A. Radioimmunoscintigraphy and biodistribution of technetium-99m- labeled monoclonal antibody U36 in patients with head and neck cancer[J]. Clin Cancer Res,1995,1(6):591-598.
[31] Stroomer J W, Roos J C, Sproll M, Quak J J, Heider K H, Wilhelm B J, Castelijns J A, Meyer R, Kwakkelstein M O, Snow G B, Adolf G R, van Dongen G A. Safety and biodistribution of 99mTechnetium-labeled anti-CD44v6 monoclonal antibody BIWA 1 in head and neck cancer patients[J]. Clin Cancer Res,2000,6(8):3046-3055.
[32] Borjesson P K, Postema E J, Roos J C, Colnot D R, Marres H A, van Schie M H, Stehle G, de Bree R, Snow G B, Oyen W J, van Dongen G A. Phase I therapy study with (186)Re-labeled humanized monoclonal antibody BIWA 4 (bivatuzumab) in patients with head and neck squamous cell carcinoma[J]. Clin Cancer Res,2003,9(10 Pt 2):3961S-3972S.
[33] Colnot D R, Roos J C, de Bree R, Wilhelm A J, Kummer J A, Hanft G, Heider K H, Stehle G, Snow G B, van Dongen G A. Safety, biodistribution, pharmacokinetics, and immunogenicity of 99mTc-labeled humanized monoclonal antibody BIWA 4 (bivatuzumab) in patients with squamous cell carcinoma of the head and neck[J]. Cancer ImmunolImmunother,2003,52(9):576-582.
[34] Koppe M, Schaijk F, Roos J, Leeuwen P, Heider K H, Kuthan H, Bleichrodt R. Safety, pharmacokinetics, immunogenicity, and biodistribution of (186)Re-labeled humanized monoclonal antibody BIWA 4 (Bivatuzumab) in patients with early-stage breast cancer[J]. Cancer Biother Radiopharm,2004,19(6):720-729.
[35] Yu Q, Stamenkovic I. Localization of matrix metalloproteinase 9 to the cell surface provides a mechanism for CD44-mediated tumor invasion[J]. Genes Dev,1999,13(1):35-48.
[36] Sleeman J, Rudy W, Hofmann M, Moll J, Herrlich P, Ponta H. Regulated clustering of variant CD44 proteins increases their hyaluronate binding capacity[J]. J Cell Biol,1996,135(4):1139-1150.
[37] Kim H R, Wheeler M A, Wilson C M, Iida J, Eng D, Simpson M A, Mccarthy J B, Bullard K M. Hyaluronan facilitates invasion of colon carcinoma cells in vitro via interaction with CD44[J]. Cancer Res,2004,64 (13):4569-4576.
[38] Naor D, Sionov R V, Ish-Shalom D. CD44: structure, function, and association with the malignant process[J]. Adv Cancer Res,1997,71: 241-319.
[39] Weber G F. The metastasis gene osteopontin: a candidate target for cancer therapy[J]. Biochim Biophys Acta,2001,1552(2):61-85.
[40] Katagiri Y U, Sleeman J, Fujii H, Herrlich P, Hotta H, Tanaka K, Chikuma S, Yagita H, Okumura K, Murakami M, Saiki I, Chambers A F, Uede T. CD44 variants but not CD44s cooperate with beta1-containing integrins to permit cells to bind to osteopontin independently of arginine-glycine-aspartic acid, thereby stimulating cell motility and chemotaxis[J]. Cancer Res,1999,59(1):219-226.
[41] Takafuji V, Forgues M, Unsworth E, Goldsmith P, Wang X W. An osteopontin fragment is essential for tumor cell invasion in hepatocellularcarcinoma[J]. Oncogene,2007,26(44):6361-6371.
[42] Jin L, Hope K J, Zhai Q, Smadja-Joffe F, Dick J E. Targeting of CD44 eradicates human acute myeloid leukemic stem cells[J]. Nat Med,2006,12 (10):1167-1174.
[43] Tavor S, Petit I, Porozov S, Avigdor A, Dar A, Leider-Trejo L, Shemtov N, Deutsch V, Naparstek E, Nagler A, Lapidot T. CXCR4 regulates migration and development of human acute myelogenous leukemia stem cells in transplanted NOD/SCID mice[J]. Cancer Res,2004,64(8):2817- 2824.
[44] Avigdor A, Goichberg P, Shivtiel S, Dar A, Peled A, Samira S, Kollet O, Hershkoviz R, Alon R, Hardan I, Ben-Hur H, Naor D, Nagler A, Lapidot T. CD44 and hyaluronic acid cooperate with SDF-1 in the trafficking of human CD34+ stem/progenitor cells to bone marrow[J]. Blood,2004,103 (8):2981-2989.
[45] Golshani R, Lopez L, Estrella V, Kramer M, Iida N, Lokeshwar V B. Hyaluronic acid synthase-1 expression regulates bladder cancer growth, invasion, and angiogenesis through CD44[J]. Cancer Res,2008,68(2): 483-491.
[46] Orian-Rousseau V, Chen L, Sleeman J P, Herrlich P, Ponta H. CD44 is required for two consecutive steps in HGF/c-Met signaling[J]. Genes Dev,2002,16(23):3074-3086.
[47] Orian-Rousseau V, Morrison H, Matzke A, Kastilan T, Pace G, Herrlich P, Ponta H. Hepatocyte growth factor-induced Ras activation requires ERM proteins linked to both CD44v6 and F-actin[J]. Mol Biol Cell,2007, 18(1):76-83.
[48] Matzke A, Herrlich P, Ponta H, Orian-Rousseau V. A five-amino-acid peptide blocks Met- and Ron-dependent cell migration[J]. Cancer Res,2005,65(14):6105-6110.
[49] Koka V, Potti A, Forseen S E, Pervez H, Fraiman G N, Koch M, Levitt R.Role of Her-2/neu overexpression and clinical determinants of early mortality in glioblastoma multiforme.[J]. Am J Clin Oncol,2003,26 (4):332-335.
[50] Andersson U, Guo D, Malmer B, Bergenheim A T, Brannstrom T, Hedman H, Henriksson R. Epidermal growth factor receptor family (EGFR, ErbB2-4) in gliomas and meningiomas.[J]. Acta Neuropathol, 2004,108(2):135-142.
[51] Liu G, Ying H, Zeng G, Wheeler C J, Black K L, Yu J S. HER-2, gp100, and MAGE-1 are expressed in human glioblastoma and recognized by cytotoxic T cells.[J]. Cancer Res,2004,64(14):4980-4986.
[52] Meurer R T, Martins D T, Hilbig A, Ribeiro M C, Roehe A V, Barbosa-Coutinho L M, Fernandes M C. Immunohistochemical expression of markers Ki-67, neun, synaptophysin, p53 and HER2 in medulloblastoma and its correlation with clinicopathological parameters. [J]. Arq Neuropsiquiatr,2008,66(2B):385-390.
[53] Ylagan L R, Quinn B. CD44 expression in astrocytic tumors.[J]. Mod Pathol,1997,10(12):1239-1246.
[54] Mineo J F, Bordron A, Baroncini M, Maurage C A, Ramirez C, Siminski R M, Berthou C, Dam H P. Low HER2-expressing glioblastomas are more often secondary to anaplastic transformation of low-grade glioma.[J]. J Neurooncol,2007,85(3):281-287.
[55] Oz B, Karayel F A, Gazio N L, Ozlen F, Balci K. The distribution of extracellular matrix proteins and CD44S expression in human astrocytomas.[J]. Pathol Oncol Res,2000,6(2):118-124.
[2] Orian-Rousseau V. CD44, a therapeutic target for metastasising tumours[J]. European Journal of Cancer,2010,46(7):1271-1277.
[3]杨树源,只达石.神经外科学[M].北京:人民卫生出版社,2008.467.
[4] Freudenberg J A, Wang Q, Katsumata M, Drebin J, Nagatomo I, Greene M I. The role of HER2 in early breast cancer metastasis and the origins of resistance to HER2-targeted therapies[J]. Experimental and Molecular Pathology,2009,87(1):1-11.
[5] Wickremesekera A, Hovens C M, Kaye A H. Expression of ErbB-1 and 2 in vestibular schwannomas[J]. Journal of Clinical Neuroscience,2007,14 (12):1199-1206.
[6] Fuller S J, Sivarajah K, Sugden P H. ErbB receptors, their ligands, and the consequences of their activation and inhibition in the myocardium[J]. Journal of Molecular and Cellular Cardiology,2008,44(5):831-854.
[7] Cai Z, Zhang H, Liu J, Berezov A, Murali R, Wang Q, Greene M I. Targeting erbB receptors[J]. Seminars in Cell & Developmental Biology, 2010,21(9):961-966.
[8] Vazquez-Martin A, Colomer R, Menendez J A. Protein array technology to detect HER2 (erbB-2)-induced `cytokine signature' in breast cancer[J]. European Journal of Cancer,2007,43(7):1117-1124.
[9] Hynes N E, Macdonald G. ErbB receptors and signaling pathways in cancer[J]. Current Opinion in Cell Biology,2009,21(2):177-184.
[10] Gilbertson R J, Bentley L, Hernan R, Junttila T T, Frank A J, Haapasalo H, Connelly M, Wetmore C, Curran T, Elenius K, Ellison D W. ERBBreceptor signaling promotes ependymoma cell proliferation and represents a potential novel therapeutic target for this disease.[J]. Clin Cancer Res,2002,8(10):3054-3064.
[11] Hernan R, Fasheh R, Calabrese C, Frank A J, Maclean K H, Allard D, Barraclough R, Gilbertson R J. ERBB2 up-regulates S100A4 and several other prometastatic genes in medulloblastoma.[J]. Cancer Res,2003,63 (1):140-148.
[12] Park I H, Ro J, Lee K S, Nam B H, Kwon Y, Shin K H. Trastuzumab treatment beyond brain progression in HER2-positive metastatic breast cancer.[J]. Ann Oncol,2009,20(1):56-62.
[13] Bravo M J. Treatment of brain metastases in patients with HER2+ breast cancer.[J]. Adv Ther,2009,26 Suppl 1:S18-S26.
[14] Ahmed N, Ratnayake M, Savoldo B, Perlaky L, Dotti G, Wels W S, Bhattacharjee M B, Gilbertson R J, Shine H D, Weiss H L, Rooney C M, Heslop H E, Gottschalk S. Regression of experimental medulloblastoma following transfer of HER2-specific T cells.[J]. Cancer Res,2007,67 (12):5957-5964.
[15] Ahmed N, Salsman V S, Kew Y, Shaffer D, Powell S, Zhang Y J, Grossman R G, Heslop H E, Gottschalk S. HER2-specific T cells target primary glioblastoma stem cells and induce regression of autologous experimental tumors.[J]. Clin Cancer Res,2010,16(2):474-485.
[16] Polkinghorn W R, Tarbell N J. Medulloblastoma: tumorigenesis, current clinical paradigm, and efforts to improve risk stratification.[J]. Nat Clin Pract Oncol,2007,4(5):295-304.
[17] Emanuel S L, Hughes T V, Adams M, Rugg C A, Fuentes-Pesquera A, Connolly P J, Pandey N, Moreno-Mazza S, Butler J, Borowski V, Middleton S A, Gruninger R H, Story J R, Napier C, Hollister B, Greenberger L M. Cellular and in vivo activity of JNJ-28871063, a nonquinazoline pan-ErbB kinase inhibitor that crosses the blood-brainbarrier and displays efficacy against intracranial tumors.[J]. Mol Pharmacol,2008,73(2):338-348.
[18] Ponta H, Sherman L, Herrlich P A. CD44: from adhesion molecules to signalling regulators[J]. Nat Rev Mol Cell Biol,2003,4(1):33-45.
[19] Lokeshwar V B, Bourguignon L Y. Post-translational protein modification and expression of ankyrin-binding site(s) in GP85 (Pgp-1/CD44) and its biosynthetic precursors during T-lymphoma membrane biosynthesis[J]. J Biol Chem,1991,266(27):17983-17989.
[20] Orian-Rousseau V. CD44, a therapeutic target for metastasising tumours [J]. Eur J Cancer,2010,46(7):1271-1277.
[21] Gunthert U, Hofmann M, Rudy W, Reber S, Zoller M, Haussmann I, Matzku S, Wenzel A, Ponta H, Herrlich P. A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells[J]. Cell,1991, 65(1):13-24.
[22] Seiter S, Arch R, Reber S, Komitowski D, Hofmann M, Ponta H, Herrlich P, Matzku S, Zoller M. Prevention of tumor metastasis formation by anti-variant CD44[J]. J Exp Med,1993,177(2):443-455.
[23] Stauder R, Eisterer W, Thaler J, Gunthert U. CD44 variant isoforms in non-Hodgkin's lymphoma: a new independent prognostic factor[J]. Blood,1995,85(10):2885-2899.
[24] Wielenga V J, van der Neut R, Offerhaus G J, Pals S T. CD44 glycoproteins in colorectal cancer: expression, function, and prognostic value[J]. Adv Cancer Res,2000,77:169-187.
[25] Kainz C, Kohlberger P, Tempfer C, Sliutz G, Gitsch G, Reinthaller A, Breitenecker G. Prognostic value of CD44 splice variants in human stage III cervical cancer[J]. Eur J Cancer,1995,31A(10):1706-1709.
[26] Hsieh H F, Yu J C, Ho L I, Chiu S C, Harn H J. Molecular studies into the role of CD44 variants in metastasis in gastric cancer[J]. Mol Pathol,1999, 52(1):25-28.
[27] Gotte M, Yip G W. Heparanase, hyaluronan, and CD44 in cancers: a breast carcinoma perspective[J]. Cancer Res,2006,66(21):10233-10237.
[28] Heider K H, Kuthan H, Stehle G, Munzert G. CD44v6: a target for antibody-based cancer therapy[J]. Cancer Immunol Immunother,2004, 53(7):567-579.
[29] Colnot D R, Wilhelm A J, Cloos J, Roos J C, de Bree R, Quak J J, Snow G B, van Dongen G A. Evaluation of limited blood sampling in a preceding 99mTc-labeled diagnostic study to predict the pharmacokinetics and myelotoxicity of 186Re-cMAb U36 radioimmunotherapy[J]. J Nucl Med,2001,42(9):1364-1367.
[30] de Bree R, Roos J C, Quak J J, den Hollander W, Snow G B, van Dongen G A. Radioimmunoscintigraphy and biodistribution of technetium-99m- labeled monoclonal antibody U36 in patients with head and neck cancer[J]. Clin Cancer Res,1995,1(6):591-598.
[31] Stroomer J W, Roos J C, Sproll M, Quak J J, Heider K H, Wilhelm B J, Castelijns J A, Meyer R, Kwakkelstein M O, Snow G B, Adolf G R, van Dongen G A. Safety and biodistribution of 99mTechnetium-labeled anti-CD44v6 monoclonal antibody BIWA 1 in head and neck cancer patients[J]. Clin Cancer Res,2000,6(8):3046-3055.
[32] Borjesson P K, Postema E J, Roos J C, Colnot D R, Marres H A, van Schie M H, Stehle G, de Bree R, Snow G B, Oyen W J, van Dongen G A. Phase I therapy study with (186)Re-labeled humanized monoclonal antibody BIWA 4 (bivatuzumab) in patients with head and neck squamous cell carcinoma[J]. Clin Cancer Res,2003,9(10 Pt 2):3961S-3972S.
[33] Colnot D R, Roos J C, de Bree R, Wilhelm A J, Kummer J A, Hanft G, Heider K H, Stehle G, Snow G B, van Dongen G A. Safety, biodistribution, pharmacokinetics, and immunogenicity of 99mTc-labeled humanized monoclonal antibody BIWA 4 (bivatuzumab) in patients with squamous cell carcinoma of the head and neck[J]. Cancer ImmunolImmunother,2003,52(9):576-582.
[34] Koppe M, Schaijk F, Roos J, Leeuwen P, Heider K H, Kuthan H, Bleichrodt R. Safety, pharmacokinetics, immunogenicity, and biodistribution of (186)Re-labeled humanized monoclonal antibody BIWA 4 (Bivatuzumab) in patients with early-stage breast cancer[J]. Cancer Biother Radiopharm,2004,19(6):720-729.
[35] Yu Q, Stamenkovic I. Localization of matrix metalloproteinase 9 to the cell surface provides a mechanism for CD44-mediated tumor invasion[J]. Genes Dev,1999,13(1):35-48.
[36] Sleeman J, Rudy W, Hofmann M, Moll J, Herrlich P, Ponta H. Regulated clustering of variant CD44 proteins increases their hyaluronate binding capacity[J]. J Cell Biol,1996,135(4):1139-1150.
[37] Kim H R, Wheeler M A, Wilson C M, Iida J, Eng D, Simpson M A, Mccarthy J B, Bullard K M. Hyaluronan facilitates invasion of colon carcinoma cells in vitro via interaction with CD44[J]. Cancer Res,2004,64 (13):4569-4576.
[38] Naor D, Sionov R V, Ish-Shalom D. CD44: structure, function, and association with the malignant process[J]. Adv Cancer Res,1997,71: 241-319.
[39] Weber G F. The metastasis gene osteopontin: a candidate target for cancer therapy[J]. Biochim Biophys Acta,2001,1552(2):61-85.
[40] Katagiri Y U, Sleeman J, Fujii H, Herrlich P, Hotta H, Tanaka K, Chikuma S, Yagita H, Okumura K, Murakami M, Saiki I, Chambers A F, Uede T. CD44 variants but not CD44s cooperate with beta1-containing integrins to permit cells to bind to osteopontin independently of arginine-glycine-aspartic acid, thereby stimulating cell motility and chemotaxis[J]. Cancer Res,1999,59(1):219-226.
[41] Takafuji V, Forgues M, Unsworth E, Goldsmith P, Wang X W. An osteopontin fragment is essential for tumor cell invasion in hepatocellularcarcinoma[J]. Oncogene,2007,26(44):6361-6371.
[42] Jin L, Hope K J, Zhai Q, Smadja-Joffe F, Dick J E. Targeting of CD44 eradicates human acute myeloid leukemic stem cells[J]. Nat Med,2006,12 (10):1167-1174.
[43] Tavor S, Petit I, Porozov S, Avigdor A, Dar A, Leider-Trejo L, Shemtov N, Deutsch V, Naparstek E, Nagler A, Lapidot T. CXCR4 regulates migration and development of human acute myelogenous leukemia stem cells in transplanted NOD/SCID mice[J]. Cancer Res,2004,64(8):2817- 2824.
[44] Avigdor A, Goichberg P, Shivtiel S, Dar A, Peled A, Samira S, Kollet O, Hershkoviz R, Alon R, Hardan I, Ben-Hur H, Naor D, Nagler A, Lapidot T. CD44 and hyaluronic acid cooperate with SDF-1 in the trafficking of human CD34+ stem/progenitor cells to bone marrow[J]. Blood,2004,103 (8):2981-2989.
[45] Golshani R, Lopez L, Estrella V, Kramer M, Iida N, Lokeshwar V B. Hyaluronic acid synthase-1 expression regulates bladder cancer growth, invasion, and angiogenesis through CD44[J]. Cancer Res,2008,68(2): 483-491.
[46] Orian-Rousseau V, Chen L, Sleeman J P, Herrlich P, Ponta H. CD44 is required for two consecutive steps in HGF/c-Met signaling[J]. Genes Dev,2002,16(23):3074-3086.
[47] Orian-Rousseau V, Morrison H, Matzke A, Kastilan T, Pace G, Herrlich P, Ponta H. Hepatocyte growth factor-induced Ras activation requires ERM proteins linked to both CD44v6 and F-actin[J]. Mol Biol Cell,2007, 18(1):76-83.
[48] Matzke A, Herrlich P, Ponta H, Orian-Rousseau V. A five-amino-acid peptide blocks Met- and Ron-dependent cell migration[J]. Cancer Res,2005,65(14):6105-6110.
[49] Koka V, Potti A, Forseen S E, Pervez H, Fraiman G N, Koch M, Levitt R.Role of Her-2/neu overexpression and clinical determinants of early mortality in glioblastoma multiforme.[J]. Am J Clin Oncol,2003,26 (4):332-335.
[50] Andersson U, Guo D, Malmer B, Bergenheim A T, Brannstrom T, Hedman H, Henriksson R. Epidermal growth factor receptor family (EGFR, ErbB2-4) in gliomas and meningiomas.[J]. Acta Neuropathol, 2004,108(2):135-142.
[51] Liu G, Ying H, Zeng G, Wheeler C J, Black K L, Yu J S. HER-2, gp100, and MAGE-1 are expressed in human glioblastoma and recognized by cytotoxic T cells.[J]. Cancer Res,2004,64(14):4980-4986.
[52] Meurer R T, Martins D T, Hilbig A, Ribeiro M C, Roehe A V, Barbosa-Coutinho L M, Fernandes M C. Immunohistochemical expression of markers Ki-67, neun, synaptophysin, p53 and HER2 in medulloblastoma and its correlation with clinicopathological parameters. [J]. Arq Neuropsiquiatr,2008,66(2B):385-390.
[53] Ylagan L R, Quinn B. CD44 expression in astrocytic tumors.[J]. Mod Pathol,1997,10(12):1239-1246.
[54] Mineo J F, Bordron A, Baroncini M, Maurage C A, Ramirez C, Siminski R M, Berthou C, Dam H P. Low HER2-expressing glioblastomas are more often secondary to anaplastic transformation of low-grade glioma.[J]. J Neurooncol,2007,85(3):281-287.
[55] Oz B, Karayel F A, Gazio N L, Ozlen F, Balci K. The distribution of extracellular matrix proteins and CD44S expression in human astrocytomas.[J]. Pathol Oncol Res,2000,6(2):118-124.