上皮细胞黏附分子在大肠癌中的表达及临床意义的研究
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摘要
背景:大肠癌(colorectal carcinoma,CRC)是消化道常见的恶性肿瘤,国内其发病率在逐年上升。手术切除肿瘤是治疗大肠癌的主要治疗方法,也是唯一可以根治本病的方法,但手术后5年生存率仅有50-60%,原因是对大肠癌的发生、发展仍缺乏深入的认识,早期发现、早期诊断率低,根治性手术后出现复发和转移。除手术治疗外,目前还有化疗、放疗等方法,但疗效有限,副作用大。肿瘤免疫治疗理论上具有靶向杀灭肿瘤细胞,副作用小的特点,是近年来肿瘤治疗的研究热点。因此,寻找一种新的大肠癌肿瘤标志物,研究其在大肠癌中的表达特点和临床意义,有利于深入了解大肠癌的演变过程,提高对本病的认识、诊断和治疗水平,具有重要的意义。
上皮细胞粘附分子(epithelial cell adhesion molecule, Ep-CAM)是一种上皮细胞单亚基跨膜糖蛋白;在正常上皮组织呈阴性或弱表达,在癌组织中常过度表达或重新表达;介导Ca2+非依赖性噬同种黏附;可能与癌细胞的增殖、侵袭、去分化及转移相关;是多种上皮恶性肿瘤主动和被动免疫治疗研究的靶分子。目前,国内外未见大肠癌组织与癌旁组织中EP-CAM定量关系以及大肠癌组织EP-CAM表达水平与患者年龄、性别及肿瘤生物学行为关系的文献,此外,其作为一项新的大肠癌肿瘤标志物及免疫治疗靶分子的可行性国内外鲜见报道。目的:(1)研究Ep-CAM在大肠癌组织中的表达水平;(2)了解Ep-CAM表达与大肠癌发生、发展的关系;(3)了解大肠癌组织Ep-CAM表达水平与患者年龄、性别及肿瘤生物学行为的关系;(4)探讨Ep-CAM能否作为大肠癌的肿瘤标志物;(5)比较Ep-CAM与C12作为大肠癌诊断方法的价值;(6)探讨Ep-CAM能否作为大肠癌免疫治疗的靶分子。
方法与步骤:(1)分别取53例原发性大肠癌组织和癌旁黏膜组织,制备组织芯片3张并进行免疫组化染色。(2)用形态学图象分析系统测定大肠癌组织和癌旁黏膜组织上皮细胞粘附分子染色积分光密度(IOD of Ep-CAM positive area,以下简称为Ep-CAMIOD)。(3)术前采集大肠癌患者非抗凝血清1ml,用血清蛋白芯片多种肿瘤标志物检测系统(C12)测定12种肿瘤标志物的血清含量。(4)分析大肠癌组织与癌旁组织Ep-CAMIOD之间的关系;大肠癌组织Ep-CAMIOD与患者年龄、性别及肿瘤生物学行为之间的关系。(5)比较C12阳性和阴性组大肠癌组织Ep-CAMIOD之间的差异。
结果:(1)大肠癌组织Ep-CAMIOD显著高于癌旁组织Ep-CAMIOD(P<0.01)。(2)大肠癌组织Ep-CAMIOD与患者年龄、性别及肿瘤生物学行为无明显相关性(P>0.05)。(3)50.9﹪的大肠癌患者C12阳性。(4)C12阳性与阴性组大肠癌组织Ep-CAMIOD比较无显著差异(P>0.05)。
结论:(1)Ep-CAM参与了大肠癌发生、发展的全过程。(2)大肠癌组织中Ep-CAM表达水平与患者年龄、性别及肿瘤生物学行为无明显相关,是大肠癌发生、发展的一种独立性影响因素。(3)Ep-CAM可能作为大肠癌的肿瘤标志物,可以检出C12阴性病例,如与C12联合检查,将提高对大肠癌的检出率。(4)Ep-CAM可能作为大肠癌主动或被动免疫治疗的靶分子。
Background: Colorectal carcinoma (CRC) is a kind of malignant tumor that frequently occurred in gastrointestinal system and its morbidity has been rising in recent years in china. The main treatment to this disease is operation which is the only method for radical cure and only about 50-60% suffers can survival 5 years. At present, it is unknown about the genesis and development of CRC and a few patients was found in the disease early phrase, so that the relapse and metastasis would frequently occurred after operation. Apart from surgical treatment, there are also chemotherapy, radiotherapy and so on for CRC. However, these treatments, generally speaking, have gloomy curative effect and considerable adverse reactions. Immunotherapy for malignant tumors, which, in theory, targets to malignant cells and has low secondary effects, has been exploring for many years. It is very important to find a CRC tumor marker and explore its expresion and clinical value, so that we can make profound apprehension about CRC and elevate the diagnosis ability and therapeutic efficacy for CRC.
Epithelial cell adhesion molecule(Ep-CAM)is a transmembrane glycoprotein including one peptide, which was negatively or weakly expressed on norm epithelial cells and frequently overexpressed or re-expressed in epithelial carcinomas. It was reported that the molecule mediates Ca2+-independent homophilic adhesions and may correlate with cellular proliferation, invasion, de-differentiation as well as migration. Now, many kinds of active passive and immunotherapies for several kinds of malignant tumor, which targeted to Ep-CAM ,have been explored.
At present, It’s still unknown about about the Ep-CAM quantitive relations between CRC tissue and adjacent mucosa as well as the relations between Ep-CAM level in CRC tissue and patients age, gender as well as tumor biological behaviors of CRC and there are a few studies the possibility to use Ep-CAM as a CRC tumor maker and a immunotherapy target all over the world.
Objective: (1)Study EP-CAM expression in malignant tissue of large intestina. (2) Investigate the relations between Ep-CAM expression and CRC genesis and development. (3)Explore the relations between EP-CAM content in colorectal tumor tissue and patients age, gender as well as tumor biological behaviors. (4)Evaluate whether EP-CAM could be used as a tumor marker for CRC. (5) Compare the diognosis value of EP-CAM and C12 for CRC. (6)Evaluate whether EP-CAM could be used as a immunotherapy target for CRC.
Methods: (1) 53 pieces of colorectal tumor tissues and the same amount of adjacent mucosa were gathered, then, 3 pieces of tissue micro-array sections were made and immunostained. (2) The integral optical density of Ep-CAM staining area (short for Ep-CAMIOD) was inspected by image analysis morphological system. (3)Before operation, 1ml non-anticoagulation serum was collected from every subject, then12 kinds of tumor markers in serum were detected by 12 tumor markers protein micro-array system. (4)The relations of Ep-CAMIOD between in colorectal tumor tissue and in adjacent mucosa groups were investigated. Malignant tissue group was divided into different sub-groups by patients age, gender and tumor biological behaviors, then, we analyze the relationships of Ep-CAMIOD among sub-groups. (5)We also researched the differences of Ep-CAMIOD between C12 positive and negative groups.
Results: (1)The Ep-CAMIOD was significantly higher in CRC group than that in control group(P<0.01). (2)Ep-CAMIOD was not related to patients age, gender and tumor biological behaviors(P>0.05. (3)we found that C12 was positive in 50.9﹪ CRC patients. (4)There was no significant difference of Ep-CAMIOD between C12 positive and negtive groups(P>0.05).
Conclusions: (1)Ep-CAM was involved in CRC genesis and development. (2)Ep-CAM expression in cancer tissues had no significant relationships with patients age, gender and tumor biological behaviors and Ep-CAM was a independent inflence factor for CRC genesis and development. (3)Ep-CAM could be used as a tumor marker for CRC, which could found C12 negtive patients, so that, if it was detected together with C12, CRC detection rate may be improved. (4)Ep-CAM may be used as a active or passive immunotherapy target CRC.
上皮细胞粘附分子(epithelial cell adhesion molecule, Ep-CAM)是一种上皮细胞单亚基跨膜糖蛋白;在正常上皮组织呈阴性或弱表达,在癌组织中常过度表达或重新表达;介导Ca2+非依赖性噬同种黏附;可能与癌细胞的增殖、侵袭、去分化及转移相关;是多种上皮恶性肿瘤主动和被动免疫治疗研究的靶分子。目前,国内外未见大肠癌组织与癌旁组织中EP-CAM定量关系以及大肠癌组织EP-CAM表达水平与患者年龄、性别及肿瘤生物学行为关系的文献,此外,其作为一项新的大肠癌肿瘤标志物及免疫治疗靶分子的可行性国内外鲜见报道。目的:(1)研究Ep-CAM在大肠癌组织中的表达水平;(2)了解Ep-CAM表达与大肠癌发生、发展的关系;(3)了解大肠癌组织Ep-CAM表达水平与患者年龄、性别及肿瘤生物学行为的关系;(4)探讨Ep-CAM能否作为大肠癌的肿瘤标志物;(5)比较Ep-CAM与C12作为大肠癌诊断方法的价值;(6)探讨Ep-CAM能否作为大肠癌免疫治疗的靶分子。
方法与步骤:(1)分别取53例原发性大肠癌组织和癌旁黏膜组织,制备组织芯片3张并进行免疫组化染色。(2)用形态学图象分析系统测定大肠癌组织和癌旁黏膜组织上皮细胞粘附分子染色积分光密度(IOD of Ep-CAM positive area,以下简称为Ep-CAMIOD)。(3)术前采集大肠癌患者非抗凝血清1ml,用血清蛋白芯片多种肿瘤标志物检测系统(C12)测定12种肿瘤标志物的血清含量。(4)分析大肠癌组织与癌旁组织Ep-CAMIOD之间的关系;大肠癌组织Ep-CAMIOD与患者年龄、性别及肿瘤生物学行为之间的关系。(5)比较C12阳性和阴性组大肠癌组织Ep-CAMIOD之间的差异。
结果:(1)大肠癌组织Ep-CAMIOD显著高于癌旁组织Ep-CAMIOD(P<0.01)。(2)大肠癌组织Ep-CAMIOD与患者年龄、性别及肿瘤生物学行为无明显相关性(P>0.05)。(3)50.9﹪的大肠癌患者C12阳性。(4)C12阳性与阴性组大肠癌组织Ep-CAMIOD比较无显著差异(P>0.05)。
结论:(1)Ep-CAM参与了大肠癌发生、发展的全过程。(2)大肠癌组织中Ep-CAM表达水平与患者年龄、性别及肿瘤生物学行为无明显相关,是大肠癌发生、发展的一种独立性影响因素。(3)Ep-CAM可能作为大肠癌的肿瘤标志物,可以检出C12阴性病例,如与C12联合检查,将提高对大肠癌的检出率。(4)Ep-CAM可能作为大肠癌主动或被动免疫治疗的靶分子。
Background: Colorectal carcinoma (CRC) is a kind of malignant tumor that frequently occurred in gastrointestinal system and its morbidity has been rising in recent years in china. The main treatment to this disease is operation which is the only method for radical cure and only about 50-60% suffers can survival 5 years. At present, it is unknown about the genesis and development of CRC and a few patients was found in the disease early phrase, so that the relapse and metastasis would frequently occurred after operation. Apart from surgical treatment, there are also chemotherapy, radiotherapy and so on for CRC. However, these treatments, generally speaking, have gloomy curative effect and considerable adverse reactions. Immunotherapy for malignant tumors, which, in theory, targets to malignant cells and has low secondary effects, has been exploring for many years. It is very important to find a CRC tumor marker and explore its expresion and clinical value, so that we can make profound apprehension about CRC and elevate the diagnosis ability and therapeutic efficacy for CRC.
Epithelial cell adhesion molecule(Ep-CAM)is a transmembrane glycoprotein including one peptide, which was negatively or weakly expressed on norm epithelial cells and frequently overexpressed or re-expressed in epithelial carcinomas. It was reported that the molecule mediates Ca2+-independent homophilic adhesions and may correlate with cellular proliferation, invasion, de-differentiation as well as migration. Now, many kinds of active passive and immunotherapies for several kinds of malignant tumor, which targeted to Ep-CAM ,have been explored.
At present, It’s still unknown about about the Ep-CAM quantitive relations between CRC tissue and adjacent mucosa as well as the relations between Ep-CAM level in CRC tissue and patients age, gender as well as tumor biological behaviors of CRC and there are a few studies the possibility to use Ep-CAM as a CRC tumor maker and a immunotherapy target all over the world.
Objective: (1)Study EP-CAM expression in malignant tissue of large intestina. (2) Investigate the relations between Ep-CAM expression and CRC genesis and development. (3)Explore the relations between EP-CAM content in colorectal tumor tissue and patients age, gender as well as tumor biological behaviors. (4)Evaluate whether EP-CAM could be used as a tumor marker for CRC. (5) Compare the diognosis value of EP-CAM and C12 for CRC. (6)Evaluate whether EP-CAM could be used as a immunotherapy target for CRC.
Methods: (1) 53 pieces of colorectal tumor tissues and the same amount of adjacent mucosa were gathered, then, 3 pieces of tissue micro-array sections were made and immunostained. (2) The integral optical density of Ep-CAM staining area (short for Ep-CAMIOD) was inspected by image analysis morphological system. (3)Before operation, 1ml non-anticoagulation serum was collected from every subject, then12 kinds of tumor markers in serum were detected by 12 tumor markers protein micro-array system. (4)The relations of Ep-CAMIOD between in colorectal tumor tissue and in adjacent mucosa groups were investigated. Malignant tissue group was divided into different sub-groups by patients age, gender and tumor biological behaviors, then, we analyze the relationships of Ep-CAMIOD among sub-groups. (5)We also researched the differences of Ep-CAMIOD between C12 positive and negative groups.
Results: (1)The Ep-CAMIOD was significantly higher in CRC group than that in control group(P<0.01). (2)Ep-CAMIOD was not related to patients age, gender and tumor biological behaviors(P>0.05. (3)we found that C12 was positive in 50.9﹪ CRC patients. (4)There was no significant difference of Ep-CAMIOD between C12 positive and negtive groups(P>0.05).
Conclusions: (1)Ep-CAM was involved in CRC genesis and development. (2)Ep-CAM expression in cancer tissues had no significant relationships with patients age, gender and tumor biological behaviors and Ep-CAM was a independent inflence factor for CRC genesis and development. (3)Ep-CAM could be used as a tumor marker for CRC, which could found C12 negtive patients, so that, if it was detected together with C12, CRC detection rate may be improved. (4)Ep-CAM may be used as a active or passive immunotherapy target CRC.
引文
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4 Strnad J, Hamilton AE, Beavers LS, et al. Molecular cloning and characterization of a human adenocarcinoma/epithelial cell surface antigen complementary DNA. Cancer Res. 1989; 49:314-317.
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6 Spizzo G, Went P, Dirnhofer S, et al. Overexpression of epithelial cell adhesion molecule (Ep-CAM) is an independent prognostic marker for reduced survival of patients with epithelial ovarian cancer. Gynecol Oncol. 2006; 103:483-488.
7 Went P, Dirnhofer S, Salvisberg T, et al. Expression of epithelial cell adhesion molecule (EpCam) in renal epithelial tumors. Am J Surg Pathol. 2005; 29:83-88.
8 Osta WA, Chen Y, Mikhitarian K, et al. EpCAM is overexpressed in breast cancer and is a potential target for breast cancer gene therapy. Cancer Res. 2004; 64:5818-5824.
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19 Litvinov SV, Balzar M, Winter MJ, et al. Epithelial cell adhesion molecule (Ep-CAM) modulates cell-cell interactions mediated by classic cadherins. J Cell Biol. 1997; 139:1337-1348.
20 Krishnakumar S, Mohan A, Mallikarjuna K, et al. EpCAM expression in retinoblastoma: a novel molecular target for therapy. Invest Ophthalmol Vis Sci. 2004; 45:4247-4250.
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24 Songun I, Litvinov SV, van de Velde CJ, et al. Loss of Ep-CAM (CO17-1A) expression predicts survival in patients with gastric cancer. Br J Cancer. 2005; 92:1767-1772.
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26 Litvinov SV, Velders MP, Bakker HA, et al. Ep-CAM: a human epithelial antigen is a homophilic cell-cell adhesion molecule. J Cell Biol. 1994; 125:437-446.
27 Furth EE, Li J, Purev E, et al. Serum antibodies to EpCAM in healthy donors but not ulcerative colitis patients.Cancer Immunol Immunother. 2006; 55:528-37.
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29 Andratschke M, Hagedorn H, Luebbers CW, et al. Limited suitability of EpCAM for molecular staging of tumor borders in head and neck cancer. Anticancer Res. 2006; 26:153-158.
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34 Abe H, Kuroki M, Imakiire T, et al. Preparation of recombinant MK-1Ep-CAM and establishment of an ELISA system for determining soluble MK-1Ep-CAM levels in sera of cancer patients. J Immunol Methods. 2002; 270:227-233.
1 Calabrese G, Crescenzi C, Morizio E, et al. Assignment of TACSTD1 (alias TROP1, M4S1) to human chromosome 2p21 and refinement of mapping of TACSTD2 (alias TROP2, M1S1) to human chromosome 1p32 by in situ hybridization. Cytogenet Cell Genet. 2001; 92 :164-165
2 Strnad J, Hamilton AE, Beavers LS, et al. Molecular cloning and characterization of a human adenocarcinoma/epithelial cell surface antigen complementary DNA. Cancer Res. 1989; 49:314-317.
3 Balzar M, Bakker HAM, Briaire-de Bruijn IH, et al. Cytoplasmic tail of the intercellular adhesion function of the epithelial adhesion molecule (Ep-CAM). Mol Cell Biol. 1998; 18:4833–4843
4 Balzar M, Briaire-de Bruijn IH, Rees-Bakker HA, et al. Epidermal growth factor-like repeats mediate lateral and reciprocal interactions of Ep-CAM molecules in homophilic adhesions. Mol Cell Biol. 2001; 21:2570-2580.
5 Pauli C, Munz M, Kieu C, et al. Tumor-specific glycosylation of the carcinoma-associated epithelial cell adhesion molecule EpCAM in head and neck carcinomas. Cancer Lett. 2003; 193:25-32.
6 Litvinov SV, Velders MP, Bakker HA, et al. Ep-CAM: a human epithelial antigen isa homophilic cell-cell adhesion molecule. J Cell Biol. 1994; 125:437-446.
7 Krishnakumar S, Mohan A, Mallikarjuna K, et al. EpCAM expression in retinoblastoma: a novel molecular target for therapy. Invest Ophthalmol Vis Sci. 2004; 45:4247-4250.
8 Osta WA, Chen Y, Mikhitarian K, et al. EpCAM is overexpressed in breast cancer and is a potential target for breast cancer gene therapy. Cancer Res. 2004; 64:5818-5824.
9 Munz M, Kieu C, Mack B, et al. The carcinoma-associated antigen EpCAM upregulates c-myc and induces cell proliferation. Oncogene. 2004; 23:5748-5758.
10 Litvinov SV, Balzar M, Winter MJ, et al. Epithelial cell adhesion molecule (Ep-CAM) modulates cell-cell interactions mediated by classic cadherins. J Cell Biol. 1997; 139:1337-1348.
11 Muenz M, Zeidler R, Gires O. The tumour-associated antigen EpCAM upregulates the fatty acid binding protein E-FABP. Cancer Lett. 2005; 225:151-157.
12 Muenz M, Hofmann T, Scheibe B, et al. The carcinoma-associated antigen EpCAM induces glyoxalase 1 resulting in enhanced methylglyoxal turnover. Cancer Genomics & Proteomics. 2004; 1:241-247.
13 Went PT, Lugli A, Meier S, et al. Frequent EpCam protein expression in human carcinomas. Hum Pathol. 2004; 35:122-128.
14 Stoecklein NH, Siegmund A, Scheunemann P, et al. EpCAM expression in squamous cell carcinoma of the esophagus: a potential therapeutic target and prognostic marker. BMC Cancer. 2006; 6:165.
15 杨建柱 张祥宏 吴文新 等. 上皮细胞黏附分子、β-环连蛋白在子宫颈鳞状上皮癌变过程中表达的研究.中华肿瘤杂志.2003; 25:372-375.
16 Spizzo G, Went P, Dirnhofer S, et al. Overexpression of epithelial cell adhesion molecule (Ep-CAM) is an independent prognostic marker for reduced survival of patients with epithelial ovarian cancer. Gynecol Oncol. 2006; 103 ;483-488.
17 Andratschke M, Hagedorn H, Luebbers CW, et al. Limited suitability of EpCAM for molecular staging of tumor borders in head and neck cancer. Anticancer Res. 2006; 26:153-158.
18 Went P, Dirnhofer S, Salvisberg T, et al. Expression of epithelial cell adhesion molecule (EpCam) in renal epithelial tumors. Am J Surg Pathol. 2005; 29:83-88.
19 Rao CG, Chianese D, Doyle GV, et al. Expression of epithelial cell adhesion molecule in carcinoma cells present in blood and primary and metastatic tumors. Int J Oncol. 2005; 27:49-57.
20 Shetye J, Christensson B, Rubio C, et al. The tumor-associated antigens BR55-2, GA73-3 and GICA 19-9 in normal and corresponding neoplastic human tissues, especially gastrointestinal tissues. Anticancer Res. 1989; 9:395–404.
21 Abe H, Kuroki M, Imakiire T, et al. Preparation of recombinant MK-1Ep-CAM and establishment of an ELISA system for determining soluble MK-1Ep-CAM levels in sera of cancer patients. J Immunol Methods. 2002; 270:227-233.
22 Ruehlmann JM, Xiang R, Niethammer AG, et al. MIG (CXCL9) chemokine gene therapy combines with antibody-cytokine fusion protein to suppress growth and dissemination of murine colon carcinoma. Cancer Res. 2001; 61:8498-8503.
23 Gronau SS, Schmitt M, Thess B, et al. Trifunctional bispecific antibody-induced tumor cell lysis of squamous cell carcinomas of the upper aerodigestive tract. Head Neck. 2005; 27:376-382.
24 Flieger D, Spengler U, Beier I, et al. Augmentation of 17-1A-induced antibody-dependent cellular cytotoxicity by the triple cytokine combination of interferon-alpha, interleukin-2, and interleukin-12. J Immunother. 2000; 23:480-486.
25 Liljefors M, Ragnhammar P, Nilsson B, et al. Anti-EpCAM monoclonal antibody (MAb17-1A) based treatment combined with alpha-interferon, 5-fluorouracil and granulocyte-macrophage colony-stimulating factor in patients with metastatic colorectal carcinoma. Int J Oncol. 2004; 25:703-711.
26 Xiang R, Lode HN, Dolman CS, et al. Elimination of established murine colon carcinoma metastases by antibody-interleukin 2 fusion protein therapy. Cancer Res. 1997; 57:4948-4955.
27 Xiang R, Lode HN, Dreier T, et al. Induction of persistent tumor-protective immunity in mice cured of established colon carcinoma metastases. Cancer Res. 1998; 58:3918-3925.
28 Moller SA, Reisfeld RA. Bispecific-monoclonal-antibody-directed lysis of ovarian carcinoma cells by activated human T lymphocytes. Cancer Immunol Immunother. 1991; 33:210-216.
29 Stemmler HJ, Salat C, Lindhofer H, et al. Combined treatment of metastatic breast cancer (MBC) by high-dose chemotherapy (HDCT) and bispecific antibodies: A pilot study. Anticancer Research. 2005; 25:3047-3054.
30 Krusch M, Hermann T, Kanz L, et al. Induction of localized TNF activity against tumors using bispecific antibodies. Blood. 2005; 106:624-625
31 Schmitt M, Gronau S, Schmitt A, et al. Opsonization by the Bispecific Trifunctional Antibody Removab Results in an Enhanced Lysis of EpCAM+ Squamous Cell Carcinoma of the Upper Aerodigestive Tract. Blood. 2002; 100:3708-3715
32 Birebent B, Somasundaram R, Purev E, et al. Anti-idiotypic antibody and recombinant antigen vaccines in colorectal cancer patients. Crit Rev Oncol Hematol. 2001; 39:107-113.
33 Maruyama H, Zaloudik J, Li W, et al. Cancer vaccines: single-epitope anti-idiotype vaccine versus multiple-epitope antigen vaccine. Cancer Immunol Immunother. 2000; 49:123-132.
34 Heideman DA, van Beusechem VW, Offerhaus GJ, et al.. Selective gene transfer into primary human gastric tumors using epithelial cell adhesion molecule-targeted adenoviral vectors with ablated native tropism. Hum Gene Ther. 2002; 13:1677-1685.
35 Woelfle U, Breit E, Zafrakas K, et al. Bi-specific immunomagnetic enrichment of micrometastatic tumour cell clusters from bone marrow of cancer patients. Journal of Immunological Methods. 2005; 300:136-145.
36 Songun I, Litvinov SV, van de Velde CJ, et al. Loss of Ep-CAM (CO17-1A) expression predicts survival in patients with gastric cancer. Br J Cancer. 2005;92:1767-1772.
2 董志伟,乔友林,李连弟 等. 中国癌症控制策略研究报告. 中国肿瘤. 2002;5:250-260
3 郑树 我国大肠癌研究的挑战和机遇. 浙江大学学报. 2004; 33:376-378
4 Strnad J, Hamilton AE, Beavers LS, et al. Molecular cloning and characterization of a human adenocarcinoma/epithelial cell surface antigen complementary DNA. Cancer Res. 1989; 49:314-317.
5 Went P, Vasei M, Bubendorf L, et al. Frequent high-level expression of the immunotherapeutic target Ep-CAM in colon, stomach, prostate and lung cancers. Br J Cancer. 2006; 94:128-135.
6 Spizzo G, Went P, Dirnhofer S, et al. Overexpression of epithelial cell adhesion molecule (Ep-CAM) is an independent prognostic marker for reduced survival of patients with epithelial ovarian cancer. Gynecol Oncol. 2006; 103:483-488.
7 Went P, Dirnhofer S, Salvisberg T, et al. Expression of epithelial cell adhesion molecule (EpCam) in renal epithelial tumors. Am J Surg Pathol. 2005; 29:83-88.
8 Osta WA, Chen Y, Mikhitarian K, et al. EpCAM is overexpressed in breast cancer and is a potential target for breast cancer gene therapy. Cancer Res. 2004; 64:5818-5824.
9 Baeuerle PA, Gires O. EpCAM (CD326) finding its role in cancer. Br J Cancer. 2007; 96:417-423.
10 Stemmler HJ, Salat C, Lindhofer H, et al. Combined treatment of metastatic breast cancer (MBC) by high-dose chemotherapy (HDCT) and bispecific antibodies: A pilot study. Anticancer Research. 2005; 25 :3047-3054.
11 张新利,周建平,王春梅 等. 多肿瘤标志物蛋白芯片检测系统的临床应用. 现代肿瘤医学. 2005; 13:782-783.
12 Schneider J, Bitterlich N, Schulze G. Improved sensitivity in the diagnosis of gastro-intestinal tumors by fuzzy logic-based tumor marker profiles including the tumor M2-PK. Anticancer Res. 2005; 25:1507-1515.
13 KononenJ, Bubendorf, L,KallioniemiA, etal. Tissue microarrays for high-throughput molecular profiling of tumors pecimens. Nat Med. 1998; 4:844-8471.
14 Braunschweig T, Chung JY, Hewitt SM. Tissue microarrays: bridging the gap between research and the clinic. Expert Rev Proteomics. 2005; 2:325-336.
15 Sallinen SL, Sallinen PK, Haapasalo HK, et al. Identification of differentially expressed genes in human gliomas by DNA microarray and tissue chip techniques. Cancer Res. 2000; 60:6617-6622.
16 Calabrese G, Crescenzi C, Morizio E, et al. Assignment of TACSTD1 (alias TROP1, M4S1) to human chromosome 2p21 and refinement of mapping of TACSTD2 (alias TROP2, M1S1) to human chromosome 1p32 by in situ hybridization. Cytogenet Cell Genet. 2001; 92, 164-165.
17 Balzar M, Briaire-de Bruijn IH, Rees-Bakker HA, et al. Epidermal growth factor-like repeats mediate lateral and reciprocal interactions of Ep-CAM molecules in homophilic adhesions. Mol Cell Biol. 2001; 21:2570-2580.
18 Balzar M, Bakker HAM, Briaire-de Bruijn IH, et al. Cytoplasmic tail of the intercellular adhesion function of the epithelial adhesion molecule (Ep-CAM). Mol Cell Biol. 1998; 18:4833–4843.
19 Litvinov SV, Balzar M, Winter MJ, et al. Epithelial cell adhesion molecule (Ep-CAM) modulates cell-cell interactions mediated by classic cadherins. J Cell Biol. 1997; 139:1337-1348.
20 Krishnakumar S, Mohan A, Mallikarjuna K, et al. EpCAM expression in retinoblastoma: a novel molecular target for therapy. Invest Ophthalmol Vis Sci. 2004; 45:4247-4250.
21 Winter MJ, Nagelkerken B, Mertens AE, et al. Expression of Ep-CAM shifts the state of cadherin-mediated adhesions from strong to weak. Exp Cell Res. 2003; 285:50-58.
22 Stoecklein NH, Siegmund A, Scheunemann P, et al. Ep-CAM expression in squamous cell carcinoma of the esophagus: a potentialtherapeutic target and prognostic marker. BMC Cancer. 2006; 6:165-172.
23 Kimura H, Kato H, Faried A, et al. Prognostic significance of EpCAM expression in human esophageal cancer. Int J Oncol. 2007; 30:171-179.
24 Songun I, Litvinov SV, van de Velde CJ, et al. Loss of Ep-CAM (CO17-1A) expression predicts survival in patients with gastric cancer. Br J Cancer. 2005; 92:1767-1772.
25 Basak S, Speicher D, Eck S, et al. Colorectal carcinoma invasion inhibition by CO17-1A/GA733 antigen and its murine homologue. J Natl Cancer Inst. 1998; 90:691-697.
26 Litvinov SV, Velders MP, Bakker HA, et al. Ep-CAM: a human epithelial antigen is a homophilic cell-cell adhesion molecule. J Cell Biol. 1994; 125:437-446.
27 Furth EE, Li J, Purev E, et al. Serum antibodies to EpCAM in healthy donors but not ulcerative colitis patients.Cancer Immunol Immunother. 2006; 55:528-37.
28 王双双,范玉晶,关景明. 大肠癌相关的肿瘤标志物. 临床消化病杂志 2006; 18:115-116.
29 Andratschke M, Hagedorn H, Luebbers CW, et al. Limited suitability of EpCAM for molecular staging of tumor borders in head and neck cancer. Anticancer Res. 2006; 26:153-158.
30 Liljefors M, Ragnhammar P, Nilsson B, et al. Anti-EpCAM monoclonal antibody (MAb17-1A) based treatment combined with alpha-interferon,5-fluorouracil and granulocyte-macrophage colony-stimulating factor in patients with metastatic colorectal carcinoma. Int J Oncol. 2004; 25:703-711.
31 Schmitt M, Gronau S, Schmitt A, et al. Opsonization by the Bispecific Trifunctional Antibody Removab Results in an Enhanced Lysis of EpCAM+ Squamous Cell Carcinoma of the Upper Aerodigestive Tract. Blood. 2002; 100:3708-3713.
32 Xiang R, Lode HN, Dolman CS, et al. Elimination of established murine colon carcinoma metastases by antibody-interleukin 2 fusion protein therapy. Cancer Res. 1997; 57:4948-4955.
33 Kirman I, Jenkins D, Fowler R, Whelan RL. Naturally occurring antibodies to epithelial cell adhesion molecule (EpCAM). Dig Dis Sci. 2003; 48:2306-2309.
34 Abe H, Kuroki M, Imakiire T, et al. Preparation of recombinant MK-1Ep-CAM and establishment of an ELISA system for determining soluble MK-1Ep-CAM levels in sera of cancer patients. J Immunol Methods. 2002; 270:227-233.
1 Calabrese G, Crescenzi C, Morizio E, et al. Assignment of TACSTD1 (alias TROP1, M4S1) to human chromosome 2p21 and refinement of mapping of TACSTD2 (alias TROP2, M1S1) to human chromosome 1p32 by in situ hybridization. Cytogenet Cell Genet. 2001; 92 :164-165
2 Strnad J, Hamilton AE, Beavers LS, et al. Molecular cloning and characterization of a human adenocarcinoma/epithelial cell surface antigen complementary DNA. Cancer Res. 1989; 49:314-317.
3 Balzar M, Bakker HAM, Briaire-de Bruijn IH, et al. Cytoplasmic tail of the intercellular adhesion function of the epithelial adhesion molecule (Ep-CAM). Mol Cell Biol. 1998; 18:4833–4843
4 Balzar M, Briaire-de Bruijn IH, Rees-Bakker HA, et al. Epidermal growth factor-like repeats mediate lateral and reciprocal interactions of Ep-CAM molecules in homophilic adhesions. Mol Cell Biol. 2001; 21:2570-2580.
5 Pauli C, Munz M, Kieu C, et al. Tumor-specific glycosylation of the carcinoma-associated epithelial cell adhesion molecule EpCAM in head and neck carcinomas. Cancer Lett. 2003; 193:25-32.
6 Litvinov SV, Velders MP, Bakker HA, et al. Ep-CAM: a human epithelial antigen isa homophilic cell-cell adhesion molecule. J Cell Biol. 1994; 125:437-446.
7 Krishnakumar S, Mohan A, Mallikarjuna K, et al. EpCAM expression in retinoblastoma: a novel molecular target for therapy. Invest Ophthalmol Vis Sci. 2004; 45:4247-4250.
8 Osta WA, Chen Y, Mikhitarian K, et al. EpCAM is overexpressed in breast cancer and is a potential target for breast cancer gene therapy. Cancer Res. 2004; 64:5818-5824.
9 Munz M, Kieu C, Mack B, et al. The carcinoma-associated antigen EpCAM upregulates c-myc and induces cell proliferation. Oncogene. 2004; 23:5748-5758.
10 Litvinov SV, Balzar M, Winter MJ, et al. Epithelial cell adhesion molecule (Ep-CAM) modulates cell-cell interactions mediated by classic cadherins. J Cell Biol. 1997; 139:1337-1348.
11 Muenz M, Zeidler R, Gires O. The tumour-associated antigen EpCAM upregulates the fatty acid binding protein E-FABP. Cancer Lett. 2005; 225:151-157.
12 Muenz M, Hofmann T, Scheibe B, et al. The carcinoma-associated antigen EpCAM induces glyoxalase 1 resulting in enhanced methylglyoxal turnover. Cancer Genomics & Proteomics. 2004; 1:241-247.
13 Went PT, Lugli A, Meier S, et al. Frequent EpCam protein expression in human carcinomas. Hum Pathol. 2004; 35:122-128.
14 Stoecklein NH, Siegmund A, Scheunemann P, et al. EpCAM expression in squamous cell carcinoma of the esophagus: a potential therapeutic target and prognostic marker. BMC Cancer. 2006; 6:165.
15 杨建柱 张祥宏 吴文新 等. 上皮细胞黏附分子、β-环连蛋白在子宫颈鳞状上皮癌变过程中表达的研究.中华肿瘤杂志.2003; 25:372-375.
16 Spizzo G, Went P, Dirnhofer S, et al. Overexpression of epithelial cell adhesion molecule (Ep-CAM) is an independent prognostic marker for reduced survival of patients with epithelial ovarian cancer. Gynecol Oncol. 2006; 103 ;483-488.
17 Andratschke M, Hagedorn H, Luebbers CW, et al. Limited suitability of EpCAM for molecular staging of tumor borders in head and neck cancer. Anticancer Res. 2006; 26:153-158.
18 Went P, Dirnhofer S, Salvisberg T, et al. Expression of epithelial cell adhesion molecule (EpCam) in renal epithelial tumors. Am J Surg Pathol. 2005; 29:83-88.
19 Rao CG, Chianese D, Doyle GV, et al. Expression of epithelial cell adhesion molecule in carcinoma cells present in blood and primary and metastatic tumors. Int J Oncol. 2005; 27:49-57.
20 Shetye J, Christensson B, Rubio C, et al. The tumor-associated antigens BR55-2, GA73-3 and GICA 19-9 in normal and corresponding neoplastic human tissues, especially gastrointestinal tissues. Anticancer Res. 1989; 9:395–404.
21 Abe H, Kuroki M, Imakiire T, et al. Preparation of recombinant MK-1Ep-CAM and establishment of an ELISA system for determining soluble MK-1Ep-CAM levels in sera of cancer patients. J Immunol Methods. 2002; 270:227-233.
22 Ruehlmann JM, Xiang R, Niethammer AG, et al. MIG (CXCL9) chemokine gene therapy combines with antibody-cytokine fusion protein to suppress growth and dissemination of murine colon carcinoma. Cancer Res. 2001; 61:8498-8503.
23 Gronau SS, Schmitt M, Thess B, et al. Trifunctional bispecific antibody-induced tumor cell lysis of squamous cell carcinomas of the upper aerodigestive tract. Head Neck. 2005; 27:376-382.
24 Flieger D, Spengler U, Beier I, et al. Augmentation of 17-1A-induced antibody-dependent cellular cytotoxicity by the triple cytokine combination of interferon-alpha, interleukin-2, and interleukin-12. J Immunother. 2000; 23:480-486.
25 Liljefors M, Ragnhammar P, Nilsson B, et al. Anti-EpCAM monoclonal antibody (MAb17-1A) based treatment combined with alpha-interferon, 5-fluorouracil and granulocyte-macrophage colony-stimulating factor in patients with metastatic colorectal carcinoma. Int J Oncol. 2004; 25:703-711.
26 Xiang R, Lode HN, Dolman CS, et al. Elimination of established murine colon carcinoma metastases by antibody-interleukin 2 fusion protein therapy. Cancer Res. 1997; 57:4948-4955.
27 Xiang R, Lode HN, Dreier T, et al. Induction of persistent tumor-protective immunity in mice cured of established colon carcinoma metastases. Cancer Res. 1998; 58:3918-3925.
28 Moller SA, Reisfeld RA. Bispecific-monoclonal-antibody-directed lysis of ovarian carcinoma cells by activated human T lymphocytes. Cancer Immunol Immunother. 1991; 33:210-216.
29 Stemmler HJ, Salat C, Lindhofer H, et al. Combined treatment of metastatic breast cancer (MBC) by high-dose chemotherapy (HDCT) and bispecific antibodies: A pilot study. Anticancer Research. 2005; 25:3047-3054.
30 Krusch M, Hermann T, Kanz L, et al. Induction of localized TNF activity against tumors using bispecific antibodies. Blood. 2005; 106:624-625
31 Schmitt M, Gronau S, Schmitt A, et al. Opsonization by the Bispecific Trifunctional Antibody Removab Results in an Enhanced Lysis of EpCAM+ Squamous Cell Carcinoma of the Upper Aerodigestive Tract. Blood. 2002; 100:3708-3715
32 Birebent B, Somasundaram R, Purev E, et al. Anti-idiotypic antibody and recombinant antigen vaccines in colorectal cancer patients. Crit Rev Oncol Hematol. 2001; 39:107-113.
33 Maruyama H, Zaloudik J, Li W, et al. Cancer vaccines: single-epitope anti-idiotype vaccine versus multiple-epitope antigen vaccine. Cancer Immunol Immunother. 2000; 49:123-132.
34 Heideman DA, van Beusechem VW, Offerhaus GJ, et al.. Selective gene transfer into primary human gastric tumors using epithelial cell adhesion molecule-targeted adenoviral vectors with ablated native tropism. Hum Gene Ther. 2002; 13:1677-1685.
35 Woelfle U, Breit E, Zafrakas K, et al. Bi-specific immunomagnetic enrichment of micrometastatic tumour cell clusters from bone marrow of cancer patients. Journal of Immunological Methods. 2005; 300:136-145.
36 Songun I, Litvinov SV, van de Velde CJ, et al. Loss of Ep-CAM (CO17-1A) expression predicts survival in patients with gastric cancer. Br J Cancer. 2005;92:1767-1772.