MUC1粘蛋白在血液系统恶性肿瘤中表达及其意义的研究
摘要
[目的]研究MUC1粘蛋白分子在血液系统恶性肿瘤患者中的表达，探讨MUC1在血液系统恶性肿瘤中的作用机制、临床意义及在肿瘤生物治疗中的应用前景。
[方法]应用免疫组织化学及免疫细胞化学SP法检测了77例血液系统恶性肿瘤患者的骨髓、淋巴结及其他组织标本中MUC1粘蛋白的表达，并分析了与一些临床指标的关系。
[结果]9例多发性骨髓瘤(MM)患者MUC1阳性表达率(90％)和19例急性髓性白血病(AML)阳性表达率(63.2％)均高于对照组(10％)(P＜0.05)。26例B细胞性恶性肿瘤患者MUC1阳性表达率(73％)明显高于对照组(P＜0.05)。17例T细胞性恶性肿瘤均为阴性，和B细胞性恶性肿瘤组相比差异有显著性(P＜0.05)。在AML中MUC1高表达与患者的年龄及髓外浸润呈正相关，而与患者的性别、白细胞计数、乳酸脱氢酶含量及缓解率无明显相关。
[结论]MUC1粘蛋白在B细胞性恶性肿瘤特别是多发性骨髓瘤及急性髓性白血病中以非糖基化的形式表达异常增高，并与患者年龄、骨髓浸润呈正相关，提示MUC1在血液系统恶性肿瘤的发病中可能起一定的作用，其表达与MM、AML的病情进展及预后相关。为MUC1免疫原作为疫苗应用于血液系统恶性肿瘤生物治疗的研究提供一定的理论依据。
[Objective]To detect MUC1 expression in the cases of hematoiogical malignant diseases and its clinical significance in these diseases, especially its targeting immunotherapeutic potency in these diseases. [Methods] The expression of MUC1 in the bone marrow, lymph nodes, and other tissues was assayed by immunocytochemical and immunohistochemical SP methods in total 77 cases of hematoiogical malignant diseases. The association between the expression of MUC1 and some clinic parameters was also analysised.
[Results]The expression of MUC1 in AML and B cell malignant lymphoproliferative diseases especially in MM was significantly higher than that in normal blood cells (P<0.05). An analysis of correlation between the expression of MUC1 and other clinic parameters showed that increased MUC1 antigen expression was associated with some poor prognostic factors such as extramedullary infiltration and the age of older than 60-year-old patients with AML.
[Conclusion] Our study showed that MUC1 was overexpressed in non-glycosylated form in AML and B cell malignant lymphoproliferative
diseases, particularly in MM, and was associated with extramedullary infiltration as well as the age of older than 60-year-old patient with AML. MUC1 may be used as a poor prognostic factor in some malignant diseases. More importantly, it could be used as a immunotherapeutic methods for these diseases.
[方法]应用免疫组织化学及免疫细胞化学SP法检测了77例血液系统恶性肿瘤患者的骨髓、淋巴结及其他组织标本中MUC1粘蛋白的表达，并分析了与一些临床指标的关系。
[结果]9例多发性骨髓瘤(MM)患者MUC1阳性表达率(90％)和19例急性髓性白血病(AML)阳性表达率(63.2％)均高于对照组(10％)(P＜0.05)。26例B细胞性恶性肿瘤患者MUC1阳性表达率(73％)明显高于对照组(P＜0.05)。17例T细胞性恶性肿瘤均为阴性，和B细胞性恶性肿瘤组相比差异有显著性(P＜0.05)。在AML中MUC1高表达与患者的年龄及髓外浸润呈正相关，而与患者的性别、白细胞计数、乳酸脱氢酶含量及缓解率无明显相关。
[结论]MUC1粘蛋白在B细胞性恶性肿瘤特别是多发性骨髓瘤及急性髓性白血病中以非糖基化的形式表达异常增高，并与患者年龄、骨髓浸润呈正相关，提示MUC1在血液系统恶性肿瘤的发病中可能起一定的作用，其表达与MM、AML的病情进展及预后相关。为MUC1免疫原作为疫苗应用于血液系统恶性肿瘤生物治疗的研究提供一定的理论依据。
[Objective]To detect MUC1 expression in the cases of hematoiogical malignant diseases and its clinical significance in these diseases, especially its targeting immunotherapeutic potency in these diseases. [Methods] The expression of MUC1 in the bone marrow, lymph nodes, and other tissues was assayed by immunocytochemical and immunohistochemical SP methods in total 77 cases of hematoiogical malignant diseases. The association between the expression of MUC1 and some clinic parameters was also analysised.
[Results]The expression of MUC1 in AML and B cell malignant lymphoproliferative diseases especially in MM was significantly higher than that in normal blood cells (P<0.05). An analysis of correlation between the expression of MUC1 and other clinic parameters showed that increased MUC1 antigen expression was associated with some poor prognostic factors such as extramedullary infiltration and the age of older than 60-year-old patients with AML.
[Conclusion] Our study showed that MUC1 was overexpressed in non-glycosylated form in AML and B cell malignant lymphoproliferative
diseases, particularly in MM, and was associated with extramedullary infiltration as well as the age of older than 60-year-old patient with AML. MUC1 may be used as a poor prognostic factor in some malignant diseases. More importantly, it could be used as a immunotherapeutic methods for these diseases.
引文
1、邢英琦，朱迅．粘蛋白核心蛋白MUC1的基因结构及其在肿瘤生物中的意义．中国肿瘤生物治疗杂志，1996，3(2)：154-9．
2、Patton SG, Gandler SJ, Spicer AP. The epithelial mucin, MUC1, of milk, mammary gland and other tissues. Biochim Biophy Acta, 1995, 1241(3):407-23.
3、Akashi H, Hinoda Y, Itoh F, et al. A novel gastric-cancer-associated mucin antigen defined by a monoclonal antibody A3D4. Int J Cancer. 1997,73:793-801.
4、阎洪彦，王立顺．MUC1粘蛋白—肿瘤生物治疗的新靶点．国外医学免疫学分册，2000，23(2)：113-115．
5、Verma M. Carcinoma associated mucins: molecular biology and clinical applications. Cancer Biochem Biophys. 1994. 14(3): 151-6.
6、王立顺，朱迅．MUC1和MUC2mRNA在不同肿瘤组织的表达及意义．中国肿瘤临床，2000，27(4)：258-261．
7、Ten-Berge RL, Snijdewint FG, von-Mensdorff-Pouilly S, et al. MUC1 (EMA) is preferentially expressed by ALK positive anaplastic large cell lymphoma in the normally glycosylated or only partly hypoglycosylated form. J Clinic Pathol.2001,54(12):933-9.
8、张之南．沈悌．血液病诊断及疗效标准．第二版．北京：科学出版社．1998．
9、Dong Y, Walsh MD, Cummings MC, et al. Expression of MUC1 and MUC2 mucins in epithelial ovarian tumors. J Pathol.1997, 183; 311-317.
10、Sen-itiroh Hakomori. Tumor malignancy defined by aberrant glycosylation and sphingo(glyco)lipid metabolism. Cancer Res. 1996, 56,5309-5318.
11、Cao Y, Schlag PM, Karsten V. Immunodetection of epithelial Mucin (MUC1, MUC3) and Mucin-associated glycotopes (TFMTn, ansialosyl-Tn) in benign and malignant lesions of colonic epithelium: apolar localization corresponds to malignant transformation. Virchows Arch. 1997, 431(31): 159-66.
12、Nicolet CM, Siegel DH, Surfus JE, et al.TAM-72-reactive antibody CC49 recognizes molecules expressed by hematopoitic cell lines. Tumour
Biol.1997, 18(6): 356-66.
13、Devine PL, Warren JA, Ward BG, et al. Glycosylation and exposure of tumor-associated epitopes on mucins. J Tumor Marker Oncol. 1990:11-26.
14、Bon GG, Von Mensdorff-Pouilly S, Kenemans P, et al. Clinical and technical evaluation of ACSBR serum assay of MUC1 gene derived glycorprotein in breast cancer and comparision with CA15.3 assay. Clin Chem. 1997, 43:583-593.
15、Treon SP, Molick JA, Urashima M, et al. Myeloma cell lines and myeloma patient clonotipic B cells express core protein MUC1 on the cell surface. Blood 1997; 90(10,Supp 1) 382a.
16、Treon SP, Molick JA, Urashima M, et al. Solube MUC1 is elevated in multiple myeloma(MM) bone marrow(BM) plasma and inhibits T cell proliferation.Blood, 1998,92(10,Supp 1 ) 411 a.
17、Cook G, Campbell JD. Immune regulation in multiple myeloma: the host-tumor conflict. Blood Rev. 1999, 13(3): 151-62.
18、Treon SP, Molick JA, Urashima M, et al. MUC1 core protein is expressed on multiple myeloma cells and is induced by dexamethasone. Blood, 1999,93(4): 1287-98.
19、Brossart P, Heinrich SK,Stuhler G, et al. Identification of HLA-A2-Restricted T-cell epitopes derived from the MUC1 tumor antigen for broadly applicable vaccine therapies. Blood. 1999,93(12), 4309-4317_
20、袁时芳，李开宗，王岭等．MUC1基因疫苗诱导小鼠特异性CTL和体液免疫应答．细胞与分子免疫学杂志，2003，19(4)：343-345．
21、Handa K, Jacobs F, Longenecker BM, et al. Association of MUC-1 and PSG-1 with Low-Density microdomain in T-lymphocytes: a preliminary note. Biochem Biophs Res Commun.2001, 285,788-794.
22、Milazzo C, Reichardt VL, Muller MR, et al. Induction of myeloma-specific cytotoxic T cells using dendritic cells transfected with tumor-derived RNA. Blood .2003,101 (3):977-82.
23、Ruffini PA, Biragyn A, Kwak LW. Recent advances in multiple myeloma immunotherapy. Biomed Pharmacother.2002,56(3): 129-32.
24、Zhong XY, Kaul S, Bastert G. Evaluation of MUC1 and EG40 in bone marrow and peripheral blood as a marker for occult breast cancer. Arch Gynecol Obstet. 2001,264(4): 177-81.
25、Gilles F, Goy A,Remache Y, et al. MUC1 dysregulation as the consequence of a t(1;14)(q21;q32) translocation in an extranodal lymphoma. Blood.2000,95(9):2930-2936.
26、Dyomin VG, Palanisamy N, Lloyd KO, et al. MUC1 is activated in a B-cell lymphoma by the t (1; 14) (q21; q32) translocation and is rearranged and amplified in B-cell lymphoma subsets. Blood, 2000,95(8): 2666-71.
27、Brugger W, Scheider A, Schammann T, et al. Dendritic cell-based vaccines in patients with hematological malignances. Ann N Y Acad Sci. 2001,938:359-62; discussion 362-3.
28、Brossart P, Schneider A, Dill P, et al. The epithelial tumor antigen MUC1 is expressed in hematological malignancies and is recognized by MUC 1-specific cytoxic T-lymphocytes. Cancer Res. 2001,61:6846-6850.
29、Soares MM, Mehta V, Finn OJ. Three different vaccines based on the140-amino acid MUC1 peptide with seven tandemly repeated tumor-specific epitopes elicit distinct immune effecter mechanisms in wild-type versus 1 MUC1-transgenic mice with different potential for tumor rejection. J Immunol.2001,166(11):6555-63.
2、Patton SG, Gandler SJ, Spicer AP. The epithelial mucin, MUC1, of milk, mammary gland and other tissues. Biochim Biophy Acta, 1995, 1241(3):407-23.
3、Akashi H, Hinoda Y, Itoh F, et al. A novel gastric-cancer-associated mucin antigen defined by a monoclonal antibody A3D4. Int J Cancer. 1997,73:793-801.
4、阎洪彦，王立顺．MUC1粘蛋白—肿瘤生物治疗的新靶点．国外医学免疫学分册，2000，23(2)：113-115．
5、Verma M. Carcinoma associated mucins: molecular biology and clinical applications. Cancer Biochem Biophys. 1994. 14(3): 151-6.
6、王立顺，朱迅．MUC1和MUC2mRNA在不同肿瘤组织的表达及意义．中国肿瘤临床，2000，27(4)：258-261．
7、Ten-Berge RL, Snijdewint FG, von-Mensdorff-Pouilly S, et al. MUC1 (EMA) is preferentially expressed by ALK positive anaplastic large cell lymphoma in the normally glycosylated or only partly hypoglycosylated form. J Clinic Pathol.2001,54(12):933-9.
8、张之南．沈悌．血液病诊断及疗效标准．第二版．北京：科学出版社．1998．
9、Dong Y, Walsh MD, Cummings MC, et al. Expression of MUC1 and MUC2 mucins in epithelial ovarian tumors. J Pathol.1997, 183; 311-317.
10、Sen-itiroh Hakomori. Tumor malignancy defined by aberrant glycosylation and sphingo(glyco)lipid metabolism. Cancer Res. 1996, 56,5309-5318.
11、Cao Y, Schlag PM, Karsten V. Immunodetection of epithelial Mucin (MUC1, MUC3) and Mucin-associated glycotopes (TFMTn, ansialosyl-Tn) in benign and malignant lesions of colonic epithelium: apolar localization corresponds to malignant transformation. Virchows Arch. 1997, 431(31): 159-66.
12、Nicolet CM, Siegel DH, Surfus JE, et al.TAM-72-reactive antibody CC49 recognizes molecules expressed by hematopoitic cell lines. Tumour
Biol.1997, 18(6): 356-66.
13、Devine PL, Warren JA, Ward BG, et al. Glycosylation and exposure of tumor-associated epitopes on mucins. J Tumor Marker Oncol. 1990:11-26.
14、Bon GG, Von Mensdorff-Pouilly S, Kenemans P, et al. Clinical and technical evaluation of ACSBR serum assay of MUC1 gene derived glycorprotein in breast cancer and comparision with CA15.3 assay. Clin Chem. 1997, 43:583-593.
15、Treon SP, Molick JA, Urashima M, et al. Myeloma cell lines and myeloma patient clonotipic B cells express core protein MUC1 on the cell surface. Blood 1997; 90(10,Supp 1) 382a.
16、Treon SP, Molick JA, Urashima M, et al. Solube MUC1 is elevated in multiple myeloma(MM) bone marrow(BM) plasma and inhibits T cell proliferation.Blood, 1998,92(10,Supp 1 ) 411 a.
17、Cook G, Campbell JD. Immune regulation in multiple myeloma: the host-tumor conflict. Blood Rev. 1999, 13(3): 151-62.
18、Treon SP, Molick JA, Urashima M, et al. MUC1 core protein is expressed on multiple myeloma cells and is induced by dexamethasone. Blood, 1999,93(4): 1287-98.
19、Brossart P, Heinrich SK,Stuhler G, et al. Identification of HLA-A2-Restricted T-cell epitopes derived from the MUC1 tumor antigen for broadly applicable vaccine therapies. Blood. 1999,93(12), 4309-4317_
20、袁时芳，李开宗，王岭等．MUC1基因疫苗诱导小鼠特异性CTL和体液免疫应答．细胞与分子免疫学杂志，2003，19(4)：343-345．
21、Handa K, Jacobs F, Longenecker BM, et al. Association of MUC-1 and PSG-1 with Low-Density microdomain in T-lymphocytes: a preliminary note. Biochem Biophs Res Commun.2001, 285,788-794.
22、Milazzo C, Reichardt VL, Muller MR, et al. Induction of myeloma-specific cytotoxic T cells using dendritic cells transfected with tumor-derived RNA. Blood .2003,101 (3):977-82.
23、Ruffini PA, Biragyn A, Kwak LW. Recent advances in multiple myeloma immunotherapy. Biomed Pharmacother.2002,56(3): 129-32.
24、Zhong XY, Kaul S, Bastert G. Evaluation of MUC1 and EG40 in bone marrow and peripheral blood as a marker for occult breast cancer. Arch Gynecol Obstet. 2001,264(4): 177-81.
25、Gilles F, Goy A,Remache Y, et al. MUC1 dysregulation as the consequence of a t(1;14)(q21;q32) translocation in an extranodal lymphoma. Blood.2000,95(9):2930-2936.
26、Dyomin VG, Palanisamy N, Lloyd KO, et al. MUC1 is activated in a B-cell lymphoma by the t (1; 14) (q21; q32) translocation and is rearranged and amplified in B-cell lymphoma subsets. Blood, 2000,95(8): 2666-71.
27、Brugger W, Scheider A, Schammann T, et al. Dendritic cell-based vaccines in patients with hematological malignances. Ann N Y Acad Sci. 2001,938:359-62; discussion 362-3.
28、Brossart P, Schneider A, Dill P, et al. The epithelial tumor antigen MUC1 is expressed in hematological malignancies and is recognized by MUC 1-specific cytoxic T-lymphocytes. Cancer Res. 2001,61:6846-6850.
29、Soares MM, Mehta V, Finn OJ. Three different vaccines based on the140-amino acid MUC1 peptide with seven tandemly repeated tumor-specific epitopes elicit distinct immune effecter mechanisms in wild-type versus 1 MUC1-transgenic mice with different potential for tumor rejection. J Immunol.2001,166(11):6555-63.