臨床検査55巻1号

2011年01月発行

記事購入ページに移動

今月の主題 -ミクログロブリン－その多様な病因，病態と検査アプローチ 総論

β₂-ミクログロブリンによる腫瘍細胞増殖とその制御

著者： 野村威雄¹ 三股浩光¹

所属機関： ¹大分大学医学部腎泌尿器外科

ページ範囲：P.27 - P.35

β₂-ミクログロブリン(β₂-m)はMHC class Iα鎖の一部であり，癌細胞増殖を刺激し，特に骨転移を誘導する増殖調節因子である可能性が報告されている．また種々の癌種において，血中または尿中β₂-mが独立した予後因子あるいは悪性度を規定するバイオマーカーとしても知られている．ある種の固形癌や血液腫瘍においては，特異的な抗β₂-m中和抗体による抗腫瘍効果を認め，正常細胞への毒性は低いことが報告されている．これらの知見は，癌治療においてβ₂-mが新たな治療標的となる可能性を示唆している．本稿では，癌細胞におけるβ₂-mの刺激伝達物質としての役割と骨転移形成への関与について概説する．

参考文献

1) Bjorkman PJ, Parham P:Structure, function, and diversity of class I major histocompatibility complex molecules. Annu Rev Biochem　59：253-288，1990

2) Ploegh HL, Orr HT, Strominger JL:Major histocompatibility antigens:the human (HLA-A, -B, -C) and murine (H-2K, H-2D) class I molecules. Cell　24：287-299，1981

3) Parham P, Ohta T:Population biology of antigen presentation by MHC class I molecules. Science　272：67-74，1996

domain of HLA-A2. Nature　345：41-46，1990

5) Garrido F, Cabrera T, Concha A, et al:Natural history of HLA expression during tumour development. Immunol Today　14：491-499，1993

6) Chen HL, Gabrilovich D, Tampe R, et al:A functionally defective allele of TAP1 results in loss of MHC class I antigen presentation in a human lung cancer. Nat Genet　13：210-213，1996

7) Amiot L, Onno M, Lamy T, et al:Loss of HLA molecules in B lymphomas is associated with an aggressive clinical course. Br J Haematol　100：655-663，1998

8) Hicklin DJ, Wang Z, Arienti F, et al:beta2-Microglobulin mutations, HLA class I antigen loss, and tumor progression in melanoma. J Clin Invest　101：2720-2729，1998

9) Seliger B, Hohne A, Knuth A, et al:Reduced membrane major histocompatibility complex class I density and stability in a subset of human renal cell carcinomas with low TAP and LMP expression. Clin Cancer Res　2：1427-1433，1996

10) Kallfelz M, Jung D, Hilmes C, et al:Induction of immunogenicity of a human renal-cell carcinoma cell line by TAP1-gene transfer. Int J Cancer　31：125-133，1999

11) Faderi S, Keating MJ, Do KA, et al:Expression profile of 11 proteins and their prognostic significance in patients with chronic lymphocytic leukemia (CLL). Leukemia　16：1045-1052，2002

12) Bataille R, Durie BG, Grenier J:Serum beta2 microglobulin and survival duration in multiple myeloma:a simple reliable marker for staging. Br J Haematol　55：439-447，1983

13) Abdul M, Hoosein N:Changes in beta-2 microglobulin expression in prostate cancer. Urol Oncol　5：168-172，2000

14) Molica S, Levato D, Cascavilla N, et al:Clinico-prognostic implications of simultaneous increased serum levels of soluble CD23 and beta2-microglobulin in B-cell chronic lymphocytic leukemia. Eur J Haematol　62：117-122，1999

15) Bethea M, Forman DT:Beta 2-microglobulin:its significance and clinical usefulness. Ann Clin Lab Sci　20：163-168，1990

16) Gatto S, Ball G, Onida F, et al:Contribution of beta-2 microglobulin levels to the prognostic stratification of survival in patients with myelodysplastic syndrome (MDS). Blood　102：1622-1625，2003

17) Nissen MH, Bjerrum OJ, Plesner T, et al:Modification of beta-2-microglobulin in sera from patients with small cell lung cancer:evidence for involvement of a serine protease. Clin Exp Immunol　67：425-432，1987

18) York IA, Rock KL:Antigen processing and presentation by the class I major histocompatibility complex. Annu Rev Immunol　14：369-396，1996

19) Shrout J, Yousefzadeh M, Dodd A, et al:beta(2)microglobulin mRNA expression levels are prognostic for lymph node metastasis in colorectal cancer patients. Br J Cancer　98：1999-2005，2008

20) Dember LM, Jaber BL:Dialysis-related amyloidosis:late finding or hidden epidemic? Semin Dial　19：105-109，2006

21) Balint E, Sprague SM:Beta(2)-microglobulin and bone cell metabolism. Nephrol Dial Transplant　16：1108-1111，2001

22) Rowley DR, Dang TD, McBride L, et al:Beta-2 microglobulin is mitogenic to PC-3 prostatic carcinoma cells and antagonistic to transforming growth factor beta 1 action. Cancer Res　55：781-786，1995

23) Huang WC, Wu D, Xie Z, et al:beta2-microglobulin is a signaling and growth-promoting factor for human prostate cancer bone metastasis. Cancer Res　66：9108-9116，2006

24) Nomura T, Huang WC, Zhau HE:Beta2-microglobulin promotes the growth of human renal cell carcinoma through the activation of the protein kinase A, cyclic AMP-reponsive element-binding protein, and vascular endothelial growth factor axis. Clin Cancer Res　12：7294-7305，2006

25) Yang J, Zhang X, Wang J, et al:Anti beta2-microglobulin monoclonal antibodies induce apoptosis in myeloma cells by recruiting MHC class I to and excluding growth and survival cytokine receptors from lipid rafts. Blood　110：3028-3035，2007

26) Tsai CY, Wu TH, Yu CL, et al:Increased excretions of beta2-microglobulin, IL-6, and IL-8 and decreased excretion of Tamm-Horsfall glycoprotein in urine of patients with active lupus nephritis. Nephron　85：207-214，2000

27) Zhau HE, Odero-Marah V, Lue HW, et al:Epithelial to mesenchymal transition (EMT) in human prostate cancer:lessons learned from ARCaP model. Clin Exp Metastasis　25：601-610，2008

28) Wu D, Zhau HE, Huang WC, et al:cAMP-responsive element-binding protein regulates vascular endothelial growth factor expression:implication in human prostate cancer bone metastasis. Oncogene　26：5070-5077，2007

29) Chung LW, Huang WC, Sung SY, et al:Stromal-epithelial interaction in prostate cancer progression. Clin Genitourin Cancer　5：162-170，2006

30) Koeneman KS, Yeung F, Chung LW:Osteomimetic properties of prostate cancer cells:a hypothesis supporting the predilection of prostate cancer metastasis and growth in the bone environment. Prostate　39：246-261，1999

31) Nomura T, Huang WC, Wu D, et al:Induction of epithelial to mesenchymal transition (EMT) in human renal cell carcinoma cells enhanced their bone metastasis and lethality in mice. J Urol　177(Suppl)：151，2007

32) Moe SM, Hack BK, Cummings SA, et al:Role of IL-1 beta and prostaglandins in beta2-micrroglobulin-induced bone mineral dissolution. Kidney Int　47：587-591，1995

33) Balint E, Marshall CF, Sprague SM:Role of interleukin-6 in beta2-microglobulin-induced bone mineral dissolution. Kidney Int　57：1599-1607，2000

34) Menaa C, Esser E, Sprague SM:Beta2-microglobulin stimulates osteoclast formation. Kidney Int　73：1275-1281，2008

35) Lazennec G, Jorgensen C:Concise review:adult multipotent stromal cells and cancer:risk or benefit? Stem Cells　26：1387-1394，2008

36) Shi C, Mai Y, Zhu Y, et al:Spontaneous transformation of a clonal population of dermis-derived multipotent cells in culture. In Vitro Cell Dev Biol Anim　43：290-296，2007

37) Shi C, Zhu Y, Su Y, et al:Stem cells and their applications in skin-cell therapy. Trends Biotechnol　24：48-52，2006

38) Shi CM, Zhu Y, Huang WC, et al:Bi-directional interactions of bone marrow mesenchymal stem cells with human prostate cancer cells. J Urol　177：92，2007

39) Zhu Y, Shi C:Beta2-microglobulin, a novel factor for the expansion of mesenchymal stem cells. J Biotechnol　136：S177，2008

40) Shi C, Zhu Y, Chung LW, et al:PC4 is a novel oncogenic gene for mesenchymal stem cell transformation and mediates the reciprocal actions between mesenchymal stem cells and prostate cancer cells. Exp Hematol 36(Suppl)：82-83，2008

41) Sohara Y, Shimada H, Minkin C, et al:Bone marrow mesenchymal stem cells provide an alternate pathway of osteoclast activation and bone destruction by cancer cells. Cancer Res　65：1129-1135，2005

42) Mori M, Terui Y, Ikeda M, et al:Beta(2)-microglobulin identified as an apoptosis-inducing factor and its characterization. Blood　94：2744-2753，1999

43) Mori M, Terui Y, Tanaka M, et al:Antitumor effect of beta2-microglobulin in leukemic cell-bearing mice via apoptosis-inducing activity:activation of caspase-3 and nuclear factor-kappaB. Cancer Res　61：4414-4417，2001

44) Min R, Li Z, Epstein J, et al:Beta(2)-microglobulin as a negative growth regulator of myeloma cells. Br J Haematol　118：495-505，2002

45) Gordon J, Wu CH, Rastegar M, et al:Beta2-microglobulin induces caspase-dependent apoptosis in the CCRF-HSB-2 human leukemia cell line independently of the caspase-3, -8 and -9 pathways but through increased reactive oxygen species. Int J Cancer　103：316-327，2003

46) Ogretmen B, McCauley MD, Safa AR:Molecular mechanisms of loss of beta2-microglobulin expression in drug-resistant breast cancer sublines and its involvement in drug resistance. Biochemistry　37：11679-11691，1998

47) Wu CH, Rastegar M, Gordon J, et al:beta(2)-microglobulin induces apoptosis in HL-60 human leukemia cell line and its multidrug resistant variants overexpressing MRP1 but lacking Bax or overexpressing P-glycoprotein. Oncogene　20：7006-7020，2001

48) Freeman MR:Beta2 microglobulin:a surprising therapeutic target for prostate cancer and renal cell carcinoma. J Urol　178：10-11，2007

49) Yang J, Qian J, Wezeman M, et al:Targeting beta2-microglobulin for induction of tumor apoptosis in human hematological malignancies. Cancer Cell　10：295-307，2006

50) Nomura T, Huang WC, Seo S, et al:Targeting beta2-microglobulin mediated signaling as a novel therapeutic approach for human renal cell carcinoma. J Urol　178：292-300，2007

51) Lentzsch S:Death by rafting. Blood　110：2791-2792，2007

52) Huang WC, Havel JJ, Zhau HE, et al:Beta2-microglobulin signaling blockade inhibited androgen receptor axis and caused apoptosis in human prostate cancer cells. Clin Cancer Res　14：5341-5347，2008

53) Huang WC, Zhau HE, Chung LW:Androgen receptor survival signaling is blocked by anti-beta 2 microglobulin monoclonal antibody via a MAPK/lipogenic pathway in human prostate cancer cells. J Biol Chem　285：7947-7956，2010

54) Nagy ZA, Hubner B, Lohning C, et al:Fully human, HLA-DR-specific monoclonal antibodies efficiently induce programmed death of malignant lymphoid cells. Nat Med　8：801-807，2002