缺氧在多发性骨髓瘤发病机制中的作用及治疗策略

doi:10.3760/cma.j.issn.1673422X.2016.07.019

摘要/Abstract

摘要： 缺氧环境在多发性骨髓瘤发病机制中起着重要作用，如促进血管生成、增加骨骼破坏、增强上皮间充质转化和药物抵抗等。目前有多种靶向多发性骨髓瘤缺氧环境的治疗策略，如缺氧激活前体药物和分子靶向抑制剂等。针对缺氧状态的多发性骨髓瘤治疗策略是未来极具吸引力的治疗靶点之一。

关键词: 缺氧诱导因子1, 多发性骨髓瘤, 肿瘤, 代谢

Abstract: ypoxia environment plays an important role in the pathogenesis of multiple myeloma such as stimulating angiogenesis, increasing bone destructiong, epithelialmesenchymal transition and drug resistance. Thus, there are many therapeutic strategies targeting the hypoxic environment of multiple myeloma, such as hypoxiaactivated prodrug and molecular targeting inhibitors. Targeting the hypoxic environment is a promising therapy for multiple myeloma in the future.

Key words: Hypoxiainducible factor 1, Multiple myeloma, Neoplasms, Metabolism

王维媛, 郭冬梅, 韩天洁, 滕清良. 缺氧在多发性骨髓瘤发病机制中的作用及治疗策略[J]. 国际肿瘤学杂志, 2016, 43(7): 552-554.

WANG Wei-Yuan, GUO Dong-Mei, HAN Tian-Jie, TENG Qing-Liang. Role and treatment strategy of hypoxia in the pathogenesis of multiple myeloma[J]. Journal of International Oncology, 2016, 43(7): 552-554.

参考文献

［1］ Keith B, Johnson RS, Simon MC. HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression［J］. Nat Rev Cancer, 2012, 12(1): 922. DOI: 10.1038/nrc3183. ［2］ Tndevold E, Eriksen J, Jansen E. Observations on long bone medullary pressure in relation to mean arterial blood pressure in the anaesthetized dog［J］. Acta Orthop Scand, 1979, 50(5): 527531. ［3］ Watanabe Y, Terashima Y, Takenaka N, et al. Prediction of avascular necrosis of the femoral head by measuring intramedullary oxygen tension after femoral neck fracture［J］. J Orthop Trauma, 2007, 21(7): 456461. DOI: 10.1097/BOT.0b013e318126bb56. ［4］ Colla S, Storti P, Donofrio G, et al. Low bone marrow oxygen tension and hypoxiainducible factor1α overexpression characterize patients with multiple myeloma: role on the transcriptional and proangiogenic profiles of CD138(+) cells［J］. Leukemia, 2010, 24(11): 19671970. DOI: 10.1038/leu.2010.193. ［5］李斑斑, 郭冬梅, 滕清良. 乏氧及Notch1在多发性骨髓瘤中作用的研究进展［J］. 国际肿瘤学杂志, 2013, 40(7): 542546. DOI: 10.3760/cma.j.issn.1673422x.2013.07.021 ［6］ Zhang P, Yao Q, Lu L, et al. Hypoxiainducible factor 3 is an oxygendependent transcription activator and regulates a distinct transcriptional response to hypoxia［J］. Cell Rep, 2014, 6(6): 11101121. DOI: 10.1016/j.celrep.2014.02.011. ［7］ Koh MY, Powis G. Passing the baton: the HIF Switch［J］. Trends Biochem Sci, 2012, 37(9): 364372. DOI: 10.1016/j.tibs.2012.06.004. ［8］ Hu J, Handisides DR, Van Valckenborgh E, et al. Targeting the multiple myeloma hypoxic niche with TH302, a hypoxiaactivated prodrug［J］. Blood, 2010, 116(9): 15241527. DOI: 10.1182/blood201002269126. ［9］ Giatromanolaki A, Bai M, Margaritis D, et al. Hypoxia and activated VEGF/receptor pathway in multiple myeloma［J］. Anticancer Res, 2010, 30(7): 28312836. ［10］ Borsi E, Terragna C, Brioli A, et al. Therapeutic targeting of hypoxia and hypoxiainducible factor 1 alpha in multiple myeloma［J］. Transl Res, 2015, 165(6): 641650. DOI: 10.1016/j.trsl.2014.12.001. ［11］ Martin SK, Diamond P, Gronthos S, et al. The emerging role of hypoxia, HIF1 and HIF2 in multiple myeloma［J］. Leukemia, 2011, 25(10): 15331542. DOI: 10.1038/leu.2011.122. ［12］ Borsi E, Perrone G, Terragna C, et al. Hypoxia inducible factor1 alpha as a therapeutic target in multiple myeloma［J］. Oncotarget, 2014, 5(7): 17791792. DOI: 10.18632/oncotarget.1736. ［13］ Umezu T, Tadokoro H, Azuma K, et al. Exosomal miR135b shed from hypoxic multiple myeloma cells enhances angiogenesis by targeting factorinhibiting HIF1［J］. Blood, 2014, 124(25): 37483757. DOI: 10.1182/blood201405576116. ［14］ Martin SK, Diamond P, Williams SA, et al. Hypoxiainducible factor2 is a novel regulator of aberrant CXCL12 expression in multiple myeloma plasma cells［J］. Haematologica, 2010, 95(5): 776784. DOI: 10.3324/haematol.2009.015628. ［15］ Storti P, Bolzoni M, Donofrio G, et al. Hypoxiainducible factor (HIF)1α suppression in myeloma cells blocks tumoral growth in vivo inhibiting angiogenesis and bone destruction［J］. Leukemia, 2013, 27(8): 16971706. DOI: 10.1038/leu.2013.24. ［16］ Maiso P, Huynh D, Moschetta M, et al. Metabolic signature identifies novel targets for drug resistance in multiple myeloma［J］. Cancer Res, 2015, 75(10): 20712082. DOI: 10.1158/00085472.CAN143400. ［17］ Bianchi G, Ghobrial IM. Molecular mechanisms of effectiveness of novel therapies in multiple myeloma［J］. Leuk Lymphoma, 2013, 54(2): 229241. DOI: 10.3109/10428194.2012.706287. ［18］ Ria R, Catacchio I, Berardi S, et al. HIF1α of bone marrow endothelial cells implies relapse and drug resistance in patients with multiple myeloma and may act as a therapeutic target［J］. Clin Cancer Res, 2014, 20(4): 847858. DOI: 10.1158/10780432.CCR131950. ［19］ Azab AK, Hu J, Quang P, et al. Hypoxia promotes dissemination of multiple myeloma through acquisition of epithelial to mesenchymal transitionlike features［J］. Blood, 2012, 119(24): 57825794. DOI: 10.1182/blood201109380410. ［20］ Rohwer N, Cramer T. Hypoxiamediated drug resistance: novel insights on the functional interaction of HIFs and cell death pathways［J］. Drug Resist Updat, 2011, 14(3): 191201. DOI: 10.1016/j.drup.2011.03.001. ［21］ Meng F, Evans JW, Bhupathi D, et al. Molecular and cellular pharmacology of the hypoxiaactivated prodrug TH302［J］. Mol Cancer Ther, 2012, 11(3): 740751. DOI: 10.1158/15357163.MCT110634. ［22］ Doedens AL, Stockmann C, Rubinstein MP, et al. Macrophage expression of hypoxiainducible factor1 alpha suppresses Tcell function and promotes tumor progression［J］. Cancer Res, 2010, 70(19): 74657475. DOI: 10.1158/00085472.CAN101439. ［23］ Hu J, Van Valckenborgh E, Xu D, et al. Synergistic induction of apoptosis in multiple myeloma cells by bortezomib and hypoxiaactivated prodrug TH302, in vivo and in vitro［J］. Mol Cancer Ther, 2013, 12(9): 17631773. DOI: 10.1158/15357163.MCT130123. ［24］ Raimondi L, Amodio N, Di Martino MT, et al. Targeting of multiple myelomarelated angiogenesis by miR199a5p mimics: in vitro and in vivo antitumor activity［J］. Oncotarget, 2014, 5(10): 30393054. DOI: 10.18632/oncotarget.1747. ［25］ Borsi E, Perrone G, Terragna C, et al. HIF1α inhibition blocks the cross talk between multiple myeloma plasma cells and tumor microenvironment［J］. Exp Cell Res, 2014, 328(2): 444455. DOI: 10.1016/j.yexcr.2014.09.018.

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