多发性骨髓瘤髓外病变发病机制的研究进展

摘要/Abstract

摘要：

多发性骨髓瘤（MM）病灶多局限于骨髓内，初诊或诊治过程中可出现远离骨髓或临近软组织的恶性浆细胞浸润即多发性骨髓瘤髓外病变（MM-EMD）。MM-EMD具有高度侵袭性，其临床行为不同于骨髓限制性骨髓瘤，该类患者预后差。但其发病机制尚未阐明，目前研究认为，MM细胞归巢受阻、侵袭力增强、细胞外基质降解及血管生成能力增强等过程可能参与MM-EMD发生。肿瘤遗传学异常和骨髓微环境改变等在上述发病过程中发挥重要作用。

关键词:多发性骨髓瘤,肿瘤转移,细胞因子类,肿瘤侵润

Abstract:

Multiple myeloma（MM） lesions are mostly localized in the marrow. Extramedullary disease in multiple myeloma （MM-EMD） is defined as malignant plasma cell infiltration away from the bone marrow or adjacent soft tissue， may occur at the initial diagnosis or during the consultation. MM-EMD may be found at initial diagnosis or during the treatment. MM-EMD has high invasiveness and poor prognosis， with clinical behavior distinct from marrow-restricted myeloma. However， its pathogenesis has not been elucidated. In general， the obstructed homing of myeloma cells， enhanced invasiveness， the degradation of extracellular matrix， and increased angiogenesis capacity may be involved in the occurrence of MM-EMD. Tumor genetic abnormalities and changes in the bone marrow microenvironment play important roles in the above pathogenesis.

Key words:Multiple myeloma,Neoplasm metastasis,Cytokines,Neoplasm invasiveness

赵建昊, 段衍超. 多发性骨髓瘤髓外病变发病机制的研究进展[J]. 国际肿瘤学杂志, 2023, 50(1): 55-59.

Zhao Jianhao, Duan Yanchao. Research progress in the pathogenesis of extramedullary disease in multiple myeloma[J]. Journal of International Oncology, 2023, 50(1): 55-59.

参考文献37

[1]	庄俊玲. 多发性骨髓瘤髓外病变诊治进展[J]. 临床血液学杂志, 2019, 32(7): 499-503. DOI: 10.13201/j.issn.1004-2806.2019.07.003. doi:10.13201/j.issn.1004-2806.2019.07.003
[2]	Moser-Katz T, Joseph NS, Dhodapkar MV, et al. Game of bones: how myeloma manipulates its microenvironment[J]. Front Oncol, 2021, 10: 625199. DOI: 10.3389/fonc.2020.625199. doi:10.3389/fonc.2020.625199
[3]	Klimienė I, Radzevičius M, Matuzevičienė R, et al. Adhesion mo-lecule immunophenotype of bone marrow multiple myeloma plasma cells impacts the presence of malignant circulating plasma cells in peripheral blood[J]. Int J Lab Hematol, 2021, 43(3): 403-408. DOI: 10.1111/ijlh.13387. doi:10.1111/ijlh.13387pmid:33185981
[4]	Katz BZ. Adhesion molecules—the lifelines of multiple myeloma cells[J]. Semin Cancer Biol, 2010, 20(3): 186-195. DOI: 10.1016/j.semcancer.2010.04.003. doi:10.1016/j.semcancer.2010.04.003
[5]	Hathi D, Chanswangphuwana C, Cho N, et al. Ablation of VLA4 in multiple myeloma cells redirects tumor spread and prolongs survival[J]. Sci Rep, 2022, 12(1): 30. DOI: 10.1038/s41598-021-03748-0. doi:10.1038/s41598-021-03748-0pmid:34996933
[6]	Li J, Pan Q, Rowan PD, et al. Heparanase promotes myeloma progression by inducing mesenchymal features and motility of myeloma cells[J]. Oncotarget, 2016, 7(10): 11299-11309. DOI: 10.18632/oncotarget.7170. doi:10.18632/oncotarget.7170pmid:26849235
[7]	Jung O, Trapp-Stamborski V, Purushothaman A, et al. Heparanase-induced shedding of syndecan-1/CD138 in myeloma and endothelial cells activates VEGFR2 and an invasive phenotype: prevention by novel synstatins[J]. Oncogenesis, 2016, 5(2): e202. DOI: 10.1038/oncsis.2016.5. doi:10.1038/oncsis.2016.5
[8]	Akhmetzyanova I, McCarron MJ, Parekh S, et al. Dynamic CD138 surface expression regulates switch between myeloma growth and dissemination[J]. Leukemia, 2020, 34(1): 245-256. DOI: 10.1038/s41375-019-0519-4. doi:10.1038/s41375-019-0519-4pmid:31439945
[9]	Harshman SW, Canella A, Ciarlariello PD, et al. Proteomic characterization of circulating extracellular vesicles identifies novel serum myeloma associated markers[J]. J Proteomics, 2016, 136: 89-98. DOI: 10.1016/j.jprot.2015.12.016. doi:10.1016/j.jprot.2015.12.016pmid:26775013
[10]	Janjetovic S, Lohneis P, Nogai A, et al. Clinical and biological characteristics of medullary and extramedullary plasma cell dyscrasias[J]. Biology (Basel), 2021, 10(7): 629. DOI: 10.3390/biology 10070629. doi:10.3390/biology 10070629
[11]	Pan Y, Wang H, Tao Q, et al. Absence of both CD56 and CD117 expression on malignant plasma cells is related with a poor prognosis in patients with newly diagnosed multiple myeloma[J]. Leuk Res, 2016, 40: 77-82. DOI: 10.1016/j.leukres.2015.11.003. doi:10.1016/j.leukres.2015.11.003
[12]	Geng S, Wang J, Zhang X, et al. Single-cell RNA sequencing reveals chemokine self-feeding of myeloma cells promotes extramedullary metastasis[J]. FEBS Lett, 2020, 594(3): 452-465. DOI: 10.1002/1873-3468.13623. doi:10.1002/1873-3468.13623pmid:31561267
[13]	Vandyke K, Zeissig MN, Hewett DR, et al. HIF-2α promotes dissemination of plasma cells in multiple myeloma by regulating CXCL12/CXCR4 and CCR1[J]. Cancer Res, 2017, 77(20): 5452-5463. DOI: 10.1158/0008-5472.CAN-17-0115. doi:10.1158/0008-5472.CAN-17-0115pmid:28855206
[14]	Zeissig MN, Hewett DR, Panagopoulos V, et al. Expression of the chemokine receptor CCR1 promotes the dissemination of multiple myeloma plasma cells in vivo[J]. Haematologica, 2021, 106(12): 3176-3187. DOI: 10.3324/haematol.2020.253526. doi:10.3324/haematol.2020.253526
[15]	Peng Y, Li F, Zhang P, et al. IGF-1 promotes multiple myeloma progression through PI3K/Akt-mediated epithelial-mesenchymal transition[J]. Life Sci, 2020, 249: 117503. DOI: 10.1016/j.lfs.2020.117503. doi:10.1016/j.lfs.2020.117503
[16]	Akhmetzyanova I, Aaron T, Galbo P, et al. Tissue-resident macrophages promote early dissemination of multiple myeloma via IL-6 and TNFα[J]. Blood Adv, 2021, 5(18): 3592-3608. DOI: 10.1182/bloodadvances.2021005327. doi:10.1182/bloodadvances.2021005327pmid:34550328
[17]	Xu J, Yu N, Zhao P, et al. Intratumor heterogeneity of MIF expression correlates with extramedullary involvement of multiple myeloma[J]. Front Oncol, 2021, 11: 694331. DOI: 10.3389/fonc.2021.694331. doi:10.3389/fonc.2021.694331
[18]	Yang Q, Shen X, Su Z, et al. Emerging roles of noncoding RNAs in multiple myeloma: a review[J]. J Cell Physiol, 2019, 234(6): 7957-7969. DOI: 10.1002/jcp.27547. doi:10.1002/jcp.27547pmid:30370557
[19]	Chen H, Zhao Y, Zhang J, et al. Promoting effects of miR-135b on human multiple myeloma cells via regulation of the Wnt/ β-catenin/Versican signaling pathway[J]. Cytokine, 2021, 142: 155495. DOI: 10.1016/j.cyto.2021.155495. doi:10.1016/j.cyto.2021.155495
[20]	Sewastianik T, Straubhaar JR, Zhao JJ, et al. MiR-15a/16-1 deletion in activated B cells promotes plasma cell and mature B-cell neoplasms[J]. Blood, 2021, 137(14): 1905-1919. DOI: 10.1182/blood.2020009088. doi:10.1182/blood.2020009088
[21]	Xu A, Zhang J, Zuo L, et al. FTO promotes multiple myeloma progression by posttranscriptional activation of HSF1 in an m⁶A-YTHDF2-dependent manner[J]. Mol Ther, 2022, 30(3): 1104-1118. DOI: 10.1016/j.ymthe.2021.12.012. doi:10.1016/j.ymthe.2021.12.012
[22]	Pang M, Li C, Zheng D, et al. S1PR2 knockdown promotes migration and invasion in multiple myeloma cells via NF-κB activation[J]. Cancer Manag Res, 2020, 12: 7857-7865. DOI: 10.2147/CMAR.S237330. doi:10.2147/CMAR.S237330pmid:32922084
[23]	孙睿婕, 单宁宁. 复发难治性多发性骨髓瘤的免疫靶向治疗及存在的问题[J]. 国际肿瘤学杂志, 2021, 48(6): 381-384. DOI: 10.3760/cma.j.cn371439-20200622-00074. doi:10.3760/cma.j.cn371439-20200622-00074
[24]	Mina R, D'Agostino M, Cerrato C, et al. Plasma cell leukemia: update on biology and therapy[J]. Leuk Lymphoma, 2017, 58(7): 1538-1547. DOI: 10.1080/10428194.2016.1250263. doi:10.1080/10428194.2016.1250263
[25]	Besse L, Sedlarikova L, Greslikova H, et al. Cytogenetics in multiple myeloma patients progressing into extramedullary disease[J]. Eur J Haematol, 2016, 97(1): 93-100. DOI: 10.1111/ejh.12688. doi:10.1111/ejh.12688pmid:26432667
[26]	Cheong CM, Mrozik KM, Hewett DR, et al. Twist-1 is upregulated by NSD2 and contributes to tumour dissemination and an epithelial-mesenchymal transition-like gene expression signature in t(4;14)-positive multiple myeloma[J]. Cancer Lett, 2020, 475: 99-108. DOI: 10.1016/j.canlet.2020.01.040. doi:S0304-3835(20)30054-9pmid:32014459
[27]	Zeissig MN, Zannettino ACW, Vandyke K. Tumour dissemination in multiple myeloma disease progression and relapse: a potential therapeutic target in high-risk myeloma[J]. Cancers (Basel), 2020, 12(12): 3643. DOI: 10.3390/cancers12123643. doi:10.3390/cancers12123643
[28]	Kriegova E, Fillerova R, Minarik J, et al. Whole-genome optical mapping of bone-marrow myeloma cells reveals association of extramedullary multiple myeloma with chromosome 1 abnormalities[J]. Sci Rep, 2021, 11(1): 14671. DOI: 10.1038/s41598-021-93835-z. doi:10.1038/s41598-021-93835-zpmid:34282158
[29]	Farre L, Sanz G, Ruiz-Xivillé N, et al. Extramedullary multiple myeloma patient-derived orthotopic xenograft with a highly altered genome: combined molecular and therapeutic studies[J]. Dis Model Mech, 2021, 14(7): dmm048223. DOI: 10.1242/dmm.048223. doi:10.1242/dmm.048223
[30]	Yue Z, Zhou Y, Zhao P, et al. p53 deletion promotes myeloma cells invasion by upregulating miR19a/CXCR5[J]. Leuk Res, 2017, 60: 115-122. DOI: 10.1016/j.leukres.2017.07.003. doi:10.1016/j.leukres.2017.07.003
[31]	Liu Y, Jelloul F, Zhang Y, et al. Genetic basis of extramedullary plasmablastic transformation of multiple myeloma[J]. Am J Surg Pathol, 2020, 44(6): 838-848. DOI: 10.1097/PAS.0000000000001459. doi:10.1097/PAS.0000000000001459pmid:32118627
[32]	Wen Z, Rajagopalan A, Flietner ED, et al. Expression of Nras^Q61Rand MYC transgene in germinal center B cells induces a highly malignant multiple myeloma in mice[J]. Blood, 2021, 137(1): 61-74. DOI: 10.1182/blood.2020007156. doi:10.1182/blood.2020007156
[33]	Cui YS, Song YP, Fang BJ. The role of long non-coding RNAs in multiple myeloma[J]. Eur J Haematol, 2019, 103(1): 3-9. DOI: 10.1111/ejh.13237. doi:10.1111/ejh.13237
[34]	Xu K, Hu X, Sun L, et al. MicroRNA-532 exerts oncogenic functions in t(4;14) multiple myeloma by targeting CAMK2N1[J]. Hum Cell, 2019, 32(4): 529-539. DOI: 10.1007/s13577-019-00276-y. doi:10.1007/s13577-019-00276-ypmid:31452083
[35]	Berenstein R, Nogai A, Waechter M, et al. Multiple myeloma cells modify VEGF/IL-6 levels and osteogenic potential of bone marrow stromal cells via Notch/miR-223[J]. Mol Carcinog, 2016, 55(12): 1927-1939. DOI: 10.1002/mc.22440. doi:10.1002/mc.22440
[36]	Handa H, Kuroda Y, Kimura K, et al. Long non-coding RNA MALAT1 is an inducible stress response gene associated with extramedullary spread and poor prognosis of multiple myeloma[J]. Br J Haematol, 2017, 179(3): 449-460. DOI: 10.1111/bjh.14882. doi:10.1111/bjh.14882
[37]	Liu N, Feng S, Li H, et al. Long non-coding RNA MALAT1 facilitates the tumorigenesis, invasion and glycolysis of multiple myeloma via miR-1271-5p/SOX13 axis[J]. J Cancer Res Clin Oncol, 2020, 146(2): 367-379. DOI: 10.1007/s00432-020-03127-8. doi:10.1007/s00432-020-03127-8pmid:31953613