Marchica Valentina, Toscani Denise, Corcione Anna, Bolzoni Marina, Storti Paola, Vescovini Rosanna, Ferretti Elisa, Dalla Palma Benedetta, Vicario Emanuela, Accardi Fabrizio, Mancini Cristina, Martella Eugenia, Ribatti Domenico, Vacca Angelo, Pistoia Vito, Giuliani Nicola
Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy.
Center for Autoinflammatory Diseases and Immunedeficiencies, IRCCS "Istituto Giannina Gaslini", 16147 Genoa, Italy.
Cancers (Basel). 2019 Mar 6;11(3):321. doi: 10.3390/cancers11030321.
C-X3-C motif chemokine ligand 1 (CX3CL1)/fractalkine is a chemokine released after cleavage by two metalloproteases, ADAM metallopeptidase domain 10 (ADAM10) and ADAM metallopeptidase domain 17 (ADAM17), involved in inflammation and angiogenesis in the cancer microenvironment. The role of the CX3CL1/ C-X3-C motif chemokine receptor 1(CX3CR1) axis in the multiple myeloma (MM) microenvironment is still unknown. Firstly, we analyzed bone marrow (BM) plasma levels of CX3CL1 in 111 patients with plasma cell disorders including 70 with active MM, 25 with smoldering myeloma (SMM), and 16 with monoclonal gammopathy of undetermined significance (MGUS). We found that BM CX3CL1 levels were significantly increased in MM patients compared to SMM and MGUS and correlated with BM microvessel density. Secondly, we explored the source of CX3CL1 in MM and BM microenvironment cells. Primary CD138⁺ cells did not express CXC3L1 but up-regulated its production by endothelial cells (ECs) through the involvement of tumor necrosis factor alpha (TNFα). Lastly, we demonstrated the presence of CX3CR1 on BM CD14⁺CD16⁺ monocytes of MM patients and on ECs, but not on MM cells. The role of CX3CL1 in MM-induced angiogenesis was finally demonstrated in both in vivo chick embryo chorioallantoic membrane and in vitro angiogenesis assays. Our data indicate that CX3CL1, present at a high level in the BM of MM patients, is a new player of the MM microenvironment involved in MM-induced angiogenesis.
C-X3-C基序趋化因子配体1（CX3CL1）/ fractalkine是一种趋化因子，由两种金属蛋白酶（ADAM金属肽酶结构域10（ADAM10）和ADAM金属肽酶结构域17（ADAM17））切割后释放，参与癌症微环境中的炎症和血管生成。CX3CL1/C-X3-C基序趋化因子受体1（CX3CR1）轴在多发性骨髓瘤（MM）微环境中的作用仍不清楚。首先，我们分析了111例浆细胞疾病患者骨髓（BM）中CX3CL1的血浆水平，其中包括70例活动性MM患者、25例冒烟型骨髓瘤（SMM）患者和16例意义未明的单克隆丙种球蛋白病（MGUS）患者。我们发现，与SMM和MGUS患者相比，MM患者的BM CX3CL1水平显著升高，且与BM微血管密度相关。其次，我们探索了MM和BM微环境细胞中CX3CL1的来源。原代CD138⁺细胞不表达CXC3L1，但通过肿瘤坏死因子α（TNFα）的参与，上调了内皮细胞（ECs）对其的产生。最后，我们证实MM患者的BM CD14⁺CD16⁺单核细胞和ECs上存在CX3CR1，但MM细胞上不存在。最终，在体内鸡胚绒毛尿囊膜和体外血管生成试验中均证实了CX3CL1在MM诱导的血管生成中的作用。我们的数据表明，MM患者BM中高水平存在的CX3CL1是MM微环境中参与MM诱导血管生成的一个新因子。
