Bone Marrow CX3CL1/Fractalkine is a New Player of the Pro-Angiogenic Microenvironment in Multiple Myeloma Patients

Valentina Marchica, Denise Toscani, Anna Corcione, Marina Bolzoni, Paola Storti, Rosanna Vescovini, Elisa Ferretti, Benedetta Dalla Palma, Emanuela Vicario, Fabrizio Accardi, Cristina Mancini, Eugenia Martella, Domenico Ribatti, Angelo Vacca, Vito Pistoia, Nicola Giuliani

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
JournalCancers
Volume11
Issue number3
DOIs
Publication statusPublished - Mar 6 2019

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Chemokine CX3CL1
Multiple Myeloma
Bone Marrow
Metalloproteases
Monoclonal Gammopathy of Undetermined Significance
CCR Receptors
C Chemokines
Endothelial Cells
Chorioallantoic Membrane
Tumor Microenvironment
Chemokine Receptors
Chick Embryo
Microvessels
Plasma Cells
Chemokines
Bone Marrow Cells
Monocytes
Tumor Necrosis Factor-alpha

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Bone Marrow CX3CL1/Fractalkine is a New Player of the Pro-Angiogenic Microenvironment in Multiple Myeloma Patients. / 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.

In: Cancers, Vol. 11, No. 3, 06.03.2019.

Research output: Contribution to journalArticle

Marchica, V, Toscani, D, Corcione, A, Bolzoni, M, Storti, P, Vescovini, R, Ferretti, E, Dalla Palma, B, Vicario, E, Accardi, F, Mancini, C, Martella, E, Ribatti, D, Vacca, A, Pistoia, V & Giuliani, N 2019, 'Bone Marrow CX3CL1/Fractalkine is a New Player of the Pro-Angiogenic Microenvironment in Multiple Myeloma Patients', Cancers, vol. 11, no. 3. https://doi.org/10.3390/cancers11030321
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. / Bone Marrow CX3CL1/Fractalkine is a New Player of the Pro-Angiogenic Microenvironment in Multiple Myeloma Patients. In: Cancers. 2019 ; Vol. 11, No. 3.
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AU - Marchica, Valentina

AU - Toscani, Denise

AU - Corcione, Anna

AU - Bolzoni, Marina

AU - Storti, Paola

AU - Vescovini, Rosanna

AU - Ferretti, Elisa

AU - Dalla Palma, Benedetta

AU - Vicario, Emanuela

AU - Accardi, Fabrizio

AU - Mancini, Cristina

AU - Martella, Eugenia

AU - Ribatti, Domenico

AU - Vacca, Angelo

AU - Pistoia, Vito

AU - Giuliani, Nicola

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N2 - 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.

AB - 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.

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