Multiple myeloma plasma cells show different chemokine receptor profiles at sites of disease activity

Trentin, Livio; Miorin, Marta; Facco, Monica; Baesso, Ilenia; Carraro, Samuela; Cabrelle, Anna; Maschio, Nilla; Bortoli, Michela; Binotto, Gianni; Piazza, Francesco; Adami, Fausto; Zambello, Renato; Agostini, Carlo; Semenzato, Gianpietro

doi:10.1111/j.1365-2141.2007.06686.x

Cited by 42 publications

(26 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3). Similar to previous reports (18,43), we found that CXCR4 is overexpressed in cancer cells, in respectively 35% and approximately 69% of samples from AML and multiple myeloma patients, with expression levels of CXCR4 on blast cells and of plasmocytes higher than those of CD34 þ cells in healthy bone marrow samples, suggesting that hz515H7 should preferentially kill the neoplastic cells while preserving normal hematopoietic cells. Indeed, our in vitro results show that hz515H7 does not decrease the viability of B cells, monocytes, T cells, or NK cells, whereas rituximab, used as a positive control for ADCC (44) and CDC (40), leads to CD20 þ B-cell depletion as described previously (44,45).…”

Section: Discussionsupporting

confidence: 90%

“…Tumor tissues from at least 23 different types of human cancers of epithelial, mesenchymal, and hematopoietic origin express CXCR4 (4). Indeed, this receptor has been found to be overexpressed in a large number of cancers, including solid tumors (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16), leukemia (17), multiple myeloma (18), and lymphomas (19). The CXCR4/SDF-1 axis is involved in cancer cell proliferation, in angiogenesis, and in antiapoptotic and metastases processes (20).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A New Anti-CXCR4 Antibody That Blocks the CXCR4/SDF-1 Axis and Mobilizes Effector Cells

Broussas

Boute

Akla

et al. 2016

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

The type IV C-X-C-motif chemokine receptor (CXCR4) is expressed in a large variety of human cancers, including hematologic malignancies, and this receptor and its ligand, stromal cell-derived factor-1 (SDF-1), play a crucial role in cancer progression. We generated a humanized immunoglobulin G1 mAb, hz515H7, which binds human CXCR4, efficiently competes for SDF-1 binding, and induces a conformational change in CXCR4 homodimers. Furthermore, it inhibits both CXCR4 receptor-mediated G-protein activation and b-arrestin-2 recruitment following CXCR4 activation. The binding of the hz515H7 antibody to CXCR4 inhibits the SDF-1-induced signaling pathway, resulting in reduced phosphorylation of downstream effectors, such as Akt, Erk1/2, p38, and GSK3b.

show abstract

Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

A New Anti-CXCR4 Antibody That Blocks the CXCR4/SDF-1 Axis and Mobilizes Effector Cells

Broussas

Boute

Akla

et al. 2016

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…response to CXCL12. (10) This has been confirmed in a number of myeloma cell lines that showed a chemotactic response to CXCL12. (11) Thus, it is likely that stromal cell expression of CXCL12 plays a significant role in the progressive colonization of the skeleton during multiple myeloma progression.…”

mentioning

confidence: 77%

CXCL12/CXCR4 Axis in Tissue Targeting and Bone Destruction in Cancer and Multiple Myeloma

Ooi

Dunstan

2009

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

The chemokine CXCL12 (also known as stromal cell derived factor ) and its receptor CXCR4 are strong candidates for regulating the mobilization and intravasation of primary cancer cells and their extravasation and formation of metastases in bone. CXCL12 has been reported to have chemo-attractive effects on both solid tumor-derived cancer cells (1) and multiple myeloma cells. (2,3) CXCL12 is produced in bone by bone marrow stromal cells, where it has a physiological role in establishing normal hematopoietic bone marrow colonization during development.(4) CXCL12 is a powerful chemoattractant for lymphocytes and monocytes. As such, CXCL12 can have the dual roles of attracting and retaining cells of these lineages in the bone environment.CXCL12 has also been implicated as a regulator of bone resorption through control of the migration of osteoclast precursors to resorption sites (5) and their maintenance within the bone environment.(6) CXCR4 is highly expressed in pre-osteoclasts and its expression decreases during the transition to mature osteoclasts.(7) CXCL12 has a role in attracting osteoclast precursors to areas of bone resorption through activation of the Akt signaling pathway (8) and may stimulate local proliferation and fusion of osteoclast precursors.(5) However, once osteoclast precursors are located in bone, RANKL seems to initiate all aspects of the resorption process (osteoclast differentiation, TRACP activity, cathepsin K activity, bone pit formation), and these effects seem independent of CXCL12. Multiple myeloma plasma cells and solid cancer cells, when metastasized to bone, are able to hijack the normal regulatory pathways to support their own growth. Extensive osteoclastic bone resorption, with the resultant bone destruction and associated morbidity, is characteristic of multiple myeloma. The paper of Diamond et al., (8) published in the Journal of Bone and Mineral Research this month, provides convincing evidence that, in multiple myeloma, plasma cell-expressed CXC12 plays a role in inducing the enhanced bone resorption characteristic of this disease.Diamond et al. (8) evaluated the effects of CXCL12 overexpression by the multiple myeloma cell line, RPMI-8226, in a murine intratibial model of multiple myeloma. They showed that increased expression of CXCL12 is associated with increased osteoclast numbers and bone loss. Conversely, dosing the mice with an inhibitor of CXCL12/ CXCR4 signaling (T140) can inhibit the increased bone resorption and the bone loss induced by the parental RPMI-8226 cells. To support the more general relevance of these observations to human multiple myeloma, the authors showed high CXCL12 expression in a primary cell isolate of CD138 + plasma cells from a multiple myeloma patient and found that CXCL12 blood levels correlated with levels of the bone resorption marker b-crosslaps in a group of normal, monoclonal gammopathy of undetermined significance (MGUS), and multiple myeloma patients. The authors suggested that CXCL12 could be increasing bone resorption by increasing the ...

show abstract

“…Several chemokines, including SDF-1, are produced by BM stromal cells and act as chemoattractants for MM cells. 13,14,[17][18][19]58,59 As a consequence, MM cells reside in the BM, where various cytokines produced in the microenvironment induce MM growth and survival. Hence, chemoattractants controlling homing of MM cells to the BM can be considered equally important for MM growth as the cytokines that provide the actual proliferative and antiapoptotic signals.…”

Section: Discussionmentioning

confidence: 99%

“…A similar pattern of Ral activation was observed after SDF-1 stimulation of Ramos and Namalwa B-cell lines as well as primary human tonsillar B cells ( Figure 1C). Similar to normal plasma cells, 6,11,12 SDF-1 is a potent chemoattractant for MM cell lines 13,14,[17][18][19] and the malignant plasma cells from MM patients, 13,14,19,58,59 as illustrated by the ability of SDF-1 to induce migration of the MM cell lines NCI-H929 and OPM-1, and of primary MM cells, in the Transwell migration assay ( Figure 2A). In addition, for MM cells (cell lines and primary patient material), SDF-1 is acting exclusively as a true chemotactic factor, that is, migration occurred only when SDF-1 was present in the lower but not the upper compartment of the Transwells ( Figure 2A).…”

Section: Sdf-1 Induces Migration and Ral Activation In B Cells And MMmentioning

confidence: 99%

The small GTPase Ral mediates SDF-1–induced migration of B cells and multiple myeloma cells

Gorter¹,

Reijmers²,

Beuling³

et al. 2008

Blood

View full text Add to dashboard Cite

IntroductionDepending on their stage of development or differentiation, B cells express specific chemokine receptors enabling them to respond to chemokines that control homing to the bone marrow (BM) and secondary lymphoid organs. [1][2][3] Here they are provided with signals crucial for progression through the consecutive stages of B-cell development and differentiation. The chemokine stromal cellderived factor-1 (SDF-1, also known as CXCL12) plays an important role in lymphocyte trafficking. SDF-1, originally identified as a growth-stimulatory factor for pre-B cells, 4 is constitutively expressed by BM stromal cells. [5][6][7] Its cognate receptor, the 7-transmembrane G-protein-coupled receptor CXCR4, is broadly expressed by cells of the immune system and mediates SDF-1-induced migration of hematopoietic progenitors and lymphocytes. [1][2][3]8,9 In the B-cell lineage, CXCR4 is prominently expressed by pre-B cells and controls localization in cellular niches in the BM obligatory for B-cell development. 3,8 Furthermore, CXCR4 expression by mature B cells is required for proper germinal center organization, which is essential for antigen-specific B-cell differentiation. 10 In addition, SDF-1 controls plasma cell migration, 6 and plasma cells require CXCR4 expression to localize in the BM compartment. 11,12 Multiple myeloma (MM), an incurable hematologic malignancy with a median survival of 3 to 4 years, is characterized by the expansion of malignant plasma cells in the BM. These tumor cells also express CXCR4, 13 and SDF-1 controls their ␣4␤1-mediated adhesion to VCAM-1, fibronectin, and endothelial cells, as well as their transendothelial migration and homing/retention in the BM tumor microenvironment. [13][14][15][16][17][18][19] MM cells are critically dependent on the BM microenvironment, where cytokines produced by BM stromal cells provide them with proliferation and survival signals required for their expansion. 16 Thus, by controlling homing and retention of MM cells in the BM, SDF-1 plays an important role in the pathogenesis of MM.The important role of chemokine-induced migration in B-cell development and differentiation, as well as in the pathogenesis of MM, prompted us to explore the underlying signaling pathways. Recently, we have established an important role for Bruton tyrosine kinase (Btk) and phospholipase C-␥2 (PLC␥2) in chemokineinduced integrin-mediated migration and homing of B cells. 20 Importantly, however, Btk is not expressed in plasma cells and MM cells. [21][22][23] Several members of the Ras superfamily of small GTPases have also been implicated in chemokine-controlled B-cell migration. [24][25][26][27] This includes members of the Rho family 24,25 and members of the Ras family, such as Ras and Rap1. 26,27 Ral, another member of the Ras family of small GTPases, has been shown to mediate a wide variety of cellular responses, including regulation of cytoskeletal rearrangements and cell motility. 28 Methods MaterialsMonoclonal antibodies used were mouse anti-RalA (IgG2a), anti-Rap1 (IgG1)...

show abstract

Multiple myeloma plasma cells show different chemokine receptor profiles at sites of disease activity

Cited by 42 publications

References 29 publications

A New Anti-CXCR4 Antibody That Blocks the CXCR4/SDF-1 Axis and Mobilizes Effector Cells

A New Anti-CXCR4 Antibody That Blocks the CXCR4/SDF-1 Axis and Mobilizes Effector Cells

CXCL12/CXCR4 Axis in Tissue Targeting and Bone Destruction in Cancer and Multiple Myeloma

The small GTPase Ral mediates SDF-1–induced migration of B cells and multiple myeloma cells

Contact Info

Product

Resources

About