Cancer Letters

Cancer Letters

Volume 207, Issue 2, April 2004, Pages 221-227
Cancer Letters

CXCR3-binding chemokines in multiple myeloma

https://doi.org/10.1016/j.canlet.2003.10.036Get rights and content

Abstract

The CXC chemokines I-TAC, Mig and IP10 and their receptor CXCR3 are associated with advanced-stage tumor and contribute to tumor progression, invasion and metastasis. The current study was designed to determine the expression of CXCR3 on four multiple myeloma (MM) cell lines and bone marrow plasma cells from 20 MM patients. Cell functions related to progression, such as tyrosine-kinase phosphorylation, proliferation, chemotaxis and matrix metalloproteinase-2 (MMP-2), and MMP-9 secretion were also investigated following the CXCR3/chemokine interaction. fluorescence activated cell sorting analysis revealed that three cell lines (75%) and 18 patients (90%) express the CXCR3 molecule. We demonstrated both in cell lines and fresh plasma cells that I-TAC, Mig and IP10 are able to induce tyrosine-kinase phosphorylation and chemotaxis, but not proliferation, and to increase the MMP-2 and MMP-9 gelatinolytic activity in the cell conditioned medium. Data suggest that CXCR3/chemokine loop may be important for progression of MM in terms of intramedullary and extramedullary dissemination.

Introduction

Chemokines are small secretory proteins that are produced by leukocytes, epithelial, endothelial and stromal cells as they exert a chemotactic activity, mainly on leukocytes. They are grouped into two classes depending on the arrangement of the first two cysteines, namely separated by one amino acid (CXC chemokines) or adjacent (CC chemokines). Their biological effects are mediated by interaction with specific receptors (R), that are referred to as CXC-R and CC-R, respectively [1].

CXCR3 is expressed by activated T cells, i.e. IL-2-cultured T cells [2]. It is also expressed by tumor T cells of angioimmunoblastic, angiocentric, histiocyte-rich and unspecified T-cell lymphoma [3], and tumor B cells of chronic lymphocytic leukemia (CLL) and small cell lymphoma, but absent on normal B cells [4], [5]. It and its transcripts were not detected in monocytes, macrophages, granulocytes, and again normal B cells [4], [5]. It is specific for the CXC chemokines I-TAC (Interferon-inducible T-cell Alpha Chemoattractant)/CXCL11, Mig (Monocyte/macrophage-activating IFNγ-inducible protein)/CXCL9 and IP10 (IFNγ-inducible 10 kDa protein)/CXCL10 which are mainly produced by monocytes and macrophages [1], [2]. The CXCR3/CXC chemokine loop acts in inflammatory processes, mainly in delayed-type hypersensitivity responses, where the chemokines (the so called ‘homing chemokines’) mediate recruitment and homing of lymphocytes. The CXCR3/Mig loop may be important for the autocrine growth of CLL [5], and the CXCR3/chemokines loop facilitates progression and spreading of human melanoma and ovary carcinoma [6].

Here, we show that CXCR3 is expressed by plasma cells of multiple myeloma (MM), and activates cell functions (tyrosine-kinase phosphorylation, chemotaxis and matrix metalloproteinase [MMP] secretion) involved in the progression and spreading of disease.

Section snippets

Patients and methods

The MM cell lines U266, DP-6, RPMI-8226 and K620 were obtained from the American Type Culture Collection (Rockville, MD, USA). Fresh bone marrow plasma cells were isolated from aspirates of 20 patients with newly diagnosed, staged II–III (Durie and Salmon) MM by Ficoll-Hypaque centrifugation and cell enrichment with CD38 immunoselection [7]. The study was approved by the local ethics committee and all patients gave their informed consent.

CXCR3 expression was determined in triplicate by

Results

Fig. 1 shows CXCR3 expression by the MM cell lines. Expression (M±1SD of three separate experiments) was found on 95%±4 U266 cells, 60% ±11 DP-6 cells, 82% ±5 RPMI-8226 cells and 15%±7 K620 cells. The expression was also studied on bone marrow plasma cells of 20 patients (Fig. 2): two patients (Pt3 and Pt11) (10%) expressed CXCR3 only marginally; 11 patients (55%) expressed CXCR3 in 20–50% plasma cells; seven patients (35%) expressed CXCR3 in more than 50% plasma cells. To sum up, 90% of

Discussion

Here we show that CXCR3 is expressed by several MM cell lines and fresh bone marrow plasma cells of newly-diagnosed MM. Similar results have been obtained with other MM cell lines by Moller et al. [11]. Expression has so far been described on activated T cells [2] but not normal peripheral B cells [4], [5], [12]. Like plasma cells, CXCR3 was also found on malignant B cells of CLL [4].

Its ligands I-TAC, Mig and IP10 induce chemotaxis of cells in the sites of chronic inflammation [13], and play

Acknowledgements

This study was supported in part by the Associazione Italiana per la Ricerca sul Cancro (AIRC), Milan, and Ministry for Education, the Universities and Research (MIUR, Molecular Engineering—CO3 funds, and Interuniversity Funds for Basic Research [FIRB]), Rome, Italy.

References (20)

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