Human Cancer Biology CXCL13 and CXCL12 in Central Nervous System Lymphoma Patients

Purpose: Homing of malignant lymphocytes to the central nervous system (CNS) may play a role in the pathogenesis of CNS lymphoma. In this study, we evaluated the chemokines CXCL12 and CXCL13 in the cerebrospinal fluid (CSF) and serum of patients with CNS lymphoma. Experimental Design: Samples from 30 patients with CNS lymphoma (23 with primary and 7 with secondary CNS lymphoma; all B-cell lymphoma) and 40 controls (10 patients with other CNS malignancies and 30 without a malignant CNS disease) were examined. CXCL12 and CXCL13 concentrations were measured using enzyme-linked immunosorbent assays. The grade of blood-brain barrier disruption was estimated by the CSF/serum albumin ratio. Results: CNS lymphoma patients and controls did not differ in CXCL12 serum and CSF levels. Serum levels of CXCL13 were generally low. CXCL13 CSF levels, however, were significantly higher in CNS lymphoma patients as compared with controls (P < 0.0001). Chemokine levels in CSF and serum did not correlate. In CNS lymphoma, CXCL13 concentration in CSF correlated with the degree of blood-brain barrier disruption (R = 0.66; P = 0.003). Elevated CSF levels of CXCL12 and CXCL13 measured in seven CNS lymphoma patients during therapy decreased in five patients who responded to chemotherapy and increased in two with lymphoma progression. Conclusions: Our results suggest a production of CXCL13 within the CNS of CNS lymphoma patients, which decreases with response to therapy. Thus, CXCL13 may represent a marker for further diagnostic and prognostic studies. (Clin Cancer Res 2009;15(19):5968–73) Primary central nervous system (CNS) lymphoma is rare subtype of extranodal non-Hodgkin's lymphoma, mostly diffuse large B-cell lymphoma, confined to the CNS in the absence of systemic disease (1). Mechanisms leading to lymphoma development in the CNS normally devoid of a lymphatic system are still unclear. Lymphocyte homing to the CNS regulated by chemokines may play an important role in the pathogenesis of this disease. CXCL12 and CXCL13 are important chemokines mediating germinal center organization in lymphoid tissue (2). CXCR5 is the prime receptor for CXCL13, which causes homing of B-helper cells and a subset of T-helper cells to the lymphoid follicle. Follicular dendritic cells located in the germinal centers of lymphoid follicles are considered the main source of CXCL13. CXCL13 expression was shown in several B-cell lymphomas, some with extranodal location such as gastric or ocular adnexal lymphomas (3–6). CXCR4, the receptor for CXCL12, is physiologically expressed on B and T cells, bone marrow stroma cells, and other hematopoietic cells. Expression of CXCR4 on malignant cells has been reported for a variety of tumors such as glioblastoma, breast cancer, and Band T-cell lymphoma. CXCL12 is expressed by a wide variety of tissues and plays a key role in the trafficking of hematopoietic cells but is also involved in tumor growth and metastasis (7–10). Recently, the expression of CXCR4 and CXCR5, as well as their chemokine ligands, CXCL12 and CXCL13, has been shown on malignant lymphocytes in primary CNS lymphoma (11–14). These findings suggest a role for chemokines in the pathogenesis of primary CNS lymphoma. We studied the levels of both chemokines in the cerebrospinal fluid (CSF) and serum of patients with CNS lymphoma before and during therapy and compared the results to controls with other CNS malignancies and nonmalignant CNS diseases. Materials and Methods Patients and samples. CSF samples obtained by lumbar puncture and serum samples were collected from patients with newly diagnosed or relapsed primary or secondary CNS lymphoma. All had B-cell non-Hodgkin's lymphoma, confirmed either by brain biopsy or CSF Authors' Affiliations: Medical Clinic for Hematology and Oncology, Charité Campus Benjamin Franklin; Department of Medical Immunology, Charité Campus Mitte, Berlin, Germany; and Clinic for Internal Medicine I, Universitätsklinikum des Saarlandes, Homburg, Germany Received 1/17/09; revised 5/14/09; accepted 5/26/09; published OnlineFirst 9/22/09. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Lars Fischer, Medical Clinic for Hematology and Oncology, Charité Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany. Phone: 49-30-8445-2337; Fax: 49-30-8445-4086; E-mail: [email protected]. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-09-0108 5968 Clin Cancer Res 2009;15(19) October 1, 2009 www.aacrjournals.org Research. on July 15, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst September 22, 2009; DOI: 10.1158/1078-0432.CCR-09-0108