Malignant B Cells From Patients With Primary Central Nervous System Lymphoma Express Stromal Cell-Derived Factor-1

Abstract

Although the pathogenesis of primary central nervous system lymphoma (PCNSL) remains unclear, it is hypothesized that specific chemokine-chemokine receptor interactions may attract malignant B lymphocytes into the CNS. Formalin-fixed, paraffin-embedded brain biopsy specimens from 40 patients with PCNSL were immunostained by an indirect immunohistochemical method incorporating antigen retrieval to detect the presence of B-cell chemokines, stromal cell-derived factor-1 (SDF-1; CXCL12) and macrophage inflammatory protein-3alpha (MIP-3alpha, CCL20), and the SDF-1 receptor, CXCR4. To assist in phenotyping of SDF-1 + cells, specimens were also stained for CD20 (B cells). Positive staining for SDF-1 was identified in all PCNSL cases and in tonsil. In biopsy specimens, SDF-1 expression was localized to resident brain cells and, in 80% of specimens, CD20+ malignant lymphocytes. Tumor cells also stained positively for CXCR4. In contrast, although expression ofMIP-3alpha was detected in tonsil, no expression of this chemokine could be demonstrated in PCNSL biopsy specimens. Our observations raise the possibility of targeting the SDF-1-CXCR4 signaling pathway as a potential treatment for PCNSL.

The perivascular microenvironment in primary central nervous system lymphomas: the role of chemokines and the endothelin B receptor

“…Since CXCR4 is expressed on several cancer cells, these CXCR4-positive cancer cells may metastasize to organs that secrete/express CXCL12 [6][7][8][9][10]29]. In addition, CXCL12/CXCR4 has recently been shown to be expressed by PCNSLs and a role for chemokines in the pathogenesis of PCNSL has been suggested [12][13][14][15]. The so-called ''lymphoid chemokines'', which include CXCL13 and their counter-receptors, including CXCR5 are constitutively expressed by and control homeostatic trafficking of B and T cells to and within secondary lymphoid organs.…”

“…B cell-attracting chemokine 1 (BCA-1, CXCL13), which is expressed on putative follicular dendritic cells, is responsible for compartmental homing of CXCR5-bearing B lymphocytes and also directs T helper cells into the lymphoid follicle [10][11][12][13][14][15]. In addition, the CXCL12/CXCR4 and CXCL13/ CXCR5 pathways have recently been shown to be expressed in PCNSL and a role for chemokines in the pathogenesis of PCNSL has been suggested [11][12][13][14]. Moreover, a recent study has demonstrated that the expression of chemokines can concurrently affect malignant B cells and tumor infiltrating lymphocytes (TILs) [16].…”

Role of lymphoid chemokines in the development of functional ectopic lymphoid structures in rheumatic autoimmune diseases

“…Interestingly, CXCL13 was found to be expressed by malignant B cells in gastric MALT-L as well as in non-Hodgkin B cell lymphoma of the central nervous system where also CXCL12 and its receptor CXCR4 were found to be expressed [5,38,39]. Our studies, performed on a large cohort of SS parotid glands with lymphoepithelial sialoadenitis (LESA) and MALT-L, have shown that CXCL13 and CCL21 were expressed at higher levels in SS salivary glands with LESA as compared to MALT-L. Conversely, CXCL12 was more expressed in parotid glands with MALT-L in comparison to LESA [37].…”

Diffuse Large B-Cell Lymphoma Involving the Central Nervous System

“…26 The expression of CXCL13 and other chemokine ligands has been demonstrated in DLBCL-CNS, suggesting a role in the pathogenesis of this type of lymphoma and a potential therapeutic and prognostic utility. [27][28][29][30] CXCL13 expression had been demonstrated both in cerebrospinal fluid (by flow cytometry) and in the malignant lymphoid cells themselves (by immunohistochemistry). 31 In the present series, we were unable to find significant expression of CXLCL13 in any of the 3 groups; we are unable to explain the discrepancy in the findings.…”