Chemokine receptors that mediate B cell homing to secondary lymphoid tissues are highly expressed in B cell chronic lymphocytic leukemia and non-Hodgkin lymphomas with widespread nodular dissemination

Abstract

B cell neoplasms present heterogeneous patterns of lymphoid organ involvement, which may be a result of the differential expression of chemokine receptors. We found that chemokine receptor (CCR)7, CXC chemokine receptor (CXCR)4, or CXCR5, the main chemokine receptors that mediate B cell entry into secondary lymphoid tissues and their homing to T cell and B cell zones therein, were highly expressed in B malignancies with widespread involvement of lymph nodes. Conversely, those pathologies with little or no nodular dissemination showed no expression to very low levels of CCR7 and CXCR5 and low to moderate levels of CXCR4. These findings provide evidence for the role of CCR7, CXCR4, and CXCR5 in determining the pattern of lymphoid organ involvement of B tumors. Functional studies were performed on B malignancies expressing different levels of CCR7, CXCR5, and CXCR4. Multiple myeloma (MM) cells did not express CCR7 nor CXCR5 and did not migrate in response to their ligands; a moderate expression of CXCR4 on MM cells was accompanied by a migratory response to its ligand, CXCL12. By contrast, cells from B cell chronic lymphocytic leukemia (B-CLL) expressed the highest levels of these chemokine receptors and efficiently migrated in response to all ligands of CCR7, CXCR4, and CXCR5. In addition, the migration index of B-CLL cells in response to both of the CCR7 ligands correlated with the presence of clinical lymphadenopathy, thus indicating that the high expression of functional chemokine receptors justifies the widespread character of B-CLL, representing a clinical target for the control of tumor cell dissemination.

Analysis of migratory and prosurvival pathways induced by the homeostatic chemokines CCL19 and CCL21 in B-cell chronic lymphocytic leukemia

“…CLL B cells show a marked tendency to invade the LNs (17), and we have demonstrated that the ability of these cells to migrate in response to CCR7 ligands correlates with lymphadenopathy, suggesting a functional role of CCR7 in guiding CLL cells to LNs (16). In addition, it has been reported a strong correlation between the expression of CCR7 by solid tumor cells and the presence of LN metastases (2).…”

“…We have previously described a high expression of CCR7 in those B-cell neoplasms that are characterized by the infiltration of secondary lymphoid tissue, like chronic lymphocytic leukemia (CLL) (16). CLL B cells show a marked tendency to invade the LNs (17), and we have demonstrated that the ability of these cells to migrate in response to CCR7 ligands correlates with lymphadenopathy, suggesting a functional role of CCR7 in guiding CLL cells to LNs (16).…”

Chemokine receptors in head and neck cancer: Association with metastatic spread and regulation during chemotherapy

“…34,35 Recently, it has been suggested that, in leukemic B cell lymphomas, CXCR5 may be associated with the spread of malignant B cells to lymphoid tissues. 40,41 Here, we show the abundant expression of CXCR5 transcripts and the presence of surface CXCR5 on SCC cells. Our observation is consistent with the concept that metastasis and leukocyte trafficking share underlying mechanisms and suggests that CXCL13/CXCR5 interactions may provide a novel complementary pathway, mediating lymphogenic spread.…”

The role of chemokines in B cell chronic lymphocytic leukaemia: pathophysiological aspects and clinical impact

“…In addition, CXCL13 was found to be significantly elevated in serum of B-CLL patients and seems to correlate with ß2-microglobulin serum levels [52][53][54]. Furthermore, the CXCL13/CXCR5 axis has been demonstrated to be part of an interesting mechanism of apoptosis inhibition in B-CLL cells: CXCL13/CXCR5, together with CCL19/CCR7, enhance the expression of the paternally expressed gene 10 (PEG10) in CD23 + CD5…”

“…CCL19 and CCL21 are expressed in the T cell zone of secondary lymphoid, mucosa-associated lymphoid tissue and high endothelial venules, but not in the B cell areas or sinuses or blood-derived leukocytes [54]. They are the known ligands of the chemokine receptor CCR7 which is a crucial receptor for trafficking of B lymphocytes as well as T lymphocytes and DCs across high endothelial venules and for positioning in T cell zones of secondary lymphoid organs (Fig.…”