Role of CXCL13-CXCR5 Crosstalk Between Malignant Neuroblastoma Cells and Schwannian Stromal Cells in Neuroblastic Tumors

Abstract

Neuroblastoma is a stroma-poor (SP) aggressive pediatric cancer belonging to neuroblastic tumors, also including ganglioneuroblastoma and ganglioneuroma, two stroma-rich (SR) less aggressive tumors. Our previous gene-expression profiling analysis showed a different CXCL13 mRNA expression between SP and SR tumors. Therefore, we studied 13 SP and 13 SR tumors by reverse transcription quantitative real-time PCR (RT-qPCR) and we found that CXCR5b was more expressed in SP than in SR and CXCL13 was predominantly expressed in SR tumors. Then, we isolated neuroblastic and Schwannian stromal cells by laser capture microdissection and we found that malignant neuroblasts express CXCR5b mRNA, whereas Schwannian stromal cells express CXCL13. Immunohistochemistry confirmed that stroma expresses CXCL13 but not CXCR5. To better understand the role of CXCL13 and CXCR5 in neuroblastic tumors we studied 11 neuroblastoma cell lines and we detected a heterogeneous expression of CXCL13 and CXCR5b. Interestingly, we found that only CXCR5b splice variant was expressed in both tumors and neuroblastoma lines, whereas CXCR5a was never detected. Moreover, we found that neuroblastoma cells expressing CXCR5 receptor migrate toward a source of recombinant CXCL13. Lastly, neuroblastoma cells induced to glial cell differentiation expressed CXCL13 mRNA and protein. The chemokine released in the culture medium was able to stimulate chemotaxis of LA1-5S neuroblastoma cells. Collectively, our data suggest that CXCL13 produced by stromal cells may contribute to the generation of an environment in which the malignant neuroblasts are retained, thus limiting the possible development of metastases in patients with SR tumor. Mol Cancer Res; 9(7); 815-23. '2011 AACR.

Immune Alterations in CD8+ T Cells Are Associated with Neuronal C-C and C-X-C Chemokine Receptor Regulation Through Adenosine A2A Receptor Signaling in a BTBR T+ Itpr3tf/J Autistic Mouse Model

“…CXCR5 is a potent chemokine receptor for the recruitment of neural precursor cells across brain endothelial cells [71]. In addition, neuroblastoma cells expressing CXCR5 chemokine receptors have been found to migrate toward CXCL13 [72]. Our results suggest that the A2A receptor agonist CGS corrects the neurodevelopmental dysregulation in autism through the downregulation of CXCR5.…”

NLRP12 Suppresses Colon Inflammation and Tumorigenesis through the Negative Regulation of Noncanonical NF-κB Signaling

“…Both of these chemokines have been shown to be highly up-regulated in various types of human cancers (Del Grosso et al 2011; Fushimi et al 2006;Wharry et al 2009). We evaluated the expression and protein levels of CXCL12 and CXCL13 in colon samples following either chronic EC or CAC and observed robust increases in their expression in Nlrp12 -/- colons following completion of the AOM/DSS treatment (Figure 7A).…”

“…In CAC, we identified robust amounts of CXCL13 (and Cxlc13 expression) and increased expression of Cxlc12 in all of the Nlrp12 -/- mice. These findings are significant as these chemokines are strongly associated with various types of cancers in human populations, including colorectal tumorigenesis (Del Grosso et al 2011;Fushimi et al 2006). The finding that these chemokines were only dysregulated in the CAC model and not the colitis models further implicates their contribution to the increased tumorigenesis observed in the Nlrp12 -/- mice.…”

Expression and clinical significance of CXCR5/CXCL13 in human non-small cell lung carcinoma

“…The CXCR5-CXCL13 axis is involved in development and progression of solid tumors, e.g., breast cancers and neuronal cancers (13,14). Recently, we demonstrated a differential expression of CXCR5 in PCa cell lines correlated with PCa progression (17,18).…”