Role of CXCL13-CXCR5 crosstalk between malignant neuroblastoma cells and Schwannian stromal cells in neuroblastic tumors

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...

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Bibliographic Details
Published in:Molecular cancer research 2011-07, Vol.9 (7), p.815-823
Main Authors: Del Grosso, Federica, Coco, Simona, Scaruffi, Paola, Stigliani, Sara, Valdora, Francesca, Benelli, Roberto, Salvi, Sandra, Boccardo, Simona, Truini, Mauro, Croce, Michela, Ferrini, Silvano, Longo, Luca, Tonini, Gian Paolo
Format: Article
Language:English
Subjects:
Alternative splicing
Cancer
Cell culture
Cell Differentiation
Cell Line, Tumor
Cell migration
Cell Movement
Chemokine CXCL13 - genetics
Chemokine CXCL13 - metabolism
Chemotaxis
Child
CXCL13 protein
CXCR5 protein
Differentiation
Gene expression
Gene Expression Profiling
Humans
Lasers
Neuroblastoma
Neuroblastoma - metabolism
Neuroblastoma - pathology
Neuroblastoma cells
Neuroblasts
Pediatrics
Polymerase chain reaction
Protein Isoforms - genetics
Protein Isoforms - metabolism
Receptors, CXCR5 - genetics
Receptors, CXCR5 - metabolism
Reverse transcription
Schwann Cells - metabolism
Schwann Cells - pathology
stromal cells
Stromal Cells - metabolism
Stromal Cells - pathology
Substance P
Tumors
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Summary: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.
ISSN:1541-7786
1557-3125
DOI:10.1158/1541-7786.mcr-10-0367