title: 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.
authors.affiliation: Translational Oncopathology, National Cancer Research Institute, L.go R. Benzi, 10-16132, Genoa, Italy. gianpaolo.tonini@istge.it
authors.forename: Federica
authors.initials: F
authors.lastname: Del Grosso
authors.forename: Simona
authors.initials: S
authors.lastname: Coco
authors.forename: Paola
authors.initials: P
authors.lastname: Scaruffi
authors.forename: Sara
authors.initials: S
authors.lastname: Stigliani
authors.forename: Francesca
authors.initials: F
authors.lastname: Valdora
authors.forename: Roberto
authors.initials: R
authors.lastname: Benelli
authors.forename: Sandra
authors.initials: S
authors.lastname: Salvi
authors.forename: Simona
authors.initials: S
authors.lastname: Boccardo
authors.forename: Mauro
authors.initials: M
authors.lastname: Truini
authors.forename: Michela
authors.initials: M
authors.lastname: Croce
authors.forename: Silvano
authors.initials: S
authors.lastname: Ferrini
authors.forename: Luca
authors.initials: L
authors.lastname: Longo
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Tonini
mesh_terms: D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D054382:Chemokine CXCL13 / Q000235:genetics / Q000378:metabolism*; D002648:Child; D020869:Gene Expression Profiling; D006801:Humans; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D054380:Receptors, CXCR5 / Q000235:genetics / Q000378:metabolism*; D012583:Schwann Cells / Q000378:metabolism* / Q000473:pathology; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology
chemical_list: C110663:CXCL13 protein, human; C095085:CXCR5 protein, human; D054382:Chemokine CXCL13; D020033:Protein Isoforms; D054380:Receptors, CXCR5