Galectin-3 is a marker of favorable prognosis and a biologically relevant molecule in neuroblastic tumors

V Veschi,C Capalbo,H P Mcdowell,A Gulino,A Castellano,R Boldrini,A Bartolazzi,B Pizer,C Dominici,M Petroni,G Giannini,P Altavista,L Frati,I Screpanti

doi:10.1038/cddis.2014.68

Abstract

Childhood neuroblastic tumors are characterized by heterogeneous clinical courses, ranging from benign ganglioneuroma (GN) to highly lethal neuroblastoma (NB). Although a refined prognostic evaluation and risk stratification of each tumor patient is becoming increasingly essential to personalize treatment options, currently only few biomolecular markers (essentially MYCN amplification, chromosome 11q status and DNA ploidy) are validated for this purpose in neuroblastic tumors. Here we report that Galectin-3 (Gal-3), a β-galactoside-binding lectin involved in multiple biological functions that has already acquired diagnostic relevance in specific clinical settings, is variably expressed in most differentiated and less aggressive neuroblastic tumors, such as GN and ganglioneuroblastoma, as well as in a subset of NB cases. Gal-3 expression is associated with the INPC histopathological categorization (P<0.001) and Shimada favorable phenotype (P=0.001), but not with other prognostically relevant features. Importantly, Gal-3 expression was associated with a better 5-year overall survival (P=0.003), and with improved cumulative survival in patient subsets at worse prognosis, such as older age at diagnosis, advanced stages or NB histopathological classification. In vitro, Gal-3 expression and nuclear accumulation accompanied retinoic acid-induced cell differentiation in NB cell lines. Forced Gal-3 overexpression increased phenotypic differentiation and substrate adherence, while inhibiting proliferation. Altogether, these findings suggest that Gal-3 is a biologically relevant player for neuroblastic tumors, whose determination by conventional immunohistochemistry might be used for outcome assessment and patient's risk stratification in the clinical setting.

Highlights

At the molecular level, MYCN represents the most relevant player, biologically and prognostically
On the basis of the International Neuroblastoma Risk Group (INRG) consensus, seven independent prognostic indices are commonly used for the stratification of patients affected with Neuroblastic tumors (NTs) into defined risk groups.[5]
According to the International Neuroblastoma Pathology Committee (INPC) and based on the differentiation status of tumor cells and abundance of Schwannian stroma, NTs might be divided into four morphological categories with subtypes:[11,12] (1) NB (Schwannian stroma-poor) undifferentiated, poorly differentiated and differentiating; (2) ganglioneuroblastoma (GNB) intermixed (Schwannian stroma-rich); (3) ganglioneuroma (GN, Schwannian stroma-dominant) maturing and mature; (4) GNB nodular

Summary

Introduction

MYCN represents the most relevant player, biologically and prognostically. On the basis of the International Neuroblastoma Risk Group (INRG) consensus, seven independent prognostic indices (stage, age, histologic category, grade of tumor differentiation, MYCN amplification status, chromosome 11q status and DNA ploidy) are commonly used for the stratification of patients affected with NTs into defined risk groups.[5] additional biological variables were eventually shown to possess prognostic value,[6] their strong linkage to established prognostic factors (i.e., NTRK1 and NTRK2 expression),[7] or their complex and expensive determination methods (i.e., gene profiling or microRNA signatures),[8,9,10] has prevented their routine application for outcome assessment and risk class stratification in the clinical setting. We investigated on Gal-3 expression in a series of primary human NTs ex vivo and assessed the biological role played by Gal-3 in regulating NB cell proliferation, differentiation and adherence, in experimental NB tumor models, in vitro

Methods

Results

Conclusion