CD44-high neural crest stem-like cells are associated with tumour aggressiveness and poor survival in neuroblastoma tumours.

BACKGROUND: Neuroblastoma is a paediatric tumour originated from sympathoadrenal precursors and characterized by its heterogeneity and poor outcome in advanced stages. Intra-tumoral cellular heterogeneity has emerged as an important feature in neuroblastoma, with a potential major impact on tumour aggressiveness and response to therapy. CD44 is an adhesion protein involved in tumour progression, metastasis and stemness in different cancers; however, there has been controversies about the significance of CD44 expression in neuroblastoma and its relationship with tumour progression. METHODS: We have performed transcriptomic analysis on patient tumour samples studying the outcome of patients with high CD44 expression. Adhesion, invasion and proliferation assays were performed in sorted CD44high neuroblastoma cells. Tumoursphere cultures have been used to enrich in undifferentiated stem-like cells and to asses self-renewal and differentiation potential. We have finally performed in vivo tumorigenic assays on cell line-derived or Patient-derived xenografts. FINDINGS: We show that high CD44 expression is associated with low survival in high-grade human neuroblastoma, independently of MYCN amplification. CD44 is expressed in a cell population with neural crest stem-like features, and with the capacity to generate multipotent, undifferentiated tumourspheres in culture. These cells are more invasive and proliferative in vitro. CD44 positive cells obtained from tumours are more tumorigenic and metastatic, giving rise to aggressive neuroblastic tumours at high frequency upon transplantation. INTERPRETATION: We describe an unexpected intra-tumoural heterogeneity within cellular entities expressing CD44 in neuroblastoma, and propose that CD44 has a role in neural crest stem-like undifferentiated cells, which can contribute to tumorigenesis and malignancy in this type of cancer. FUNDING: Research supported by grants from the "Asociación Española contra el Cáncer" (AECC), the Spanish Ministry of Science and Innovation SAF program (SAF2016-80412-P), and the European Research Council (ERC Starting Grant to RP).

Neural crest derived progenitor cells contribute to tumor stroma and aggressiveness in stage 4/M neuroblastoma.

Pediatric tumors arise upon oncogenic transformation of stem/progenitor cells during embryonic development. Given this scenario, the existence of non-tumorigenic stem cells included within the aberrant tumoral niche, with a potential role in tumor biology, is an intriguing and unstudied possibility. Here, we describe the presence and function of non-tumorigenic neural crest-derived progenitor cells in aggressive neuroblastoma (NB) tumors. These cells differentiate into neural crest typical mesectodermal derivatives, giving rise to tumor stroma and promoting proliferation and tumor aggressiveness. Furthermore, an analysis of gene expression profiles in stage 4/M NB revealed a neural crest stem cell (NCSC) gene signature that was associated to stromal phenotype and high probability of relapse. Thus, this NCSC gene expression signature could be used in prognosis to improve stratification of stage 4/M NB tumors. Our results might facilitate the design of new therapies by targeting NCSCs and their contribution to tumor stroma.

The relationship between the site of metastases and outcome in children with stage IV Wilms Tumor: data from 3 European Pediatric Cancer Institutions.

The aim of this study was to analyze in detail the site of metastasis of stage 4 Wilms tumor (WT) and its correlation with outcome. The databases from 3 major European pediatric cancer institutions were screened for children with WT between 1994 and 2011. Of 208 children identified, 31 (14.9%) had metastases at diagnosis. The lung was affected in 29 children (93.5%) and the liver in 6 children (19.4%). Twenty-seven children (87.1%) had metastases isolated to 1 organ, with the lung being the most common site (80.7%). Five-year overall survival was significantly better in those children with distant disease in either lung or liver (95.8%) compared with those affected in both lung and liver (57.1%, P=0.028). Further, prognostic markers were the response of metastases to preoperative chemotherapy (P=0.0138), high-risk histology (P=0.024), and local stage (P=0.026). Five-year overall survival was 82.1% and 5-year event-free survival was 67.9%. The overall follow-up time was 74.1 and 87.2 (2 to 151) months among survivors, and the treatment-related complication rate was 16.7%. In conclusion, in our series of stage 4 WT, prognosis was excellent if histology was favorable, metastatic disease was isolated to either lungs or liver, and if metastases responded to preoperative chemotherapy.

Surgical management of Wilms tumor with intravascular extension: a single-institution experience.

The purpose of this study was to retrospectively analyze the clinical presentation, treatment, and outcomes of children with Wilms tumor (WT) and intravascular extension who were treated at a single institution. A retrospective review was conducted of medical records of all children with Wilms tumor and intravascular extension treated at Virgen del Rocio Children's Hospital between 1992 and 2010. Seven patients (median age 3.4 years, range 2-8.1 years) were identified. At diagnosis, 6 of the 7 patients (85.7%) presented with tumor thrombus that reached the right atrium (RA) and 1 patient with infrahepatic inferior vena cava (IVC) thrombus. All patients received neoadjuvant chemotherapy (SIOP 2001 protocol) with vincristine, doxorubicin, and actinomycin D. Regression of the intravascular extension of the tumor was documented in all patients. Postchemotherapy level of extension was suprahepatic IVC in 1 patient, infrahepatic IVC in 2 patients, renal vein (RV) in 1 patient, and RA in 3 patients. Nephrectomy and thrombectomy were performed in all cases, requiring cardiopulmonary bypass for the 4 patients who presented with suprahepatic IVC and RA thrombus. The other 3 patients with infrahepatic IVC and RV involvement underwent cavotomy and thrombus extraction. Computed tomography, ultrasonography, and echocardiography were used for diagnosis and follow-up. All patients remain disease-free with a median follow-up of 6.3 years (range, 2-19 years). Neoadjuvant chemotherapy for WT with intravascular extension may facilitate the resection by decreasing the extent of the tumor thrombus. Cardiopulmonary bypass is indicated for suprahepatic IVC and RA involvement. Accurate diagnostic imaging is necessary.