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

Abstract

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.

CD44 as a tumor biomarker and therapeutic target

“…The 3′ untranslated region of CD44, acting as a competing endogenous RNA to microRNA-34a, boosts the sensitivity of liver CSCs to natural kill cells-mediated cytotoxicity via regulating UL16 binding protein 2 [26]. In addition, CD44 also exerts significant effects on caner invasion and metastasis of various tumor types [27], such as lung adenocarcinoma [18], breast cancer [28][29][30], neuroblastoma [31], gastric cancer [32], esophageal squamous cell carcinoma (ESCC) [33], colorectal cancer [34][35][36][37], prostate cancer [38], nasopharyngeal carcinoma [39], endometrial cancer [40], clear cell renal cell (RCC) carcinoma [41], pancreatic cancer [42], meningioma [43] and ovarian cancer [44]. As has been reported, the intracellular domain (ICD) of CD44 interacting with RUNX2 to form a co-transcription factor drives the migration of prostate cancer cell line PC3 through upregulating the levels of metastasis-related genes, such as matrix metalloproteinase 9 (MMP9) and osteopontin [38].…”

“…However, CD44 epithelial isoform has been found to be negatively correlated with lymphatic invasion and metastasis of colorectal cancer based on the statistical analysis of a total of 494 colorectal tumor samples [34]. Besides, numerous studies suggest that CD44 can be a promising predictor for clinical outcomes among cancer population, including gastric cancer [45,46], colorectal cancer [34], neuroblastoma [31], myxofibrosarcoma [47], glioma [21], endometrial cancer [40] and osteosarcoma [48]. According to survival analysis, grade II/III glioma patients with high mRNA expression of CD44 experienced poor overall survival (OS) and progression-free survival (PFS) in comparison with low mRNA level of CD44 in an independent manner [21].…”

The Important Role of Perituberal Tissue in Epileptic Patients with Tuberous Sclerosis Complex by the Transcriptome Analysis

“…In addition to their role in regulating tumor progression [ 33 , 34 ], APLNR is mainly involved in the neuroactive ligand-receptor interaction and vascular development [ 35 , 36 ], while ANXA2 mainly participates in the modulation of depressive behavior and signal transduction pathways [ 37 , 38 ]. CD44 encodes a cell-surface glycoprotein and affects the cell-cell interactions, cell adhesion, and migration, leading to a low survival in high-grade neuroblastoma, as well as synaptic remodeling and epileptogenesis [ 39 – 41 ]. GLU encodes a secreted chaperone and affects cell death, tumor progression, and neuroprotective role [ 42 , 43 ].…”

Hypoxia in the Initiation and Progression of Neuroblastoma Tumours

“…The correlation between NB tumour differentiation, prognosis and clinical outcome is well established, with a worse outcome attributed to tumours with undifferentiated histology [32]. Furthermore, NB cellular heterogeneity, and in particular the presence of an undifferentiated neural crest stem-like cell population, has been proposed to have a fundamental effect on tumour progression and response to therapy [33,34]. Putative markers for cancer stem cells (CSCs) in NB have also been described, although there is not a definitive conclusion on this matter [35].…”