Characteristics of Stem Cells from Human Neuroblastoma Cell Lines and in Tumors

Abstract

Cellular heterogeneity is a hallmark of human neuroblastoma tumors and cell lines. Within a single neuroblastoma are cells from distinct neural crest lineages whose relative abundance is significant for prognosis. We postulate that a self-renewing multipotent tumor stem cell, which gives rise to diverse cell lineages, is the malignant progenitor of this cancer. To test this hypothesis, we have established 22 cloned, phenotypically homogeneous populations of the three major cell types from 17 neuroblastoma cell lines. In vitro, malignant neuroblastoma stem cells, termed I-type (intermediate type), have distinct morphologic, biochemical, differentiative, and tumorigenic properties. I-type cells express features of both neuroblastic (N) cells (scant cytoplasm, neuritic processes, neurofilaments, pseudoganglia, and granin and neurotransmitter enzyme expression) and substrate-adherent (S) cells (extensive cytoplasm and vimentin and CD44 expression). Moreover, they show bidirectional differentiation to either N or S cells when induced by specific agents. I-type cells are significantly more malignant than N- or S-type cells, with four- to five-fold greater plating efficiencies in soft agar and six-fold higher tumorigenicity in athymic mice. Differences in malignant potential are unrelated to N-myc amplification/overexpression or the ability to digest and migrate through the extracellular matrix. Immunocytochemical analyses of a small series of tumors reveal that frequency of cells coexpressing N and S cell markers correlates with poor prognosis. Thus, I-type stem cells may be instrumental in the genesis and growth of tumors in the patient. Their unique biology deserves attention and further investigation.

Targeting Suppressive Myeloid Cells Potentiates Checkpoint Inhibitors to Control Spontaneous Neuroblastoma

“…Given that long-term in vitro culture could result in growth of selected tumor cell subsets, it is important to validate these findings with primary or short-passage human neuroblastoma cells (47). It is well documented that MDSCs and TAMs are associated with poor clinical outcome in patients with solid tumors (22)(23)(24).…”

Sialyltransferase STX (ST8SiaII): A novel molecular marker of metastatic neuroblastoma

“…These subtypes have distinct biochemical, morphologic and tumorigenic properties, mimicking the clinical and pathologic heterogeneity of clinical NB. 18 …”

Neuroblastoma stem cells – mechanisms of chemoresistance and histonedeacetylase inhibitors

“…Stem cells derived from I type have more ability to differentiate into different cell types than other types, having a high colony-forming capacity and high growth potential in immunodeficient mice. It has been proved that malignant stem cell phenotype (CD133 and c-kit expression), but not MYCN amplification status or its expression, defines the tumorigenic potential of the various NBL cell lines [52]. Those results were also proved by examination of 40 tumor samples which showed that percentage of CD133+ cells was higher in neuroblastoma than in ganglioneuroblastoma, correlated with clinical stage, and was higher in tumors with unfavorable than favorable histology.…”