Elsevier

Neoplasia

Volume 6, Issue 6, November–December 2004, Pages 838-845
Neoplasia

Characteristics of Stem Cells from Human Neuroblastoma Cell Lines and in Tumors1

https://doi.org/10.1593/neo.04310Get rights and content
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open access

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 1-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.

Keywords

Human neuroblastoma
I-type cell
stem cell
tumorigenicity
differentiation

Abbreviations

ACTN
α-actinin4
BUdR
5-bromo-2'-deoxyuridine
CFE
colony-forming efficiency
CgA
chromogranin A
ECM
extracellular matrix
FSK
forskolin
Hu-IR
Hu protein immunoreactivity
NF
neurofilament protein
RA
all-trans retinoic acid
VIM
vimentin

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1

This research was supported by the NCI, National Institutes of Health Grant CA 77593, and the GRATIS Fund (to R.A.R) and the Hope Street Kids (to N.K.V.C).