Large-scale molecular comparison of human schwann cells to malignant peripheral nerve sheath tumor cell lines and tissues.
Malignant peripheral nerve sheath tumors (MPNST) are highly invasive soft tissue sarcomas that arise within the peripheral nerve and frequently metastasize. To identify molecular events contributing to malignant transformation in peripheral nerve, we compared eight cell lines derived from MPNSTs and seven normal human Schwann cell samples. We found that MPNST lines are heterogeneous in their in vitro growth rates and exhibit diverse alterations in expression of pRb, p53, p14(Arf), and p16(INK4a) proteins. All MPNST cell lines express the epidermal growth factor receptor and lack S100beta protein. Global gene expression profiling using Affymetrix oligonucleotide microarrays identified a 159-gene molecular signature distinguishing MPNST cell lines from normal Schwann cells, which was validated in Affymetrix microarray data generated from 45 primary MPNSTs. Expression of Schwann cell differentiation markers (SOX10, CNP, PMP22, and NGFR) was down-regulated in MPNSTs whereas neural crest stem cell markers, SOX9 and TWIST1, were overexpressed in MPNSTs. Previous studies have implicated TWIST1 in apoptosis inhibition, resistance to chemotherapy, and metastasis. Reducing TWIST1 expression in MPNST cells using small interfering RNA did not affect apoptosis or chemoresistance but inhibited cell chemotaxis. Our results highlight the use of gene expression profiling in identifying genes and molecular pathways that are potential biomarkers and/or therapeutic targets for treatment of MPNST and support the use of the MPNST cell lines as a primary analytic tool.
Miller
Shyra J
SJ
Division of Experimental Hematology, Cincinnati Children's Hospital Research Foundation, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.
Rangwala
Fatima
F
Williams
Jon
J
Ackerman
Peter
P
Kong
Sue
S
Jegga
Anil G
AG
Kaiser
Sergio
S
Aronow
Bruce J
BJ
Frahm
Silke
S
Kluwe
Lan
L
Mautner
Victor
V
Upadhyaya
Meena
M
Muir
David
D
Wallace
Margaret
M
Hagen
Jussara
J
Quelle
Dawn E
DE
Watson
Mark A
MA
Perry
Arie
A
Gutmann
David H
DH
Ratner
Nancy
N
D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D006801:Humans; D018317:Nerve Sheath Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D034741:RNA, Small Interfering / Q000235:genetics; D012583:Schwann Cells / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D051879:Twist-Related Protein 1 / Q000096:biosynthesis / Q000235:genetics
D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1