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PMID: 18519691 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Identification and characterization of ovarian cancer-initiating cells from primary human tumors.

Cancer research ·Vol. 68 ·No. 11 ·2008-06-01 ·Pages 4311-20

Zhang S, Balch C, Chan MW, Lai HC, Matei D, Schilder JM, Yan PS, Huang TH, Nephew KP

Abstract

The objective of this study was to identify and characterize a self-renewing subpopulation of human ovarian tumor cells (ovarian cancer-initiating cells, OCICs) fully capable of serial propagation of their original tumor phenotype in animals. Ovarian serous adenocarcinomas were disaggregated and subjected to growth conditions selective for self-renewing, nonadherent spheroids previously shown to derive from tissue stem cells. To affirm the existence of OCICs, xenoengraftment of as few as 100 dissociated spheroid cells allowed full recapitulation of the original tumor (grade 2/grade 3 serous adenocarcinoma), whereas >10(5) unselected cells remained nontumorigenic. Stemness properties of OCICs (under stem cell-selective conditions) were further established by cell proliferation assays and reverse transcription-PCR, demonstrating enhanced chemoresistance to the ovarian cancer chemotherapeutics cisplatin or paclitaxel and up-regulation of stem cell markers (Bmi-1, stem cell factor, Notch-1, Nanog, nestin, ABCG2, and Oct-4) compared with parental tumor cells or OCICs under differentiating conditions. To identify an OCIC cell surface phenotype, spheroid immunostaining showed significant up-regulation of the hyaluronate receptor CD44 and stem cell factor receptor CD117 (c-kit), a tyrosine kinase oncoprotein. Similar to sphere-forming OCICs, injection of only 100 CD44(+)CD117(+) cells could also serially propagate their original tumors, whereas 10(5) CD44(-)CD117(-) cells remained nontumorigenic. Based on these findings, we assert that epithelial ovarian cancers derive from a subpopulation of CD44(+)CD117(+) cells, thus representing a possible therapeutic target for this devastating disease.

MeSH Terms
Cell Adhesion Cell Separation Female Fluorescent Antibody Technique Humans Neoplastic Stem Cells/pathology Ovarian Neoplasms/pathology Reverse Transcriptase Polymerase Chain Reaction
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Zhang Shu
Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana 47405, USA.
Balch Curt
Chan Michael W
Lai Hung-Cheng
Matei Daniela
Schilder Jeanne M
Yan Pearlly S
Huang Tim H-M
Nephew Kenneth P
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Article Info
Journal
Cancer research
Abbr.
Cancer Res
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-08-0364
Published
2008-06-01
Pages
4311-20
Language
English
Region
United States
NLM ID
2984705R
PMCID
PMC2553722
Subset
IM
Grants
NCI NIH HHS · U54 CA113001-030004 · United States
NCI NIH HHS · U54 CA113001-04 · United States
NCI NIH HHS · CA085289 · United States
NCI NIH HHS · CA113001 · United States
NCI NIH HHS · U54 CA113001-040004 · United States
NCI NIH HHS · R01 CA085289 · United States
NCI NIH HHS · U54 CA113001 · United States
NCI NIH HHS · R01 CA085289-05A1 · United States
External Links
PubMed source DOI: 10.1158/0008-5472.CAN-08-0364 PMC Full Text View journal details
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