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

Shu Zhang, Curt Balch, Michael W. Chan, Hung Cheng Lai, Daniela Matei, Jeanne Schilder, Pearlly S. Yan, Tim H M Huang, Kenneth Nephew

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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 >105 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 105 CD44 -CD117- cells remained non-tumorigenic. 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.

Original languageEnglish
Pages (from-to)4311-4320
Number of pages10
JournalCancer Research
Volume68
Issue number11
DOIs
StatePublished - Jun 1 2008

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Ovarian Neoplasms
Neoplasms
Stem Cells
Adenocarcinoma
Up-Regulation
Proto-Oncogene Proteins c-kit
Phenotype
Nestin
Stem Cell Factor
Oncogene Proteins
Protein-Tyrosine Kinases
Reverse Transcription
Cell Proliferation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Identification and characterization of ovarian cancer-initiating cells from primary human tumors. / Zhang, Shu; Balch, Curt; Chan, Michael W.; Lai, Hung Cheng; Matei, Daniela; Schilder, Jeanne; Yan, Pearlly S.; Huang, Tim H M; Nephew, Kenneth.

In: Cancer Research, Vol. 68, No. 11, 01.06.2008, p. 4311-4320.

Research output: Contribution to journalArticle

Zhang, Shu ; Balch, Curt ; Chan, Michael W. ; Lai, Hung Cheng ; Matei, Daniela ; Schilder, Jeanne ; Yan, Pearlly S. ; Huang, Tim H M ; Nephew, Kenneth. / Identification and characterization of ovarian cancer-initiating cells from primary human tumors. In: Cancer Research. 2008 ; Vol. 68, No. 11. pp. 4311-4320.
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