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

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.

SUBMITTER: Zhang S

PROVIDER: S-EPMC2553722 | biostudies-literature | 2008 Jun

REPOSITORIES: biostudies-literature

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

Zhang Shu S Balch Curt C Chan Michael W MW Chan Michael W MW Lai Hung-Cheng HC Matei Daniela D Schilder Jeanne M JM Yan Pearlly S PS Huang Tim H-M TH Nephew Kenneth P KP

Cancer research 20080601 11

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 dis ...[more]

PMID: 18519691

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Project description:The majority of meningiomas are benign tumors associated with favorable outcomes; however, the less common aggressive variants with unfavorable outcomes often recur and may be due to sub-populations of less-differentiated cells residing within the tumor. These sub-populations of tumor cells, termed tumor-initiating cells, may be isolated from heterogeneous tumors when sorted or cultured in defined medium designed for enrichment of the tumor-initiating cells. We report the isolation and characterization of a population of tumor-initiating cells derived from an atypical meningioma. These meningioma-initiating cells (MICs) self-renew, differentiate, and can recapitulate the histological characteristics of the parental tumor when transplanted into athymic nude mice. Immunohistochemistry reveals protein expression patterns similar to neural stem and progenitor cells while genomic profiling verified the isolation of cancer cells (with defined meningioma chromosomal aberrations) from the bulk tumor. Furthermore, microarray analysis of gene expression reveals that many epithelial to mesenchymal transition genes are upregulated in the MICs, consistent with the presence of both neural stem cell and mature neural cell molecular markers seen in the derived cultures. Pathway analysis identifies biochemical processes and gene networks related to aberrant cell cycle progression, particularly the loss of heterozygosity of tumor suppressor genes CDKN2A (p16INK4A), p14ARF, and CDKN2B (p15INK4B). Flow cytometric analysis revealed the expression of CD44 and activated leukocyte adhesion molecule (ALCAM/CD166); these may prove to be markers able to identify this cell type. In conclusion, we identify a tumor-initiating population from an atypical meningioma that displays a unique phenotype and these results provide increased understanding of atypical meningioma progression. Part 1 of 2: Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from primary tissue and their counterpart cell lines Part 2 of 2: Illumina gene expression array analysis was performed according to the manufacturer's directions on RNA extracted from cultured primary Meningioma and neural stem cell lines

Project description:BackgroundTreatment failures in cancers, including multiple myeloma (MM), are most likely due to the persistence of a minor population of tumor-initiating cells (TICs), which are noncycling or slowly cycling and very drug resistant.MethodsGene expression profiling and real-time quantitative reverse transcription polymerase chain reaction were employed to define genes differentially expressed between the side-population cells, which contain the TICs, and the main population of MM cells derived from 11 MM patient samples. Self-renewal potential was analyzed by clonogenicity and drug resistance of CD24+ MM cells. Flow cytometry (n = 60) and immunofluorescence (n = 66) were applied on MM patient samples to determine CD24 expression. Therapeutic effects of CD24 antibodies were tested in xenograft MM mouse models containing three to six mice per group.ResultsCD24 was highly expressed in the side-population cells, and CD24+ MM cells exhibited high expression of induced pluripotent or embryonic stem cell genes. CD24+ MM cells showed increased clonogenicity, drug resistance, and tumorigenicity. Only 10 CD24+ MM cells were required to develop plasmacytomas in mice (n = three of five mice after 27 days). The frequency of CD24+ MM cells was highly variable in primary MM samples, but the average of CD24+ MM cells was 8.3% after chemotherapy and in complete-remission MM samples with persistent minimal residual disease compared with 1.0% CD24+ MM cells in newly diagnosed MM samples (n = 26). MM patients with a high initial percentage of CD24+ MM cells had inferior progression-free survival (hazard ratio [HR] = 3.81, 95% confidence interval [CI] = 5.66 to 18.34, P < .001) and overall survival (HR = 3.87, 95% CI = 16.61 to 34.39, P = .002). A CD24 antibody inhibited MM cell growth and prevented tumor progression in vivo.ConclusionOur studies demonstrate that CD24+ MM cells maintain the TIC features of self-renewal and drug resistance and provide a target for myeloma therapy.

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

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

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