title: Ovarian carcinoma tumor-initiating cells have a mesenchymal phenotype.
abstract: Solid tumors appear to contain a subpopulation of cells (tumor-initiating cells, TICs) that not only drives and sustains tumor growth, but is possibly responsible for recurrence. We isolated, after enzymatic digestion of primary ovarian carcinoma samples, a subpopulation of cells propagating as non-adherent spheres in medium suitable for tumor stem cells. These cells were able to self-renew in vitro, as suggested by PKH-26 staining studies, were tumorigenic and acquired an epithelial morphology when grown in FBS-supplemented medium, losing their tumorigenic potential. Interestingly, the tumorigenic potential of PKH-26 (high) - and PKH-26 (neg) -sorted cells was similar. These TIC-enriched cultures showed higher levels of genes involved in stemness than differentiated cells derived from them and were more resistant to the cytotoxic effects of some drugs but equally sensitive to others. The higher level of ABCG2 efflux pump could explain increased resistance to taxol and VP16, and higher levels of genes involved in nucleotide excision repair partially explain the resistance to cisplatin. These cells express mesenchymal markers, and epithelial transition could be induced when cultured in differentiating conditions, with a loss of invasive potential. These data suggest that ovarian cancer is a stem cell disease and should help elucidate the role of these cells in the aggressive phenotype of this tumor and find new therapeutic strategies to reduce resistance to current chemotherapeutic drugs.
authors.affiliation: Department of Oncology; Istituto di Ricerche Farmacologiche Mario Negri; Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Ricci
authors.forename: Sergio
authors.initials: S
authors.lastname: Bernasconi
authors.forename: Patrizia
authors.initials: P
authors.lastname: Perego
authors.forename: Monica
authors.initials: M
authors.lastname: Ganzinelli
authors.forename: Giorgio
authors.initials: G
authors.lastname: Russo
authors.forename: Francesca
authors.initials: F
authors.lastname: Bono
authors.forename: Costantino
authors.initials: C
authors.lastname: Mangioni
authors.forename: Robert
authors.initials: R
authors.lastname: Fruscio
authors.forename: Mario
authors.initials: M
authors.lastname: Signorelli
authors.forename: Massimo
authors.initials: M
authors.lastname: Broggini
authors.forename: Giovanna
authors.initials: G
authors.lastname: Damia
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism; D009930:Organic Chemicals / Q000737:chemistry; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D009930:Organic Chemicals; C070080:PKH 26; D005047:Etoposide; D017239:Paclitaxel; D002945:Cisplatin