title: Predictive markers of chemoresistance in advanced stages epithelial ovarian carcinoma.
abstract: OBJECTIVE
  DNA repair mechanisms, environment-mediated drug resistance and cancer initiating cells (CIC) are three major research concepts that can explain the chemoresistance of epithelial ovarian cancer (EOC). The objective was to test if changes in the expression of potential markers associated with drug resistance before and after chemotherapy would correlate with platinum resistance, defined as a recurrence within the first year after chemotherapy cessation, and with survival, in advanced EOC.
  
  
  METHODS
  We included 32 patients with stage IIIC-IV EOC who underwent laparoscopy to evaluate the extent of carcinomatosis, neoadjuvant chemotherapy (carboplatin/taxol) and interval surgery. Biopsies taken during the initial laparoscopies and interval surgeries were evaluated using immunohistochemistry for the expression of 7 proteins: CD117, CD44 and ALDH1 to evaluate CIC; IL-6, IL-8 and BMP2 to evaluate environment-mediated drug resistance; and ERCC1 to evaluate DNA repair. Expression measurements were correlated with platin resistance and survival. The markers' relevance was confirmed in vitro using chemoresistance tests and flow cytometric measurements of the proportion of CD44+ cells.
  
  
  RESULTS
  17 patients were chemoresistant and 15 patients were chemosensitive. We observed increases in CD44, IL-6 and ERCC1 expression and stable ALDH1, CD117, IL-8, and BMP2 expression. Reduced expression of cancer initiating cell markers and increased expression of environment-mediated drug resistance markers were associated with poor prognosis. We also demonstrated that CD44+ cells had survival advantages in vitro.
  
  
  CONCLUSIONS
  Changes in CD44 and IL-8 expression on tumor cells appeared to correlate with overall survival and should be further tested as predictors of chemoresistance using larger cohort.
authors.affiliation: UMRS 938 INSERM, Université Pierre et Marie Curie-Paris 6, 27 rue de Chaligny, 75571 Paris cedex 12, France; Department of Gynecology-Obstetrics and Reproductive Medicine, Hôpitaux Universitaires Paris-Est, Assistance Publique des Hôpitaux de Paris, Hôpital Tenon, Institut Universitaire de Cancérologie, Université Pierre et Marie Curie, 4 Rue de la Chine, 75020 Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Bonneau
authors.affiliation: Department of Surgery, Institut Curie, Paris Saint-Cloud, Université Versailles-Saint-Quentin-en-Yvelines, 35 Rue Dailly, 92210 Saint-Cloud, France.
authors.forename: Roman
authors.initials: R
authors.lastname: Rouzier
authors.affiliation: UMR INSERM U965, Angiogenèse et Recherche translationnelle, Hôpital Lariboisière, 49 bd de la chapelle, 75010 Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Geyl
authors.affiliation: Department of Pathology, Hôpital Tenon, 4 Rue de la Chine, 75020 Paris, France.
authors.forename: Annie
authors.initials: A
authors.lastname: Cortez
authors.affiliation: UMRS 938 INSERM, Université Pierre et Marie Curie-Paris 6, 27 rue de Chaligny, 75571 Paris cedex 12, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Castela
authors.affiliation: Weill Cornell Medical College, Department of Genetic Medicine, Shahin Rafii' Laboratory, Ansary Stem Cell Institute, 510 East 70th Street, Building A, New York, NY 10065, USA.
authors.forename: Raphael
authors.initials: R
authors.lastname: Lis
authors.affiliation: UMRS 938 INSERM, Université Pierre et Marie Curie-Paris 6, 27 rue de Chaligny, 75571 Paris cedex 12, France; Department of Gynecology-Obstetrics and Reproductive Medicine, Hôpitaux Universitaires Paris-Est, Assistance Publique des Hôpitaux de Paris, Hôpital Tenon, Institut Universitaire de Cancérologie, Université Pierre et Marie Curie, 4 Rue de la Chine, 75020 Paris, France.
authors.forename: Emile
authors.initials: E
authors.lastname: Daraï
authors.affiliation: UMR INSERM U965, Angiogenèse et Recherche translationnelle, Hôpital Lariboisière, 49 bd de la chapelle, 75010 Paris, France; Department of Obstetrics and Gynecology, Hôpital Intercommunal de Créteil, Université Paris Est, Paris XII, 40 avenue de Verdun, 94000 Créteil, France. Electronic address: cyril.touboul@gmail.com.
authors.forename: Cyril
authors.initials: C
authors.lastname: Touboul
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D016190:Carboplatin / Q000008:administration & dosage; D000077216:Carcinoma, Ovarian Epithelial; D017024:Chemotherapy, Adjuvant; D004268:DNA-Binding Proteins / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004720:Endonucleases / Q000378:metabolism; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D017239:Paclitaxel / Q000008:administration & dosage
chemical_list: D014408:Biomarkers, Tumor; C497483:CD44 protein, human; D004268:DNA-Binding Proteins; D018960:Hyaluronan Receptors; D015850:Interleukin-6; D016209:Interleukin-8; D016190:Carboplatin; C071447:ERCC1 protein, human; D004720:Endonucleases; D017239:Paclitaxel
keywords: Cancer associated stroma; Cancer stem cells; Chemoresistance; Cytokines; Ovarian carcinoma