title: Upregulation of Periostin and Reactive Stroma Is Associated with Primary Chemoresistance and Predicts Clinical Outcomes in Epithelial Ovarian Cancer.
abstract: OBJECTIVE
  Up to one third of ovarian cancer patients are intrinsically resistant to platinum-based treatment. However, predictive and therapeutic strategies are lacking due to a poor understanding of the underlying molecular mechanisms. This study aimed to identify key molecular characteristics that are associated with primary chemoresistance in epithelial ovarian cancers.
  
  
  METHODS
  Gene expression profiling was performed on a discovery set of 85 ovarian tumors with clinically well-defined response to chemotherapies as well as on an independent validation dataset containing 138 ovarian patients from the chemotreatment arm of the ICON7 trial.
  
  
  RESULTS
  We identified a distinct "reactive stroma" gene signature that is specifically associated with primary chemoresistant tumors and was further upregulated in posttreatment recurrent tumors. Immunohistochemistry (IHC) and RNA in situ hybridization (RNA ISH) analyses on three of the highest-ranked signature genes (POSTN, LOX, and FAP) confirmed that modulation of the reactive stroma signature genes within the peritumoral stromal compartments was specifically associated with the clinical chemoresistance. Consistent with these findings, chemosensitive ovarian cells grown in the presence of recombinant POSTN promoted resistance to carboplatin and paclitaxel treatment in vitro. Finally, we validated the reactive stroma signature in an independent dataset and demonstrated that a high POSTN expression level predicts shorter progression-free survival following first-line chemotherapy.
  
  
  CONCLUSIONS
  Our findings highlight the important interplay between cancer and the tumor microenvironment in ovarian cancer biology and treatment. The identified reactive stromal components in this study provide a molecular basis to the further development of novel diagnostic and therapeutic strategies for overcoming chemoresistance in ovarian cancer.
authors.affiliation: Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, California.
authors.forename: Lisa
authors.initials: L
authors.lastname: Ryner
authors.affiliation: Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, California.
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Guan
authors.affiliation: Department of Pathology, Genentech, Inc., South San Francisco, California.
authors.forename: Ron
authors.initials: R
authors.lastname: Firestein
authors.affiliation: Department of Biostatistics, Genentech, Inc., South San Francisco, California.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Department of Biostatistics, Genentech, Inc., South San Francisco, California.
authors.forename: Younjeong
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Department of Biostatistics, Genentech, Inc., South San Francisco, California.
authors.forename: Christina
authors.initials: C
authors.lastname: Rabe
authors.affiliation: Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, California.
authors.forename: Shan
authors.initials: S
authors.lastname: Lu
authors.affiliation: Department of Pathology, Genentech, Inc., South San Francisco, California.
authors.forename: Eloisa
authors.initials: E
authors.lastname: Fuentes
authors.affiliation: Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, California.
authors.forename: Ling-Yuh
authors.initials: LY
authors.lastname: Huw
authors.affiliation: Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, California.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Lackner
authors.affiliation: Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, California.
authors.forename: Ling
authors.initials: L
authors.lastname: Fu
authors.affiliation: Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, California.
authors.forename: Lukas C
authors.initials: LC
authors.lastname: Amler
authors.affiliation: Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, California.
authors.forename: Carlos
authors.initials: C
authors.lastname: Bais
authors.affiliation: Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, California. wang.yulei@gene.com.
authors.forename: Yulei
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016190:Carboplatin / Q000494:pharmacology; D000077216:Carcinoma, Ovarian Epithelial; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D017239:Paclitaxel / Q000494:pharmacology; D059467:Transcriptome; D016896:Treatment Outcome; D059016:Tumor Microenvironment; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; C512835:POSTN protein, human; D016190:Carboplatin; D017239:Paclitaxel