title: Complement pathway is frequently altered in endometriosis and endometriosis-associated ovarian cancer.
abstract: OBJECTIVE
  Mechanisms of immune dysregulation associated with advanced tumors are relatively well understood. Much less is known about the role of immune effectors against cancer precursor lesions. Endometrioid and clear-cell ovarian tumors partly derive from endometriosis, a commonly diagnosed chronic inflammatory disease. We performed here a comprehensive immune gene expression analysis of pelvic inflammation in endometriosis and endometriosis-associated ovarian cancer (EAOC).
  
  
  METHODS
  RNA was extracted from 120 paraffin tissue blocks comprising of normal endometrium (n = 32), benign endometriosis (n = 30), atypical endometriosis (n = 15), and EAOC (n = 43). Serous tumors (n = 15) were included as nonendometriosis-associated controls. The immune microenvironment was profiled using Nanostring and the nCounter GX Human Immunology Kit, comprising probes for a total of 511 immune genes.
  
  
  RESULTS
  One third of the patients with endometriosis revealed a tumor-like inflammation profile, suggesting that cancer-like immune signatures may develop earlier, in patients classified as clinically benign. Gene expression analyses revealed the complement pathway as most prominently involved in both endometriosis and EAOC. Complement proteins are abundantly present in epithelial cells in both benign and malignant lesions. Mechanistic studies in ovarian surface epithelial cells from mice with conditional (Cre-loxP) mutations show intrinsic production of complement in epithelia and demonstrate an early link between Kras- and Pten-driven pathways and complement upregulation. Downregulation of complement in these cells interferes with cell proliferation.
  
  
  CONCLUSIONS
  These findings reveal new characteristics of inflammation in precursor lesions and point to previously unknown roles of complement in endometriosis and EAOC.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine and Magee Women's Research Institute, Pittsburgh, Pennsylvania.
authors.forename: Swati
authors.initials: S
authors.lastname: Suryawanshi
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine and Magee Women's Research Institute, Pittsburgh, Pennsylvania.
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Magee Women's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh Pennsylvania.
authors.forename: Esther
authors.initials: E
authors.lastname: Elishaev
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine and Magee Women's Research Institute, Pittsburgh, Pennsylvania.
authors.forename: Raluca A
authors.initials: RA
authors.lastname: Budiu
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine and Magee Women's Research Institute, Pittsburgh, Pennsylvania.
authors.forename: Lixin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Statistics University of Pittsburgh, Graduate School of Public Health, Pittsburgh Pennsylvania.
authors.forename: SungHwan
authors.initials: S
authors.lastname: Kim
authors.affiliation: Magee Women's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh Pennsylvania.
authors.forename: Nicole
authors.initials: N
authors.lastname: Donnellan
authors.affiliation: Section of Gynecologic Oncology, Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Gina
authors.initials: G
authors.lastname: Mantia-Smaldone
authors.affiliation: Department of Statistics University of Pittsburgh, Graduate School of Public Health, Pittsburgh Pennsylvania.
authors.forename: Tianzhou
authors.initials: T
authors.lastname: Ma
authors.affiliation: Department of Statistics University of Pittsburgh, Graduate School of Public Health, Pittsburgh Pennsylvania.
authors.forename: George
authors.initials: G
authors.lastname: Tseng
authors.affiliation: Magee Women's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh Pennsylvania.
authors.forename: Ted
authors.initials: T
authors.lastname: Lee
authors.affiliation: Magee Women's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh Pennsylvania.
authors.forename: Suketu
authors.initials: S
authors.lastname: Mansuria
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine and Magee Women's Research Institute, Pittsburgh, Pennsylvania. Magee Women's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh Pennsylvania.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Edwards
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine and Magee Women's Research Institute, Pittsburgh, Pennsylvania. vladam@upmc.edu.
authors.forename: Anda M
authors.initials: AM
authors.lastname: Vlad
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000276:immunology; D016000:Cluster Analysis; D003167:Complement Activation / Q000235:genetics / Q000276:immunology*; D003184:Complement C7 / Q000235:genetics / Q000276:immunology; D003165:Complement System Proteins / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D004715:Endometriosis / Q000150:complications* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D007157:Immunologic Surveillance; D051379:Mice; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000209:etiology* / Q000473:pathology; D012307:Risk Factors
chemical_list: D003184:Complement C7; D003165:Complement System Proteins