Expression of the peroxisome proliferator-activated receptors-alpha, -beta, and -gamma in ovarian carcinoma effusions is associated with poor chemoresponse and shorter survival

Hum Pathol. 2009 May;40(5):705-13. doi: 10.1016/j.humpath.2008.09.019. Epub 2009 Jan 20.

Abstract

Peroxisome proliferator-activated receptors regulate lipid metabolism, affecting inflammation and cancer. The present study analyzed the anatomical site-related expression and prognostic role of peroxisome proliferator-activated receptors in ovarian carcinoma. Fresh-frozen effusions (n = 79), primary carcinomas (n = 44), and solid metastases (n = 16) were studied for peroxisome proliferator-activated receptor-alpha, -beta, and -gamma messenger RNA expression using reverse transcriptase polymerase chain reaction. Peroxisome proliferator-activated receptor-gamma messenger RNA expression was further assessed in 60 tumors (30 effusions, 20 primary carcinomas, 10 metastases) using in situ hybridization. Peroxisome proliferator-activated receptor-gamma protein expression was immunohistochemically analyzed in 160 effusions. All peroxisome proliferator-activated receptors were expressed in most tumors at all anatomical sites using reverse transcriptase polymerase chain reaction, but peroxisome proliferator-activated receptor-alpha (P = .004) and peroxisome proliferator-activated receptor-beta (P = .002) messenger RNA levels were higher in effusions compared with primary carcinomas and solid metastases. In situ hybridization localized peroxisome proliferator-activated receptor-gamma messenger RNA to carcinoma cells in both effusions and solid lesions. Peroxisome proliferator-activated receptor-gamma protein was detected in carcinoma cells in 102 of 160 (64%) effusions. Higher effusion messenger RNA levels of all peroxisome proliferator-activated receptors were associated with less favorable response to chemotherapy at diagnosis (P = .009). In univariate survival analysis, higher messenger RNA expression of all peroxisome proliferator-activated receptors was associated with poor progression-free (P = .045) and overall (P = .014) survival. Higher peroxisome proliferator-activated receptor-gamma protein expression was similarly associated with poor overall survival for the entire cohort (P = .046) and for patients with disease recurrence effusions (P = .009). Peroxisome proliferator-activated receptors were not independent predictors of survival in Cox multivariate analysis. Peroxisome proliferator-activated receptor members are frequently expressed in ovarian carcinoma, with upregulated expression in effusions. Peroxisome proliferator-activated receptor expression in effusions is associated with poor response to chemotherapy at disease recurrence and poor survival, suggesting a role in tumor biology at this unique microenvironment.

MeSH terms

  • Adult
  • Aged
  • Antigens, Human Platelet / biosynthesis
  • Antineoplastic Agents / therapeutic use
  • Ascitic Fluid
  • Carcinoma / metabolism*
  • Carcinoma / mortality
  • Carcinoma / pathology
  • Disease-Free Survival
  • Female
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization
  • Kaplan-Meier Estimate
  • Middle Aged
  • Ovarian Neoplasms / metabolism*
  • Ovarian Neoplasms / mortality
  • Ovarian Neoplasms / pathology
  • PPAR alpha / biosynthesis*
  • PPAR gamma / biosynthesis*
  • PPAR-beta / biosynthesis*
  • Pleural Effusion, Malignant
  • Prognosis
  • RNA, Messenger / analysis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Treatment Outcome

Substances

  • Antigens, Human Platelet
  • Antineoplastic Agents
  • PPAR alpha
  • PPAR gamma
  • PPAR-beta
  • RNA, Messenger
  • human platelet antigen 1b