TSAP6 is a novel candidate marker of poor survival in metastatic high-grade serous carcinoma.
The objective of this study was to analyze the expression and clinical role of molecules involved in exosome synthesis and secretion in high-grade serous carcinoma, with focus on malignant effusions. The mRNA expression levels of ARF6, nSMase2, TSAP6, Rab27a and Rab27b by quantitative real-time reverse-transcription polymerase chain reaction were analyzed in 103 HGSC effusions and 65 solid specimens (35 ovarian, 30 abdominal metastases). Protein expression of ARF6, nSMase2, TSAP6 and Rab27a by Western blotting was analyzed in 150 specimens (94 effusions, 29 ovarian carcinomas, 27 solid metastases). Secreted ARF6, nSMase2 and Rab27a protein levels in exosomes were analyzed in supernatants from 75 effusions. Expression levels were analyzed for association with anatomic site and clinical parameters, including survival. nSMase2 and TSAP6 mRNA was overexpressed in effusions compared to solid lesions (P<.001 and P=.003, respectively), whereas ARF6, nSMase2, TSAP6 and Rab27a protein was overexpressed in solid specimens (ovarian and peritoneal) compared to effusions (P<.001 for all). Secreted ARF6, nSMase2 and Rab27a levels were found in all effusion supernatants. In univariate survival analysis, higher TSAP6 protein levels in effusions were associated with shorter overall survival (P=.01), a finding which was reproduced in analysis of specimens from patients with pre-chemotherapy effusions tapped at diagnosis (P=.026). Higher levels of exosomal Rab27a protein were significantly related to longer overall survival (P=.025). Molecules which are part of the exosome secretion machinery are differentially expressed in HGSC effusions and solid lesions and are present in effusion supernatant-derived exosomes. TSAP6 and Rab27a may be novel prognostic markers in metastatic HGSC.
Institute of Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, 91120, Israel.
Esther Channah
EC
Broner
University of Oslo, Faculty of Medicine, Institute of Clinical Medicine, N-0316, Oslo, Norway.
Claes G
CG
Tropé
Institute of Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, 91120, Israel. Electronic address: reich@cc.huji.ac.il.
Reuven
R
Reich
University of Oslo, Faculty of Medicine, Institute of Clinical Medicine, N-0316, Oslo, Norway; Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital, N-0310, Oslo, Norway. Electronic address: bend@medisin.uio.no.
Ben
B
Davidson
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D015153:Blotting, Western; D018797:Cell Cycle Proteins; D018572:Disease-Free Survival; D055354:Exosomes / Q000737:chemistry* / Q000473:pathology; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D060787:Neoplasm Grading; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000737:chemistry* / Q000235:genetics / Q000556:secondary / Q000628:therapy; D015513:Oncogene Proteins / Q000032:analysis* / Q000235:genetics; D010051:Ovarian Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000473:pathology / Q000628:therapy; D010088:Oxidoreductases; D010534:Peritoneal Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000556:secondary / Q000628:therapy; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D016896:Treatment Outcome; D020691:rab GTP-Binding Proteins / Q000032:analysis; D000075745:rab27 GTP-Binding Proteins
D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D015513:Oncogene Proteins; D012333:RNA, Messenger; D000075745:rab27 GTP-Binding Proteins; D010088:Oxidoreductases; C486677:STEAP3 protein, human; C066694:RAB27A protein, human; D020691:rab GTP-Binding Proteins
Effusion; Exosomes; High-grade serous carcinoma; Survival; Tumor progression