title: Circulating levels of TNF-related apoptosis inducing-ligand are decreased in patients with large adult-type granulosa cell tumors-implications for therapeutic potential.
abstract: Targeted treatments are needed for advanced adult-type granulosa cell tumors (AGCTs). We set out to assess tumor tissue and circulating levels of TNF-related apoptosis-inducing ligand (TRAIL), a promising anti-cancer cytokine, in patients affected by AGCT. We analyzed tissue expression of TRAIL in 127 AGCTs using immunohistochemistry or RT-PCR. Soluble TRAIL was measured by means of ELISA from 141 AGCT patient serum samples, as well as the conditioned media of 15 AGCT patient-derived primary cell cultures, and the KGN cell line. Tissue and serum TRAIL levels were analyzed in relationship with clinical parameters, and serum estradiol, FSH, and LH levels. We found that AGCT samples expressed TRAIL mRNA and protein at levels comparable to normal granulosa cells. AGCT cells did not release soluble TRAIL. TRAIL protein levels were decreased in tumors over 10 cm in diameter (p = 0.04). Consistently, circulating TRAIL levels correlated negatively to tumor dimension (p = 0.01). Circulating TRAIL levels negatively associated with serum estradiol levels. In multiple regression analysis, tumor size was an independent factor contributing to the decreased levels of soluble TRAIL in AGCT patients. AGCTs associate with significantly decreased tumor tissue and serum TRAIL levels in patients with a large tumor mass. These findings encourage further study of agonistic TRAIL treatments in patients with advanced or recurrent AGCT.
authors.affiliation: Deparment of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, 00014, Helsinki, Finland. anniina.farkkila@helsinki.fi.|Children's Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, 00014, Helsinki, Finland. anniina.farkkila@helsinki.fi.
authors.forename: Anniina
authors.initials: A
authors.lastname: Färkkilä
authors.affiliation: Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Zauli
authors.affiliation: Deparment of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, 00014, Helsinki, Finland.|Children's Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, 00014, Helsinki, Finland.
authors.forename: Ulla-Maija
authors.initials: UM
authors.lastname: Haltia
authors.affiliation: Deparment of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, 00014, Helsinki, Finland.|Children's Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, 00014, Helsinki, Finland.
authors.forename: Marjut
authors.initials: M
authors.lastname: Pihlajoki
authors.affiliation: Deparment of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, 00014, Helsinki, Finland.
authors.forename: Leila
authors.initials: L
authors.lastname: Unkila-Kallio
authors.affiliation: Department of Morphology, Surgery, Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Secchiero
authors.affiliation: Children's Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, 00014, Helsinki, Finland.|Department of Pediatrics, Washington University School of Medicine, St Louis Children's Hospital, St Louis, MO, 63110, USA.
authors.forename: Markku
authors.initials: M
authors.lastname: Heikinheimo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D004958:Estradiol / Q000097:blood; D005260:Female; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D006106:Granulosa Cell Tumor / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D053221:TNF-Related Apoptosis-Inducing Ligand; D004958:Estradiol
keywords: Estradiol; FSH; GATA4; Granulosa cell tumor; LH; Ovarian cancer; TRAIL; Targeted treatment