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Tumor Biology

, Volume 37, Issue 9, pp 11909–11916 | Cite as

Circulating levels of TNF-related apoptosis inducing-ligand are decreased in patients with large adult-type granulosa cell tumors—implications for therapeutic potential

  • Anniina Färkkilä
  • Giorgio Zauli
  • Ulla-Maija Haltia
  • Marjut Pihlajoki
  • Leila Unkila-Kallio
  • Paola Secchiero
  • Markku Heikinheimo
Original Article

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.

Keywords

Estradiol FSH GATA4 Granulosa cell tumor LH Ovarian cancer Targeted treatment TRAIL 

Notes

Acknowledgments

We thank Dr. Annika Riska and the staff from the Department of Obstetrics and Gynecology of Helsinki University Central Hospital for patient recruitment, Dr. Noora Andersson for excellent practical assistance, and PhD Emmi Tikkanen for statistical advice. This study was supported by grants from from the Academy of Finland, the Clinical Chemistry Research Foundation Finland, the Helsinki University Central Hospital Research Funds, the Maud Kuistila Memorial Foundation, the Sigrid Juselius Foundation, and the Sladjana M. Crosley Foundation for AGCT research.

Author contributions

AF collected the samples, produced and analyzed the data, carried out the statistical analyses and wrote the manuscript; GZ produced and analyzed the data and drafted the manuscript; U-MH and MP performed immunohistochemistry, cell culture studies, qPCR, and analyzed the data; PS, LU-K and MH collected the samples, conceived of the study and interpreted the data; All authors wrote the manuscript, and read and approved this version of the manuscript.

Compliance with ethical standards

The ethical committee of Helsinki University Central Hospital (HUCH) and the National Supervisory Authority for Welfare and Health in Finland approved the study, and all patients gave their informed consent.

Conflicts of Interest

None

Supplementary material

13277_2016_5042_Fig4_ESM.gif (24 kb)
Supplemental Figure 1

Relative TRAIL mRNA expression in 46 AGCT samples and human granulosa-luteal cells. (GIF 24 kb)

13277_2016_5042_MOESM1_ESM.tif (843 kb)
High Resolution Image (TIF 843 kb)
13277_2016_5042_MOESM2_ESM.xlsx (57 kb)
Supplemental Table 1 qPCR data from 46 AGCT samples and one human granulosa cell sample. (XLSX 56 kb)

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Anniina Färkkilä
    • 1
    • 2
  • Giorgio Zauli
    • 3
  • Ulla-Maija Haltia
    • 1
    • 2
  • Marjut Pihlajoki
    • 1
    • 2
  • Leila Unkila-Kallio
    • 1
  • Paola Secchiero
    • 4
  • Markku Heikinheimo
    • 2
    • 5
  1. 1.Deparment of Obstetrics and GynecologyUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland
  2. 2.Children’s Hospital, Pediatric Research CenterUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland
  3. 3.Institute for Maternal and Child HealthIRCCS “Burlo Garofolo”TriesteItaly
  4. 4.Department of Morphology, Surgery, Experimental Medicine and LTTA CentreUniversity of FerraraFerraraItaly
  5. 5.Department of PediatricsWashington University School of Medicine, St Louis Children’s HospitalSt LouisUSA

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