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The extrinsic apoptosis pathway and its prognostic impact in ovarian cancer

Evelien W Duiker1, Ate G J van der Zee, Pauline de Graeff

  • 1Department of Medical Oncology, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands.

Gynecologic Oncology
|December 5, 2009
PubMed
Abstract

Insights

Loss of Fas and TRAIL expression in ovarian cancer correlates with poorer prognosis and dedifferentiation. While most tumors express DR4, DR5, caspase 8, and c-FLIP, only Fas and TRAIL levels impact survival, suggesting targeted therapies should consider c-FLIP levels.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Death ligands (FasL, TRAIL) and their receptors (Fas, DR4, DR5) are implicated in cancer development, immune surveillance, and chemotherapy response.
  • Tumor necrosis factor related apoptosis inducing ligand (TRAIL) receptor agonists are under investigation as anti-cancer therapeutics.
  • Caspase 8 and its inhibitor c-FLIP play crucial roles in apoptosis signaling pathways relevant to cancer.

Purpose of the Study:

  • To investigate the correlation between the expression of death pathway components (Fas, FasL, TRAIL, DR4, DR5, caspase 8, c-FLIP) in ovarian cancers.
  • To determine the relationship between these molecular markers and patient response to chemotherapy.
  • To assess the association of these markers with overall survival and progression-free survival in ovarian cancer patients.

Main Methods:

  • Immunohistochemistry was employed to quantify the expression of Fas, FasL, TRAIL, DR4, DR5, caspase 8, and c-FLIP.
  • Protein expression levels were analyzed on a tissue microarray comprising 382 ovarian cancer samples.
  • Statistical correlations were performed between marker expression, clinicopathologic variables, chemotherapy response, and survival outcomes.

Main Results:

  • High expression of c-FLIP was frequently observed and associated with caspase 8 and TRAIL receptor expression.
  • Loss of TRAIL expression correlated with lower tumor grade and improved progression-free survival (HR 0.63).
  • Loss of Fas expression was linked to better progression-free survival (HR 0.54) and disease-specific survival (HR 0.49), and associated with lower tumor grade.

Conclusions:

  • Reduced expression of Fas and TRAIL in ovarian cancers is linked to dedifferentiation and a poorer prognosis.
  • Widespread expression of DR4, DR5, caspase 8, and c-FLIP in ovarian cancers did not show a direct correlation with patient survival.
  • The expression level of c-FLIP should be considered when developing targeted therapies aimed at death receptors in ovarian cancer treatment.

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