Activity and clinical relevance of autotaxin and lysophosphatidic acid pathways in high-grade serous carcinoma

Abstract

The aim of this study was to analyze the expression, biological role and clinical relevance of autotaxin (ATX), the enzyme synthetizing lysophosphatidic acid (LPA), and LPA receptors (LPAR) in high-grade serous carcinoma (HGSC). mRNA expression by qRT-PCR of LPAR1-6 was analyzed in 155 HGSC specimens (88 effusions, 67 solid lesions). ATX mRNA expression was analyzed in 97 specimens. ATX, ERK, and AKT protein expression was studied by Western blotting. LPAR2 mRNA was overexpressed in HGSC cells in effusions compared to solid lesions, with opposite findings for LPAR3 and LPAR6 mRNA and ATX protein. Higher LPAR1 levels were significantly related to longer overall survival (OS) in pre-chemotherapy effusions (p = 0.027). Conversely, higher expression of LPAR1, LPAR2, and LPAR5 in post-chemotherapy effusions was significantly associated with shorter OS (p = 0.037, p = 0.025 and p = 0.021, respectively) and progression-free survival (PFS) (p < 0.001, p = 0.007 and p < 0.001, respectively) in univariate survival analysis. LPAR1 mRNA expression was an independent prognosticator of OS in patients with pre-chemotherapy effusions and PFS in patients with post-chemotherapy effusions (p = 0.013 both). In conclusion, LPAR mRNA and ATX protein levels are anatomic site-dependent in HGSC and the former are informative of disease outcome.

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Funding

This work was supported by The Inger and John Fredriksen Foundation for Ovarian Cancer Research.

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Authors

Contributions

HO performed the experiments and wrote the manuscript. LJC participated in performing the experiments and critically read the manuscript. CGT provided clinical data and critically read the manuscript. TEHF provided clinical data and critically read the manuscript. BD designed the study, performed the statistical analysis, and supervised the writing of the manuscript. RR designed the study, supervised the experiments, and participated in writing the manuscript.

Corresponding authors

Correspondence to Reuven Reich or Ben Davidson.

Ethics declarations

The study was approved by the Regional Committee for Medical Research Ethics in Norway.

Conflict of interest

The authors declare that they have no conflicts of interest.

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Onallah, H., Catane, L.J., Tropé, C.G. et al. Activity and clinical relevance of autotaxin and lysophosphatidic acid pathways in high-grade serous carcinoma. Virchows Arch 473, 463–470 (2018). https://doi.org/10.1007/s00428-018-2418-x

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Keywords

  • Lysophosphatidic acid
  • Autotaxin
  • High-grade serous carcinoma
  • Effusion
  • Survival