High Cysteinyl Leukotriene Receptor 1 Expression Correlates with Poor Survival of Uveal Melanoma Patients and Cognate Antagonist Drugs Modulate the Growth, Cancer Secretome, and Metabolism of Uveal Melanoma Cells

Cancers

SarahE. Coupland¹  Helen Kalirai¹  JosepM. Piulats²  AislingB. Heeran³  Fiona O’Connell³  Jacintha O’Sullivan³  Nebras Al-Attar⁴  BreandánN. Kennedy⁴  WilliamM. Gallagher⁴  Arman Rahman⁴  Kayleigh Slater⁴  Rebeca Sanz-Pamplona⁵  Sandra Garcia-Mulero⁵  LasseD. Jensen⁶  Mays Helmi⁶  Anna Portela⁷  Rosa Bosch⁷  Alberto Villanueva⁷ 

[1] Liverpool Ocular Oncology Research Group, Department of Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L7 8TX, UK;Medical Oncology Department, Catalan Institute of Cancer (ICO), IDIBELL-OncoBell, Hospitalet de Llobregat, 08908 Barcelona, Spain;Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St. James’s Hospital, D08 W9RT Dublin, Ireland;UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, D04 V1W8 Dublin, Ireland;Unit of Biomarkers and Susceptibility, Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL) and CIBERESP, L’Hospitalet de Llobregat, 08908 Barcelona, Spain;Unit of Cardiovascular Medicine, Division of Diagnostics and Specialist Medicine, Department of Health, Medical and Caring Sciences, Linköping University, SE-581 83 Linköping, Sweden;Xenopat S.L., Parc Científic de Barcelona, Baldiri Reixac, 15-21 Edifici Hèlix, 08028 Barcelona, Spain;

关键词: uveal melanoma;    cysteinyl leukotriene receptors;    patient survival;    G protein-coupled receptors;    angiogenesis;    inflammation;   

DOI  :  10.3390/cancers12102950

来源: DOAJ

【 摘 要 】

Metastatic uveal melanoma (UM) is a rare, but often lethal, form of ocular cancer arising from melanocytes within the uveal tract. UM has a high propensity to spread hematogenously to the liver, with up to 50% of patients developing liver metastases. Unfortunately, once liver metastasis occurs, patient prognosis is extremely poor with as few as 8% of patients surviving beyond two years. There are no standard-of-care therapies available for the treatment of metastatic UM, hence it is a clinical area of urgent unmet need. Here, the clinical relevance and therapeutic potential of cysteinyl leukotriene receptors (CysLT₁ and CysLT₂) in UM was evaluated. High expression of CYSLTR1 or CYSLTR2 transcripts is significantly associated with poor disease-free survival and poor overall survival in UM patients. Digital pathology analysis identified that high expression of CysLT₁ in primary UM is associated with reduced disease-specific survival (p = 0.012; HR 2.76; 95% CI 1.21–6.3) and overall survival (p = 0.011; HR 1.46; 95% CI 0.67–3.17). High CysLT₁ expression shows a statistically significant (p = 0.041) correlation with ciliary body involvement, a poor prognostic indicator in UM. Small molecule drugs targeting CysLT₁ were vastly superior at exerting anti-cancer phenotypes in UM cell lines and zebrafish xenografts than drugs targeting CysLT₂. Quininib, a selective CysLT₁ antagonist_, significantly inhibits survival (p < 0.0001), long-term proliferation (p < 0.0001), and oxidative phosphorylation (p < 0.001), but not glycolysis, in primary and metastatic UM cell lines. Quininib exerts opposing effects on the secretion of inflammatory markers in primary versus metastatic UM cell lines. Quininib significantly downregulated IL-2 and IL-6 in Mel285 cells (p < 0.05) but significantly upregulated IL-10, IL-1β, IL-2 (p < 0.0001), IL-13, IL-8 (p < 0.001), IL-12p70 and IL-6 (p < 0.05) in OMM2.5 cells. Finally, quininib significantly inhibits tumour growth in orthotopic zebrafish xenograft models of UM. These preclinical data suggest that antagonism of CysLT₁, but not CysLT₂, may be of therapeutic interest in the treatment of UM.

【 授权许可】

Unknown