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Cathepsin L-induced galectin-1 may act as a proangiogenic factor in the metastasis of high-grade serous carcinoma.
Pranjol, Md Zahidul I; Zinovkin, Dmitry A; Maskell, Annelie R T; Stephens, Laura J; Achinovich, Sergey L; Los', Dmitry M; Nadyrov, Eldar A; Hannemann, Michael; Gutowski, Nicholas J; Whatmore, Jacqueline L.
Afiliación
  • Pranjol MZI; Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, Devon, EX1 2LU, UK.
  • Zinovkin DA; William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.
  • Maskell ART; Department of Pathology, Gomel State Medical University, 246000, Gomel, Belarus.
  • Stephens LJ; Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, Devon, EX1 2LU, UK.
  • Achinovich SL; Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, Devon, EX1 2LU, UK.
  • Los' DM; Department of Anatomical Pathology, Gomel Regional Clinical Oncological Dispensary, 246012, Gomel, Belarus.
  • Nadyrov EA; Gomel Regional Clinical Oncological Dispensary, 246012, Gomel, Belarus.
  • Hannemann M; Department of Pathology, Gomel State Medical University, 246000, Gomel, Belarus.
  • Gutowski NJ; Royal Devon and Exeter NHS Foundation Trust, Exeter, Devon, EX2 5DW, UK.
  • Whatmore JL; Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, Devon, EX1 2LU, UK.
J Transl Med ; 17(1): 216, 2019 07 03.
Article en En | MEDLINE | ID: mdl-31269957
BACKGROUND: New treatment options for metastasised high-grade serous carcinoma (HGSC) are urgently needed. HGSC frequently metastasises to the omentum, inducing angiogenesis in the local omental microvasculature to facilitate tumour growth. We previously showed that HGSC-secreted cathepsin L (CathL) induces pro-angiogenic changes in disease relevant human omental microvascular endothelial cells (HOMECs), suggesting a role in tumour angiogenesis. Here we investigate whether CathL acts by inducing local production of the carbohydrate-binding protein galectin-1 (Gal1), which has been reported to be involved in tumourigenesis in other tumours. METHODS: HOMECs were used for all experiments. Gal1 mRNA and protein levels were measured by RT-PCR and ELISA respectively. Gal1-induced cell proliferation was assessed using WST-1 assay, migration using a transwell assay and in vivo Gal1 expression by immunohistochemistry. RESULTS: CathL transcriptionally regulated HOMEC production and secretion of Gal1 via activation of NFκB (significantly inhibited by sulfasalazine). Gal1 significantly enhanced HOMEC migration (p < 0.001) and proliferation (p < 0.001), suggesting an autocrine action. The latter was significantly reduced by the MEK/ERK1/2 inhibitors U0126 and PD98059 suggesting downstream activation of this pathway. Immunohistochemical analysis of omenta from HGSC patients with or without metastatic disease demonstrated a positive correlation between Gal1 expression and number of microvessels (r = 0.8702, p < 0.001), and area of vessels (r = 0.7283, p < 0.001), supporting a proangiogenic role for Gal1 in omental metastases. CONCLUSION: HOMEC Gal1 transcription and release in response to CathL secreted from metastasising HGSC acts in an autocrine manner on the local microvasculature to induce pro-angiogenic changes, highlighting a potential new therapeutic target.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Peritoneales / Neoplasias Quísticas, Mucinosas y Serosas / Galectina 1 / Catepsina L / Neovascularización Patológica Límite: Adult / Female / Humans / Middle aged Idioma: En Revista: J Transl Med Año: 2019 Tipo del documento: Article Pais de publicación: Reino Unido
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Peritoneales / Neoplasias Quísticas, Mucinosas y Serosas / Galectina 1 / Catepsina L / Neovascularización Patológica Límite: Adult / Female / Humans / Middle aged Idioma: En Revista: J Transl Med Año: 2019 Tipo del documento: Article Pais de publicación: Reino Unido