Cathepsin L-induced galectin-1 may act as a proangiogenic factor in the metastasis of high-grade serous carcinoma

Md Zahidul I Pranjol,Dmitry M Los’,Annelie R T Maskell,Jacqueline L Whatmore,Nicholas J Gutowski,Dmitry A Zinovkin,Laura J Stephens,Eldar A Nadyrov,Sergey L Achinovich,Michael Hannemann

doi:10.1186/s12967-019-1963-7

Abstract

BackgroundNew 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.MethodsHOMECs 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.ResultsCathL 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.ConclusionHOMEC 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.

Highlights

New treatment options for metastasised high-grade serous carcinoma (HGSC) are urgently needed
cathepsin L (CathL) induces secretion of Gal1 Our recent data suggests a mitogen ligand-like activity for CathL in human omental microvascular endothelial cells (HOMECs) [11], and our unpublished, preliminary data indicates that CathL induces a differential expression of galectin1 (Gal1) mRNA (LGALS1) in these cells
Gal1 release was not induced in HOMECs treated with the other HGSC-secreted factors insulin-like growth factor binding protein 7 and cathepsins D (CathD), suggesting that Gal1 secretion may be CathL-specific

Summary

Introduction

New treatment options for metastasised high-grade serous carcinoma (HGSC) are urgently needed. Primary HGSC cells commonly metastasise to the omentum where secondary tumour establishment requires local neoangiogenesis to supply oxygen and nutrients This process involves activation of a proangiogenic phenotype in the local microvascular endothelial cells (ECs), facilitated by complex cross-talk between the host omental cells and tumour cells. The observation that these therapies have only limited benefit in advanced disease [3,4,5,6,7], and that non-VEGF pathways may play a role in HGSC metastasis to the omentum has raised the possibility that alternative pro-angiogenic factors may be important e.g. cathepsins D (CathD) and L (CathL) [8,9,10,11].

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