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

Abstract

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. Electronic supplementary material The online version of this article (10.1186/s12967-019-1963-7) contains supplementary material, which is available to authorized users.

The Anti-VEGF(R) Drug Discovery Legacy: Improving Attrition Rates by Breaking the Vicious Cycle of Angiogenesis in Cancer

“…In patients with solid tumors treated with carlumab, a human anti-CCL2 monoclonal antibody targeting the monocyte chemotactic protein 1 (MCP1), the growth of tumors has been delayed [ 132 ]. Treatment of pancreatic neuroendocrine tumors with Ang2 and VEGFR-2 blockers decreased Tie2 monocyte infiltration and suppressed revascularization and tumor progression [ 133 ], prompting next-generation anti-angiogenesis ( Figure 2 ) [ 22 , 102 , 134 ]. The crosstalk between angiogenesis and immune cells explains the efficacy of combining anti-angiogenic drugs with immune check-point inhibitors.…”

“…Cathepsins are lysosomal enzymes with enhanced concentration in malignant cells, in response to low oxygen levels and increased lactic acid concentration within the cancer niche [ 145 , 146 ]. Since the cathepsin and galectins axis may fuel the vicious cycle of a pro-vasculogenic environment [ 134 ], cathepsin/galectin targeting prompted novel strategies combining anti-angiogenic therapy and immunotherapy, with the potential to tip the balance of the tumor microenvironment and improve treatment response [ 141 , 147 , 148 , 149 ].…”

The complexity of tumour angiogenesis based on recently described molecules

“…Similarly, in human multiple myeloma, gal-1 expression was shown to be regulated by hypoxia-inducible factor 1a (HIF-1a), and its suppression resulted in reduced angiogenesis and bone lesion formations in vivo in 2 different murine models [ 27 ]. Gal-1 secreted by human omental microvascular endothelial cells (HOMECs) in metastasized high-grade serous carcinoma (HGSC) of the ovary was proven to increase the number of microvessels in omental metastases, potentially via the MEK/ERK1/2 signalling pathway [ 28 ]. Moreover, in pancreatic ductal adenocarcinoma (PDA), gal-1 mediates the action of human pancreatic stellate cells (HPSCs), which encompass the stimulation of cancer proliferation, migration, and invasion.…”

Advances in Anti-Cancer Immunotherapy: Car-T Cell, Checkpoint Inhibitors, Dendritic Cell Vaccines, and Oncolytic Viruses, and Emerging Cellular and Molecular Targets

“…Tumour-secreted dimeric Gal1 binds to extracellular matrix proteins such as fibronectin, collagen and laminin, and cell-surface glycoconjugates mediating a bivalent cross-linking between tumour cells and the stroma, inducing homotypic tumour cell aggregation, invasion and metastasis [191]. Interestingly, in the later stage of tumour development, tumour cells, tumour-associated macrophages and T cells, and local microvascular endothelial cells overexpress and secrete Gal1, resulting in further tumour growth and angiogenesis via both autocrine and paracrine interactions [191][192][193][194][195][196][197]. However, the poor prognosis associated with this elevated level of Gal1 is now thought to be primarily related to its immunosuppressive mechanisms [198].…”