| Popis: |
Background: evidences suggest a marked angiogenic dependency in triple-negative breast cancer (TNBC) tumorigenesis and a potential sensitivity to anti-angiogenic agents. Herein, the putative role of Hedgehog (Hh) pathway in regulating TNBC-dependent angiogenesis was investigated. Moreover Studies of meta-analysis indicate that PD-L1 expression was associated with triple-negative breast cancer (TNBC). Moreover TNBCs have high level of tumor-infiltrating lymphocytes suggesting that these tumors may be particularly amenable to targeting with immune checkpoint inhibitors. Since Hh signalling mediates a crosstalk between breast cancer cells and tumor microenvironment, it was evaluated the complexity of aberrant Hh pathway functions in TNBC and its putative effect in sustaining TNBC microenvironment, suggesting the Hh pathway inhibition as new anti-angiogenic and immune-stimulating therapeutic options in this subtype of tumor. Results:Tissue microarray analysis on 200 TNBC patients showed GLI1 overexpression paired with vascular endothelial growth factor receptor 2 (VEGFR2) expression and PDL1. In vitro, Hh pathway promotes TNBC progression in an autocrine manner, regulating the VEGF/VEGFR2 loop on cancer cell surface, and in a paracrine manner, orchestrating tumour vascularization. To better understand the link between Hh pathway and PDL1, we selected a panel of TNBC cell lines; we investigated the expression of main Hh pathway trasducers and PDL1; GLI1 overexpressing cells showed high PDL1 protein and mRNA levels. Moreover we found that PDL1 protein and mRNA levels decreased after pharmacological Hh pathway inhibition, using a SMO antagonist NVP-LDE225; these effects were recapitulated when GLI1 genomic knock-down was performed. Conclusions: This study identifies the Hh pathway as one of the main regulators of tumour angiogenesis in TNBC and suggests that Hh pathway has a specific role in cancer immune evasion trough PDL-1 modulation. Due to their ability to target both tumor cells and the pro-tumor microenvironment, Hh inhibitors represent promising therapeutics to be clinically investigated in GLI1 overexpressing TNBC patients. |
