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  • At the cellular level TGF has been involved


    At the cellular level, TGF-β1 has been involved in the formation of invadosomes (Mandal et al., 2008, Varon et al., 2006). Invadosomes are actin-based structures involved in matrix degradation and cell invasion through metalloproteinases (MMP) activity (Linder et al., 2011). Invadosomes, constitutively formed by various tumor cells, correspond to dynamic structures able to adapt to the microenvironment. Indeed, depending on the ECM context, invadosomes can adopt different shapes as dots, Ponesimod receptor or lines (Di Martino et al., 2016). Invadosomes could be constitutively formed or induced after different stimulations. Indeed, various cytokines or growth factors, including epidermal growth factor (EGF), vascular endothelial growth factor (VEGF) and TGF-β1 were described to enhance invadosome formation, maturation and activity in different cellular models (Mader et al., 2011, Osiak et al., 2005, Pignatelli et al., 2012). TGF-β1 was found to induce invadosome formation in endothelial and cancer cells (Mandal et al., 2008, Varon et al., 2006). Recently, we identified the linear invadosomes as a new class of invadosomes specifically induced by the fibrillar type I collagen (Juin et al., 2012). Linear invadosomes formation is dependent on the discoidin domain receptor 1 (DDR1), a specific collagen type I receptor (Juin et al., 2014). DDR1 leads to the recruitment of the active small GTPase Cdc42, the invadosome marker Tks5 and the metalloproteinase MT1-MMP along type I collagen fibrils allowing invadosome formation and degradation activity. The DDR receptor family, consisting of two members DDR1 and DDR2, are distinctive receptor tyrosine kinases (RTKs) that signal in response to interaction with collagen instead of growth factors (Leitinger, 2014). However, we previously demonstrated that the kinase activity of DDR1 is not required for linear invadosome formation. DDR1 is overexpressed in HCC cell lines and HCCs (Jian et al., 2012, Park et al., 2007, Shen et al., 2010). Moreover its overexpression was associated with advanced tumor stages (Shen et al., 2010). Cancerous ECM is composed of various elements such as proteoglycans, hyaluronic acid, fibronectin, elastin and collagens. During cancer progression, associated ECM evolves in parallel and modulates tumor cells behavior (Pickup et al., 2014). Different studies clearly established the link between collagen and matrix stiffness with metastasis formation in many solid tumors (Cox et al., 2013, Ramaswamy et al., 2003). Lysyl oxidase (LOX) is a secreted copper-dependent amine oxidase that creates intra and inter-molecular cross-linking of collagen. Lysyl oxidase-like (LOXL) proteins (1 to 4) present homology with the LOX and are also able to cross-link collagen. This cross-linking enhances collagen fiber formation and increases the matrix stiffness. A recent study demonstrated that TGF-β1 induces the expression of LOXL2 in HCC cells (Wong et al., 2014). Interestingly, it is known that matrix stiffness enhances invadosome formation and/or activity (Alexander et al., 2008, Juin et al., 2013) and invadosomes correspond to mechanosensors (Labernadie et al., 2014). Moreover, TGF-β1 promotes type I collagen secretion in many organs and cellular models (Cutroneo, 2003, Leask and Abraham, 2004).
    Material and methods
    Discussion We previously reported that type I collagen is a potent inducer of linear invadosomes (Juin et al., 2012) and that DDR1 is required for their formation and matrix degradation activity (Juin et al., 2014) (Di Martino et al., 2015). As TGF-β1 was described to enhance type I collagen and LOXL2 expression (Wong et al., 2014), to promote HCC invasion (Fransvea et al., 2009) (van Zijl et al., 2009) and invadosomes in vitro (Pignatelli et al., 2012), we decided to study the role of this cytokine in linear invadosome formation. Transcriptomic data analysis obtained from 86 patient liver samples reveals that TGFB1 expression positively correlates with DDR1 and MMP14 (encoding MT1-MMP), expression. These data also confirm the link between TGFB1, COL1A1, COL1A2 and LOXL2. Moreover, this analysis establishes a significant correlation between the expression of DDR1 and SH3PXD2A (Tks5) and between collagen-related genes (COL1A1, COL1A2 and LOXL2) and MT1-MMP. Lysyl oxidase is a family of enzymes composed of five members LOX, LOXL1 to 4. As published earlier (Wong et al., 2014), only LOXL2 expression appears up-regulated upon analysis of HCC transcriptomic data (data not shown). The enzyme involved in type I collagen cross-linking seems to be organ specific, as LOX, but not LOXL2, was implicated in breast cancer (Cox et al., 2013).