These MMPs are secreted in an inactive form and acquire their active form extracellularly [139,140]. from the cell (Figure 1B). Once secreted, extracellular HSP90 (eHSP90) promotes the conversion of soluble FN to its insoluble form (Figure 1B). The intra- and extracellular roles of HSP90 as an FN chaperone can be considered as another HSP90 mechanism, which promotes cell migration and metastasis through the degradation and remodeling of ECM . FN over-expression has been reported in specimens of various tumor types such as breast, lung, thyroid and esophageal cancer . Additionally, FN over-expression has been correlated with poor clinical outcome in breast cancer patients, whilst its involvement in breast cancer invasion and metastasis has been demonstrated to involve the up-regulation of matrix metalloproteinases (MMPs) MMP-2 and MMP-9 via the FAK/ILK//ERK/PI3K/NF-B cascade of pathways [23,24] (Figure 1C). Most recently Hong  proposed a new model regarding the down-regulation of FN by pigment epithelium-derived factor (PEDF), a molecule well-known for its important anti-cancer role, mainly through the inhibition of angiogenesis and the induction of tumor differentiation and apoptosis in various types of cancer. In particular, they showed that PEDF inhibits MMP-2 and MMP-9 expression by binding to the laminin receptor and consequently inhibiting the AKT/ERK tumorigenic pathway, thereby down-regulating FN expression (Figure 1D). 2.3. SIBLING The Small Integrin-Binding Ligand, N-linked Glycoprotein (SIBLING) family includes bone sialoprotein (BSP), osteopontin (OPN), dentin matrix protein 1 (DMP1), dentin sialoprotein (DSPP), and matrix extracellular phosphoglycoprotein (MEPE). They comprise a class of non-structural ECM proteins. Expression of SIBLING family members was first characterized in mineralized tissue including bone and teeth. Additionally, SIBLING proteins are T-1095 localized in neoplastic tissues and induce metastasis [25,26]. Elevated SIBLING expression has been associated with an analogous increased expression of MMPs in breast, stomach, colon, ovarian, rectal and lung cancers . Amongst the SIBLING proteins mentioned above, OPN is a secreted phosphoprotein characterized as a biomarker of tumor metastasis because increased OPN expression was found within tumor cells and in the surrounding stroma of multiple human cancers [27,28,29,30,31,32,33,34]. Nowadays, OPN is considered a serum biomarker in predicting tumor metastasis. Elevated OPN levels can be specific in predicting disease progression in head and neck, gastric, renal, hepatocellular, lung, and pancreatic cancers as well as uveal melanoma. Additionally, it has Rabbit polyclonal to ADPRHL1 been established that OPN is a strong prognostic indicator for overall survival as its circulating levels are proportional with tumor stage and metastasis [35,36]. Two main mediators of OPN signaling pathways are integrins and CD44. OPN binds various types of integrins, such as 3 which participates in the metastatic phenomenon in several ways. 3-OPN interaction promotes cancer cell migration and invasion in prostate and breast cancer as well as in chondrosarcoma where OPN-3 binding leads to MMP-9 up-regulation through the FAK/MEK/ERK/NF- pathway [37,38,39,40] (Figure 1E). Moreover, OPN-3 integrin ligation promotes neo-vascularization by up-regulating endothelial cell migration, survival and lumen formation during angiogenesis [41,42,43,44,45]. Finally, OPN interaction with CD44v6 is observed T-1095 in metastasis of breast, hepatocellular, pancreatic, lung, colorectal cancers and lymphomas [26,46,47,48,49,50,51] (Figure 1F). Primary tumor formation and metastatic processes are clearly the result of the co-participation of genetically modified tumor and normal cells. OPN is mainly secreted by tumor cells while in myeloid cells OPN is localized intracellularly. Most recently, Sangaletti clarified an aspect of the dual role of OPN whereby tumor cells secrete OPN in order to support their survival in the blood circulation, whereas both tumor- and host-derived OPN, particularly from myeloid cells, render the metastatic site more immunosuppressive . 3. ECM Receptors 3.1. Integrins Integrins are the major and most characterized cell surface receptors of several ECM proteins such as laminin, fibronectin, collagen IV and vitronectin. Integrins are composed of non-covalent, heterodimeric complexes of an and subunit . Many members of the integrin family, such as 51, 81, IIb3, V3, V5, V6, and V8 recognize an Arg-Gly-Asp (RGD) motif within their ligands, which include FN, fibrinogen, vitronectin, von Willebrand factor, and various other large glycoproteins . Both the and subunits are transmembrane glycoproteins. As the cytoplasmic tails of integrins are devoid of enzymatic features, they transduce signals by associating with adaptor proteins that connect the integrin to the cytoskeleton, cytoplasmic kinases, and transmembrane growth factor receptors . Integrins constitute the mediators between ECM and the actin cytoskeleton with focal adhesion sites representing the regions of transmission transduction controlling proliferation, differentiation, survival, wound healing, migration, tumorigenesis, . It has been suggested that bone metastasis derived from advanced prostate malignancy process is characterized by the integrin-mediated connection of metastatic malignancy T-1095 cells and bone microenvironment . In fact, it has been demonstrated that in the majority of tumors, 3 integrin is the perfect initial receptor to support adhesion and migration to.