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    • The miR signature of exosomes

    2019-05-09

    The miR signature of exosomes isolated from bulk prostate cancer buy ACY1215 (Fig. 1A, blue cells) and from their cancer stem cell compartment (Fig. 1A, green cells), display high levels of miR-21, miR-30 and miR-218 [23] (Fig. 1A, blue arrow). miR-21 and miR-30 have been identified as key regulators of osteoblast differentiation and have been included in a panel of microRNA biomarkers designated as “OstemiR” [24]. Therefore, high levels of these miRs may lead to increased bone remodeling “at a distance” and may facilitate subsequent metastatic colonization and cancer cell growth in the bone marrow microenvironment. Moreover, miR-21 increased expression of MMP2, MMP9 and MMP13, inducing extracellular matrix (ECM) remodeling and facilitating EMT. In the same study, CSC-derived exosomes (Fig. 1A, green arrow), were found to contain high amounts of miR-183 (Fig. 1). Furthermore, miR-183 has been shown to increase osteoclastogenesis by repressing heme oxygenase-1 (HO-1) [25]. It appears, therefore, that exosomal miR-183 may represent a supportive factor in the conditioning of the bone microenvironment by highly metastatic cells and reinforce their role in the conditioning and formation of the ‘receptive pre-metastatic niches’.
    miRs and metastatic bone niches In primary and metastatic cancers, tumor cells interact with different cell types that constitute the bone/bone marrow stroma such as osteoblast and osteoclasts, tumor-associated macrophages (TAMs), bone marrow stromal fibroblasts, endothelial cells, pericytes, MSCs and immune cells like myeloid-derived suppressor cells (MDSCs) [26]. Multiple miRs have been associated with the interaction between tumor cells and stromal cells, reviewed in [27]. miR-511-3p reduced the pro-tumoral activity of TAMs [28]; up-regulation of miR-31 and miR-214 while inhibition of miR-155, abrogated the CAF phenotype [29]. Tumor cells produce several factors that “activate” the surrounding stromal cells and induce remodeling of extracellular matrices. These factors include fibroblast growth factor 2 (FGF2), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), epidermal growth factor (EGF), interleukins colony-stimulating factors, the transforming growth factor (TGF-β) superfamily and proteolytic enzymes that remodel ECM, thus enabling cell migration [6,30]. Interestingly, TGF-β-induced factor 2 (Tgif2) induces osteoclastogenesis due to the down regulation of miR-34a expression in osteoclasts and administration of miR-34a-carrying nanoparticles in mice prevented bone metastasis of human breast cancer cell [31]. Tumor cells with stem cell-like characteristics, that survive in the circulation, seem to preferably extravasate at those distant sites where “pre-metastatic niches” have been established, i.e. a distant microenvironment that facilitates metastatic colonization. Typically, the bone metastatic niches are anatomically localized at perivascular locations and endosteal bone surfaces, although it cannot be excluded that these may represent the same entity [32]. CTCs and DTCs may, establish a metastatic niche through competition with hematopoietic stem cells (HSCs) at the level of the endosteal niche [33]. DTCs can survive in the bone microenvironment as non-proliferating (dormant) cells that originate micrometastases and the perivascular niche has been shown to regulate tumor cell dormancy [34]. Recently, high levels of miR-23b has been found in exosomes isolated from bone marrow mesenchymal stem cells and miR-23b was shown to promote dormancy in metastatic breast cancer cells [35]. The mechanisms that induce exit from dormancy are largely unknown and have remained largely elusive. It was found that the cytoskeletal reorganization in dormant cells mediated by a collagen-I enriched fibrotic environment contributes to exit from dormancy [36]. Once disseminated cancer cells ‘awake’, they can induce a local inflammatory environment, followed by vascular and bone remodeling and progression to a distant overt bone metastasis. Recently, it was revealed that the molecular signature of the stroma response in prostate cancer-induced osteoblastic bone metastasis highlights the amplification of hematopoietic and prostate epithelial stem cell niche [6]. This observation further supports the notion that expansion of such perivascular metastatic niches in osteoblastic metastases may occur via the induction of angiogenesis (Fig. 1B, light-brown arrow) that, in turn, leads to osteoinduction (Fig. 1B, orange arrow). Indeed, it was recently demonstrated that a specific type of vessels, namely “Type H vessels” orchestrate the coupling of angiogenesis and osteogenesis [37]. In this respect, miR-26a may positively regulate the angiogenesis-osteogenesis coupling [38] (Fig. 1B). Interestingly, the above-mentioned miR-26a is considered a tumor-suppressor miR and low miR-26a levels have been detected in breast and prostate cancer tissues [39,40]. Together, these data suggest that miR-26a might function in several steps during tumor progression. Moreover, low miR-26a levels would have a negative impact on the angiogenesis-osteogenesis coupling, thus de-regulating this mechanism and facilitating the formation of bone metastases.