br miRs and deregulation of bone

miRs and deregulation of bone remodeling Bone remodeling can be affected by osteotropic cancers at a distance (e.g. pre-metastatic niches) or in close proximity. It has been hypothesized that osteolytic cancer Sulindac sulfide produce various osteolytic factors (e.g. PTHrP) that stimulate osteoblasts to secrete RANKL and stimulate osteoclastic development and subsequent bone resorption (Fig. 1C, white arrows). During this process, many factors such as TGF-β, IGF-1 and calcium are released from the mineralized matrix to further feed cancer cell growth, thus perpetuating this “vicious cycle” [41]. In addition to the stimulation of osteoclast activity, osteolytic cancer cells can produce factors (DKK1, Noggin, Sclerostin) that modulate Wnt and BMP signaling pathways leading to osteoblast suppression and vice versa for osteoinductive cancers. The involvement of miRs in the process of bone remodeling have been extensively studied and the outcome of these studies were reviewed recently [42]. Among the variety of signaling pathways that orchestrate the balance between osteoclastic- and osteoblastic-activity, TGF-β, Wnt and Notch signaling are the three fundamental networks involved in the maintenance and expansion of osteoprogenitor cells and differentiation towards osteoblasts. Recently, we have identified a signature of 30 validated miRs linked to EMT that are linked to key genes of TGF-β, Wnt and Notch signaling pathways [43]. Strikingly, this signature contains multiple miRs that have also been directly linked to the formation of bone metastasis and to the interference with normal osteoblast and osteoclast activity. In particular, loss of miR-15 and miR-16 and gain of miR-21 in prostate cancer cells has been shown to activate TGF-β signaling and promote bone marrow colonization and osteolysis in prostate cancer [44] (Fig. 1C). Additionally, miR-16, together with miR-378, positively correlate with detection of bone metastases, which makes them interesting targets as biomarkers [45]. Moreover miR-34a, that downregulates Notch signaling, inhibits osteoclastogenesis and reduces bone metastasis in breast cancer [31]. Additionally, miR-155 can block the cytostatic signaling of TGF-β, modulate osteogenic differentiation [46], and promote invasion and metastasis in breast cancer [47].
miRs and potential treatment of bone metastases Non-coding RNAs/miRs may have clear diagnostic and prognostic value and can be employed as predictors of therapy response and biomarkers [21]. However, the applicability of miRs as therapeutic agents in oncology is still in its infancy due a number of challenges (specificity, drug delivery etc.). The principle of therapeutic delivery of siRNA or miR sequences to selected cells in order to modulated expression of key metastasis oncogenes, has remained a major impediment. Several limitations of this approach exist. On one hand, a drug carrier or nanodrug delivery system should be coupled to the administration of these small molecules, on the other hand, some siRNA sequences might also evoke an immune response by activating the Toll-Like Receptor (TLR) pathway [48]. Improvement of nanodrug delivery systems and lipid-based nanoparticles, may pave the way to clinical translation. Only few miRs seem to prevent metastatic bone disease in vivo. These include miR-141 and miR-219, that have been shown to decrease osteolytic breast cancer bone metastases presumably via inhibition of osteoclast activity [49]. Two other miRs, miR-203 and miR-135, were found to reduce breast cancer bone metastases via targeting of Runx2 [50]. Currently, only one candidate miR is studied in clinical trials in liver cancer and other selected solid tumors: MRX34 (Mirna therapeutics, Inc.; ClinicalTrials.gov Identifier: NCT01829971). MRX34 is a liposomal formulation of a miR-34 mimic employed to restore this tumor suppressor miR. Interestingly, miR-34 is downregulated in metastatic breast cancer and it protects breast cancer induced osteolytic disease [51]. Taken together, the employment of miRs as therapeutic agents remains challenging and is still strictly dependent on the identification of a specific targeting strategy to selectively target highly metastatic cells.