In the past decade preclinical

In the past decade, preclinical studies have addressed the putative role of non-coding RNAs in tumorigenesis, metastasis and therapy response in osteotropic cancers. Besides long non-coding RNAs, microRNAs (miRs) represent a class of small non-coding RNAs, (18–25 nucleotides long), that regulate protein abundance by promoting mRNA degradation or translational repression [7], thus acting as oncogenes (oncomiRs) or tumor suppressor miRs. Several miRs have been identified as key molecules in tumorigenesis, bone tropism and the development of metastatic bone disease [8].
Osteotropism and miRs The dissemination of prostate and breast cancer metastatic src inhibitors specifically to the skeleton is defined as osteotropism and is determined by multiple factors expressed by the tumor cells and the bone microenvironment. The interactions between cancer cells and the endothelium of the bone marrow vasculature is one of the key processes which precedes extravasation from the blood vessels and suggested to underlie the bone-specific dissemination [9]. During this process, surface molecules expressed on cancer cells such as the chemokine (C-X-C motif) receptor (CXCR) 4 (CXCR4), αvβ3 integrin, CD44 and RANK are directly involved in homing to bone [10]. Briefly, the interaction between CXCR4 and its ligand stromal derived factor 1 (SFD1, also known as CXCL12) is critically important in the formation of prostate and breast cancer bone metastasis. CXCR4 is significantly elevated in breast carcinoma compared to normal tissue and miR-218 has been shown to up-regulate CXCR4 [11]. Moreover, CXCR4 signaling induces expression of matrix metallopeptidase (MMP) 9 and MMP13 in tumor cells. Interestingly, miR-218 has also been shown to reduce MMP9 expression [12] and appears to be a crucial regulator of osteomimicry in breast cancer, a process which regulate the expression of osteoblast specific genes by tumor cells, that may facilitate the growth of metastatic cells in the bone microenvironment [13]. MMP13 is, on the other hand, regulated by miR-126, which has been shown to reduce the formation of breast cancer bone metastases [14] and has also been associated with prostate cancer metastases [15]. Osteotropic breast cancer cells express vascular-endothelial molecule-1 (VCAM1) that is also targeted by miR-126 [16]. VCAM1 binds α4β7 and α4β1 integrins on osteoclast progenitors that, in turn, can induce excess osteoclastogenesis and subsequently lead to radiologically-evident osteolytic lesions. Furthermore other members of the integrin family, αv integrins, have been shown to be required for the maintenance of cancer stem cell properties and to be involved in bone colonization, angiogenesis by activated endothelial cells and osteoclastic bone resorption [17]. CXCL12 has been shown to induce the activation of integrin αvβ3, that mediates multiple cell-extracellular matrix interactions during tumor progression and skeletal metastasis, including stromal processes like osteoclastic bone resorption and angiogenesis. Recently, our group demonstrated that miR-25 is strongly decreased in the highly osteotropic cancer stem/progenitor subpopulation of human prostate cancer cells and directly regulates integrin-αv expression [18]. Overexpression of miR-25 reduces the metastatic dissemination, thus supporting the notion that miR-25 is a key regulator of cancer stemness and in the formation of distant bone metastases.
miRs and the ‘pre-metastatic’ bone niches As described above, the reciprocal interaction between cancer cells and the tissue-specific stroma is critical for primary and metastatic tumor growth progression. In organ-confined primary tumors soluble factors and extracellular vesicles (e.g. exosomes) can be released in the circulation. These factors may contribute to the conditioning of the future, distant metastatic sites, the so-called ‘pre-metastatic niche’ [3]. During this process, hematopoietic progenitor cells (HPCs) expressing VEGF receptor 1 (VEGFR1) are recruited to metastatic target organs by specific factors released by the primary tumor. Among these factors, LOXL enzymes, VEGFA, VEGFC, TNFα and TGF-β produced by the primary tumor stimulate inflammation, attachment, differentiation and recruitment of, for example, immunosuppressive myeloid cells. Recently, miR-26a and miR-29 have been shown to decrease LOXL2 [19] which suggest a tumor suppressive role for these two miRs. Additionally, miR-29 has been proven to inhibit cell migration in prostate cancer [20]. Interestingly, it has been proposed that extracellular vesicles and exosomes released from the primary tumor represent a mechanism of communication between the primary cancer cells and the metastatic sites during the induction of the “pre-metastatic niche”, recently reviewed in [21]. Additionally, extracellular vesicles released from bone marrow mesenchymal stem/stromal cells (MSCs) have been shown to transport tumor supportive miRs [22]. Together these observations reinforce the notion that bi-directional interactions tumor-bone stroma participate in the establishment of bone metastases.