Tumour-derived miRNAs and bone metastasis

Abstract

Skeletal metastases are complications of epithelial cancers, among which breast, prostate and lung carcinomas are the most osteotropic. In primary tumours, a subset of cancer cells undergoes epithelial-mesenchymal transition, acquires mobility to migrate into the surrounding stroma and seeds at distant sites to grow. The specific development of bone metastasis requires the recruitment of circulating tumour cells in the bone marrow, their adaptation to survive in the surrounding microenvironment where they alter the functions of osteoclasts and osteoblasts, and hijack signals coming from the bone matrix. Each of the molecular pathways underlining these steps is regulated by multiple factors, through the tight control of genes expressed by cancer cells interacting with cells from the bone microenvironment. In this context, miRNAs can act as master regulators of gene expression to control multiple aspects of bone metastasis formation, including cancer cell escape from the primary tumour site, cancer cell dissemination to bone and invasion of the bone marrow, as well as secondary outgrowth and tumour-stroma cell interactions. In the clinic, specific miRNA signatures have been identified in osteotropic cancer cells, raising the possibility that miRNAs could be used as biomarkers of bone metastasis. The regulatory activity of miRNAs in the bone microenvironment also suggests that miRNAs could be promising therapeutic targets.

Figure 1

MicroRNAs regulate various steps of bone metastasis progression in solid tumours. MiRNAs control critical steps in cancer cell dissemination. Up- (↑) or downregulation (↓) of these miRNAs may result in the positive (+) or negative (−) regulation of gene sets and/or pathways involved in bone metastasis through the regulation of the following gene targets, indicated in brackets: BMI1, Polycomb complex protein; KLF4, Kruppel-like factor; HEF-1, Human enhancer of filamentation; HMGA2, High-mobility group AT-hook 2; Rock, Rho-associated kinase; IGFBP2, Insulin-like growth factor binding protein2; DLX5, Distal-less homeobox5; WNT, Wingless type; CTGF, Connective tissue growth factor; Mitf, bHLHe32; Calcr, Calcitonin receptor; Tnc, Tenascin C; RDX, Radixin; TGIF2, TGFβ-induced factor homeobox2; FIH-1, Factor inhibiting HIF.