Towards a molecular basis of oligometastatic disease: potential role of micro-RNAs

Abstract

Oligometastasis is a cancer disease state characterized by a limited number of metastatic tumors involving single or few organs and with biological properties that make them potentially amenable to locoregional antitumor therapy. Current clinical data show that they are potentially curable with surgical resection or/and radiotherapy. Yet, mechanisms of progression from primary tumor to oligometastasis, rather than to polymetastases, is lacking in detail. In the current review we focus on the role of micro-RNAs in the regulation of metastases development and the role they may play in the differentiation of oligometastatic from polymetastatic progression. We also discuss the analyses of metastatic samples from oligo-and polymetastatic patients, which suggest that oligometastasis is a distinct biologic entity regulated in part by micro-RNAs. In addition, a review of the known functions of oligometastatic-specific micro-RNAs suggest that they regulate multiple steps in the metastatic cascade, including epithelial-mesenchymal transition, tumor invasion, intravasation, distant vascular extravasation and proliferation in a distant organ. Understanding the role of micro-RNAs and their target genes in oligometastatic disease may allow for the development of targeted therapies to effectively conrol the spread of metastases.

Fig. 1

Pathways of oligo-and polymetastases development. Two hypotheses of Oligometastastic Disease: Hypothesis 1 Oligometastases and Polymetastases may be distinct metastasis phenotypes determined by dissemination of clonal populations with differing metastatic potential. Hypothesis 2 Metastasis may be a continuum of phenotypes identified early (oligometastases) or late (polymetastases) in the progression of disease

Fig. 2

Multiple steps of metastases development and role of micro-RNA in their regulation. Sequential steps of metastases development are presented based on the current reviews [25, 26, 28, 51]. Note that final selection of metastatic clones can lead to the formation of radio/chemoresistant secondary tumors, as was described elsewhere [33], presumably due to selection against cytotoxic factors of host microenvironment (see g–h). Boxes below diagram represent major functions involved in each step, while boxes above illustrate some micro-RNAs involved in the regulation of each step (see text for explanations and references)

Fig. 3

Processing and maturation of micro-RNAs. Genomic sequence of primary micro-RNA (pri-miR) encodes ~80 nt sequence of the stem-loop pre-micro-RNA (Fig. 3a). This stem-loop structure (pre-miR) is recognized and excised from transcribed RNA by multiple proteins including Drosha and DGCR8. The stem-loop pre-miR is exported in cytoplasm by Exportin-5/Ran-GTP complexes (Fig. 3b) and is further processed by Ago2/Dicer1 nucleases into the mature single-stranded 5p and 3p miRs (Fig. 3c). The 5p and 3p mature single-stranded miRs will bind to different down-stream target mRNAs and can lead to different functional outcomes (Fig. 3d). Therefore the balance of micro-RNA precursors and mature forms can determine different phenotypes of normal and tumor cells. Current data indicate that this balance is susceptible to post-translational modifications and/or mutations of enzymes, responsible for miRs processing, including Ago2 and Dicer1 (Fig. 3c). These mutations and post-translational modifications of Ago2, associated with EGFR signaling, hypoxia and proteasome functions are described elsewhere [–20]

Fig. 4

Cross-talk between micro-RNA patterns obtained in surgical and stereotactic body radiotherapy (SBRT) cohorts. a Only 3 overlapping micro-RNAs were identified in the surgical and SBRT cohorts (miR-328, miR-502-5p and miR-199b-5p (Table 1). b Unsupervised clustering of patients in the surgical and SBRT cohorts based on differentially expressed micro-RNAs successfully segregated patients with oligo-and polymetastatic disease independently on clinical parameters of disease progression (heat maps represent normalized CT values; green are up- and red are down-regulated micro-RNAs). c Application of the SBRT micro-RNA signature to surgical patients successfully separated them into oligo-and polymetastatic clusters (left panel); the same was true for application of the surgery micro-RNA signature to SBRT cohort

Fig. 5

Potential functions of oligomiRs. Multiple micro-RNAs up-regulated in oligometastases datasets (black SBRT, red Surgery and blue both datasets) are each capable of inhibiting multiple points along the metastatic cascade. These include epithelial–mesenchymal transition (EMT); invasion through parenchyma and intravasation into vasculature; adhesion to distant vasculature and extravasation into the distant organ parenchyma; and proliferation in the distal organ. Table 1 details biological processes/functions and down-stream targets of oligomiRs presented in this figure. (Color figure online)