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Abstract
miRNAs are short, non-coding, regulatory RNAs that exert cell type-dependent, context-dependent, transcriptome-wide gene expression control under physiological and pathological conditions. Tissue slide-based assays provide qualitative (tumor compartment) and semi-quantitative (expression levels) information about altered miRNA expression at single-cell resolution in clinical tumor specimens. Reviewed here are key technological advances in the last 5 years that have led to implementation of fully automated, robust and reproducible tissue slide-based assays for in situ miRNA detection on US FDA-approved instruments; recent tissue slide-based discovery studies that suggest potential clinical applications of specific miRNAs in cancer medicine are highlighted; and the challenges in bringing tissue slide-based miRNA assays into the clinic are discussed, including clinical validation, biomarker performance, biomarker space and integration with other biomarkers.
Acknowledgements
The author thanks H Calderone, G Hostetter and J Westerhuis for critical reading and suggestions during preparation of this manuscript, and K Habermehl and D Nadziejka for technical editing.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.
No writing assistance was utilized in the production of this manuscript.
Key issues
The use of altered miRNAs as new biomarkers for diagnostic, prognostic and therapeutic applications in cancer medicine is a rapidly growing field. Various detection methods exist to measure changes of miRNA levels.
Tissue slide-based assays for in situ miRNA detection on tumor tissues offer unique advantages over other methods of determining miRNA expression in individual cells (tumor compartment) and of registering the location and distribution (intratumoral heterogeneity) of the miRNA-expressing cells.
Tissue slide-based assays characterize miRNA expression in its intact and native tumor context, in contrast to free miRNA in solution that is used for quantitative real-time PCR or other detection methods.
Tissue slide-based assays can provide more precise and accurate diagnostic information because they provide qualitative and semiquantitative information of altered miRNA expression at single-cell resolution.
Recent tissue slide-based discovery studies suggest the diagnostic and prognostic potential of altered miRNAs in specific tumor compartments. Cancer cells are not the only tumor compartment in which altered miRNA expression can be informative. Indeed, altered expression of miR-21 in the stromal compartment (mainly tumor-associated fibroblasts) provides prognostic information in breast, colon and pancreas cancer.
These tissue slide-based in situ hybridization assays are compatible and can be combined with standard clinical immunohistochemistry assays. miRNA and protein diagnostic information can be integrated in a single tissue section.
Recent advances in multispectral analysis and digital pathology enable whole-slide high-content image analysis. Multiplexing of up to 12 markers is feasible using work flow that is comparable to the routine/standard procedures in translational pathology research and clinical laboratories.
Clinical validation of lead miRNA biomarkers in large prospective and longitudinal studies is required to ignite the interest of clinicians to consider using miRNA in their practice and of industry partners in developing business plans for miRNA-based clinical tools.
