Refers to article:
Exosomal miR-1290 and miR-375 as Prognostic Markers in Castration-resistant Prostate Cancer
Accepted 28 July 2014
February 2015 (Vol. 67, Issue 2, pages 33 - 41)
Castration-resistant prostate cancer (CRPC) develops as metastatic prostate cancer inevitably progresses and becomes resistant to treatment targeting the androgen signaling axis; CRPC represents the final stage of the disease, with a median survival of less than 2 yr. Although CRPC remains incurable, a number of treatment alternatives that yield modest prolongation of life have been developed and approved by the US Food and Drug Administration (FDA) during the last few years. These alternatives include selective adrenal inhibitors, androgen receptor signaling inhibitors, novel immune compounds, and less toxic radionuclides. However, progression towards more personalized treatment strategies is hampered by the lack of easily measured reliable biomarkers predicting response to therapy and survival. In this issue ofEuropean Urology, Huang et al.  attempt to address this issue. They investigated the prognostic potential of microRNAs (miRNAs) within exosomes in circulation, and propose that two miRNAs, miR-375 and miR-1290, can serve as prognostic biomarkers for CRPC.
The miRNAs identified by Huang et al. were derived from exosomes in the blood circulation; extensive attention is now focusing on these vesicles as a source of biomarkers because their contents resemble those of the cell of origin. In 2008, Skog et al.  showed that the miRNA content of extracellular vesicles reflects the miRNA expression profile of the cells they originated from; however, it should be noted that the miRNA content of exosomes is not an uncorrupted sample of the contents of the parental cells. When investigating the content of plasma-derived exosomes (or extracellular vesicles), Huang et al.  found that mature miRNAs were the most common RNA species. This is in agreement with earlier sequencing of the RNA content in prostatic tissues, which also identified miRNA as the most abundant class, constituting 95% of the RNA pool  . miRNAs are not only the most abundant RNA species but are also technically suitable as biomarkers. They can be easily and sensitively detected in small samples sizes via quantitative reverse transcription polymerase chain reaction, they are stable in serum and plasma, and they are resistant to extended storage, freeze-thawing, and extreme pH  . Research over the last decade has revealed that miRNAs are deregulated in prostate cancer, and they have emerged as key players in cancer progression, with many studies highlighting their diagnostic and prognostic potential  . Nevertheless, the study by Huang et al. does not confirm that it is the expression of the individual miRNAs that is changed; it could also be the exosomal content in circulation or the RNA content of the exosomes. Since clarification of this issue is of great interest, it would have been informative to combine the evaluation of individual miRNAs with determination of the amount of extracellular vesicles and their RNA content. The choice of reference genes is as important as the target genes in such studies. Huang et al. investigated 192 plasma samples to identify an endogenous reference control; they included male and female healthy individuals and patients with other types of cancer, as well as a screening cohort of 23 CRPC cases. One of the reference miRNAs, miR-30e, is highly expressed in blood cells, particularly monocytes  , which could indicate that a difference in exosomal content is an important factor.
The first report of miRNAs as potential diagnostic markers for noninvasive measurement in a prostate cancer setting came in 2008. Mitchell et al.  compared a panel of serum miRNAs between healthy men and men with advanced prostate cancer, and found that miR-141 was elevated in the cancer samples  . Given the heterogeneity of prostate cancer, it is not surprising that although many miRNAs have been identified as potential diagnostic and prognostic makers, no single miRNA has been consistently validated or implemented as a biomarker for the clinical management of prostate cancer. In line with this, Huang et al. show that the combination of miR-375 and miR-1290 increases the significance for prediction of survival compared to each miRNA individually. Patients with high levels of both miR-375 and miR-1290 had a significantly higher mortality rate than patients with low levels of the two miRNAs at 20-mo follow-up. There was also a significant difference in median overall survival between patients with high levels and patients with low levels of miR-375/miR-1290. Incorporation of miR-1290/miR-375 into a model comprising clinical prognostic factors based on prostate-specific antigen and the failure time for androgen deprivation therapy significantly improved the predictive performance. It would have been very interesting to compare the exosomal miRNA results to CellSearch results, as CellSearch is currently the only FDA-approved prognostic test for CRPC. This would also facilitate comparison with other similar studies. For example, a recent study by Danila et al. found that a five-gene panel measured in blood samples from 97 metastatic CRPC patients was a prognostic predictor for survival that was comparable to the CellSearch system. Furthermore, combining the gene panel with CellSearch enhanced the prognostic power compared to CellSearch alone  .
It is evident that CRPC is a heterogeneous disease; given the complexity of the androgen receptor signaling cascade, the idea of a more complex panel of markers is appealing. Investigation into whether inclusion of several miRNAs would give more representative information on patient status and the degree to which this could be improved would be possible using the data set of Huang et al., which contains data for 375 known miRNAs and 57 putative miRNAs. For example, one of the predicted miRNAs on chromosome 12 seems to have excellent potential. It is encouraging that one of the miRNAs identified, miR-375, was elevated in metastatic CRPC serum in several previous independent studies, as discussed by Huang et al.  . Two cohorts were used in their study, a screening cohort of 23 individuals and a validation cohort of 100 men. We hope that these two biomarkers will be validated in larger independent cohorts in the future to establish their reliability and potential clinical applicability. To conclude, the paper by Huang et al. reinforces the notion that novel noninvasive methods for predicting the prognosis for patients with CRPC will soon be a reality.
-  X. Huang, T. Yuan, M. Liang, et al. Exosomal miR-1290 and miR-375 as prognostic markers in castration-resistant prostate cancer. Eur Urol. 2015;67:33-41
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a Institute of Biosciences and Medical Technology, University of Tampere and Tampere University Hospital, Tampere, Finland
b Department of Laboratory Medicine, Lund, Division of Translational Cancer Research, Lund University, Lund, Sweden
© 2014 European Association of Urology, Published by Elsevier B.V.