Diagnostic, prognostic and predictive value of cell-free miRNAs in prostate cancer: a systematic review

Molecular Cancer, May 2016

Prostate cancer, the second most frequently diagnosed cancer in males worldwide, is estimated to be diagnosed in 1.1 million men per year. Introduction of PSA testing substantially improved early detection of prostate cancer, however it also led to overdiagnosis and subsequent overtreatment of patients with an indolent disease. Treatment outcome and management of prostate cancer could be improved by the development of non-invasive biomarker assays that aid in increasing the sensitivity and specificity of prostate cancer screening, help to distinguish aggressive from indolent disease and guide therapeutic decisions. Prostate cancer cells release miRNAs into the bloodstream, where they exist incorporated into ribonucleoprotein complexes or extracellular vesicles. Later, cell-free miRNAs have been found in various other biofluids. The initial RNA sequencing studies suggested that most of the circulating cell-free miRNAs in healthy individuals are derived from blood cells, while specific disease-associated miRNA signatures may appear in the circulation of patients affected with various diseases, including cancer. This raised a hope that cell-free miRNAs may serve as non-invasive biomarkers for prostate cancer. Indeed, a number of cell-free miRNAs that potentially may serve as diagnostic, prognostic or predictive biomarkers have been discovered in blood or other biofluids of prostate cancer patients and need to be validated in appropriately designed longitudinal studies and clinical trials. In this review, we systematically summarise studies investigating cell-free miRNAs in biofluids of prostate cancer patients and discuss the utility of the identified biomarkers in various clinical scenarios. Furthermore, we discuss the possible mechanisms of miRNA release into biofluids and outline the biological questions and technical challenges that have arisen from these studies.

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Diagnostic, prognostic and predictive value of cell-free miRNAs in prostate cancer: a systematic review

Endzeliņš et al. Molecular Cancer Diagnostic, prognostic and predictive value of cell-free miRNAs in prostate cancer: a systematic review Edgars Endzeliņš 0 1 Vita Melne 0 1 3 Zane Kalniņa 1 Vilnis Lietuvietis 1 3 Una Riekstiņa 2 Alicia Llorente 4 Aija Linē 1 0 Equal contributors 1 Latvian Biomedical Research and Study Centre , Ratsupites Str 1, k-1, LV-1067 Riga , Latvia 2 Faculty of Medicine, University of Latvia , 19 Raina blvd., Riga LV-1586 , Latvia 3 Riga Stradiņš University , Dzirciema Str 16, Riga LV-1007 , Latvia 4 Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital , 0379 Oslo , Norway Prostate cancer, the second most frequently diagnosed cancer in males worldwide, is estimated to be diagnosed in 1.1 million men per year. Introduction of PSA testing substantially improved early detection of prostate cancer, however it also led to overdiagnosis and subsequent overtreatment of patients with an indolent disease. Treatment outcome and management of prostate cancer could be improved by the development of non-invasive biomarker assays that aid in increasing the sensitivity and specificity of prostate cancer screening, help to distinguish aggressive from indolent disease and guide therapeutic decisions. Prostate cancer cells release miRNAs into the bloodstream, where they exist incorporated into ribonucleoprotein complexes or extracellular vesicles. Later, cell-free miRNAs have been found in various other biofluids. The initial RNA sequencing studies suggested that most of the circulating cell-free miRNAs in healthy individuals are derived from blood cells, while specific disease-associated miRNA signatures may appear in the circulation of patients affected with various diseases, including cancer. This raised a hope that cell-free miRNAs may serve as non-invasive biomarkers for prostate cancer. Indeed, a number of cell-free miRNAs that potentially may serve as diagnostic, prognostic or predictive biomarkers have been discovered in blood or other biofluids of prostate cancer patients and need to be validated in appropriately designed longitudinal studies and clinical trials. In this review, we systematically summarise studies investigating cell-free miRNAs in biofluids of prostate cancer patients and discuss the utility of the identified biomarkers in various clinical scenarios. Furthermore, we discuss the possible mechanisms of miRNA release into biofluids and outline the biological questions and technical challenges that have arisen from these studies. Prostate cancer; Cell-free miRNAs; Extracellular vesicles; Exosomes; Microvesicles; Biomarkers; Liquid biopsy; Overdiagnosis Background Prostate cancer is a global health problem. Approximately 1.1 million cases are diagnosed per year, making this malignancy the second most common cancer in men worldwide and the most common cancer in men in more developed regions [ 1, 2 ]. In terms of mortality, prostate cancer is the fifth leading cause of death from cancer in men [ 1, 2 ]. In the economically developed countries, over 80 % of prostate cancer cases are diagnosed at localised stage [ 3 ], when the disease can often be cured by localised therapies such as radical prostatectomy and radiotherapy. Technical developments in radical prostatectomy as well as targeted external beam radiation therapy have significantly reduced patient morbidity after curative treatment. Cancer specific survival 5 years after the time of diagnosis is high for localised prostate cancer, and it reaches almost 100 % in USA according to the American Cancer Society. However, the more advanced the cancer at diagnosis, the poorer the prognosis. When metastatic prostate cancer is diagnosed, androgen deprivation is the initial line of therapy. Androgen deprivation therapy (ADT), however, is a palliative and not a curative treatment for patients with metastases, and eventually the patients will develop metastatic castrationresistant prostate cancer (mCRPC), for which currently available treatment options have limited efficacy [ 4, 5 ]. Once the disease is androgen independent, the estimated 5year survival drops to 28 % and the average survival time is 2 years [4]. The discovery of prostate specific antigen (PSA) almost 30 years ago has changed the way how prostate cancer is diagnosed and managed. The serum PSA test is currently the most commonly used tool for organised screening programs, opportunistic screening and monitoring of prostate cancer. Evidence obtained in numerous clinical trials suggests that the PSA test may improve the early detection of localised prostate cancer, however it has substantial drawbacks due to overdiagnosis and overtreatment. The balance of benefits and harms is still a matter of active debate, and improving the performance of PSA-based screening for prostate cancer is essential [ 6–8 ]. Furthermore, recent advances in the development of therapeutics for prostate cancer ha (...truncated)


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Edgars Endzeliņš, Vita Melne, Zane Kalniņa, Vilnis Lietuvietis, Una Riekstiņa, Alicia Llorente, Aija Linē. Diagnostic, prognostic and predictive value of cell-free miRNAs in prostate cancer: a systematic review, Molecular Cancer, 2016, pp. 41, 15, DOI: 10.1186/s12943-016-0523-5