Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Clinical relevance of circulating cell-free microRNAs in cancer

Key Points

  • Alterations in microRNAs (miRNAs) are involved in the pathogenesis of various types of human cancers, and because of the stability of tumour-derived cell-free microRNAs, these show potential as novel biomarkers

  • Cell-free miRNAs can be detected not only in plasma and serum, but also in other body fluids, such as urine and saliva, and serve as a non-invasive diagnostic tool

  • miRNAs also have an important role in chemo-resistance of cancer cells, and could be useful predictors of therapeutic response

  • Methods of detection, such as microarray analysis and deep-sequencing, enable a comprehensive profiling of cell-free miRNAs (including various isoforms) from low amounts of RNA samples

Abstract

Efficient patient management relies on early diagnosis of disease and monitoring of treatment. In this regard, much effort has been made to find informative, blood-based biomarkers for patients with cancer. Owing to their attributes—which are specifically modulated by the tumour—circulating cell-free microRNAs found in the peripheral blood of patients with cancer may provide insights into the biology of the tumour and the effects of therapeutic interventions. Moreover, the role of microRNAs in the regulation of different cellular processes points to their clinical utility as blood-based biomarkers and future therapeutic targets. MicroRNAs are optimal biomarkers owing to high stability under storage and handling conditions and their presence in blood, urine and other body fluids. In particular, detection of levels of microRNAs in blood plasma and serum has the potential for an earlier cancer diagnosis and to predict prognosis and response to therapy. This Review article considers the latest developments in the use of circulating microRNAs as prognostic and predictive biomarkers and discusses their utility in personalized medicine.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Biogenesis and diverse functions of miRNAs.
Figure 2: Release of miRNAs from cells into the blood circulation.

References

  1. Pritchard, C. C., Cheng, H. H. & Tewari, M. MicroRNA profiling: approaches and considerations. Nat. Rev. Genet. 13, 358–369 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Cortez, M. A. et al. MicroRNAs in body fluids—the mix of hormones and biomarkers. Nat. Rev. Clin. Oncol. 8, 467–477 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Turchinovich, A., Weiz, L. & Burwinkel, B. Extracellular miRNAs: the mystery of their origin and function. Trends Biochem. Sci. 37, 460–465 (2012).

    Article  CAS  PubMed  Google Scholar 

  4. Kim, V. N. MicroRNA biogenesis: coordinated cropping and dicing. Nat. Rev. Mol. Cell Biol. 6, 376–385 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Krol, J., Loedige, I. & Filipowicz, W. The widespread regulation of microRNA biogenesis, function and decay. Nat. Rev. Genet. 11, 597–610 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. Bartel, D. P. MicroRNAs: target recognition and regulatory functions. Cell 136, 215–233 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Höck, J. & Meister, G. The Argonaute protein family. Genome Biol. 9, 210 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Portnoy, V., Huang, V., Place, R. F. & Li, L. C. Small RNA and transcriptional upregulation. Wiley Interdiscip. Rev. RNA 2, 748–760 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Place, R. F., Li, L. C., Pookot, D., Noonan, E. J. & Dahiya, R. MicroRNA-373 induces expression of genes with complementary promoter sequences. Proc. Natl Acad. Sci. USA 105, 1608–1613 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Vasudevan, S., Tong, Y. & Steitz, J. A. Switching from repression to activation: microRNAs can up-regulate translation. Science 318, 1931–1934 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Suzuki, H. I. & Miyazono, K. Emerging complexity of microRNA generation cascades. J. Biochem. 149, 15–25 (2011).

    Article  CAS  PubMed  Google Scholar 

  12. Suzuki, H. I. et al. MCPIP1 ribonuclease antagonizes dicer and terminates microRNA biogenesis through precursor microRNA degradation. Mol. Cell 44, 424–436 (2011).

    Article  CAS  PubMed  Google Scholar 

  13. Esquela-Kerscher, A. & Slack, F. J. Oncomirs—microRNAs with a role in cancer. Nat. Rev. Cancer 6, 259–269 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Heneghan, H. M., Miller, N., Lowery, A. J., Sweeney, K. J. & Kerin, M. J. MicroRNAs as novel biomarkers for breast cancer. J. Oncol. 2009, 950201 (2009).

    CAS  PubMed  Google Scholar 

  15. Stroun, M., Lyautey, J., Lederrey, C., Olson-Sand, A. & Anker, P. About the possible origin and mechanism of circulating DNA apoptosis and active DNA release. Clin. Chim. Acta 313, 139–142 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Okada, H., Kohanbash, G. & Lotze, M. T. MicroRNAs in immune regulation--opportunities for cancer immunotherapy. Int. J. Biochem. Cell Biol. 42, 1256–1261 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ha, T. Y. The role of microRNAs in regulatory T cells and in the immune response. Immune Netw. 11, 11–41 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Toffanin, S., Sia, D. & Villanueva, A. microRNAs: new ways to block tumor angiogenesis? J. Hepatol. 57, 490–491 (2012).

    Article  CAS  PubMed  Google Scholar 

  19. Pegtel, D. M. et al. Functional delivery of viral miRNAs via exosomes. Proc. Natl Acad. Sci. USA 107, 6328–6333 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Valadi, H. et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9, 654–659 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Vickers, K. C. & Remaley, A. T. Lipid-based carriers of microRNAs and intercellular communication. Curr. Opin. Lipidol. 23, 91–97 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Skog, J. et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat. Cell Biol. 10, 1470–1476 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lu, J. et al. MicroRNA expression profiles classify human cancers. Nature 435, 834–838 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Volinia, S. et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc. Natl Acad. Sci. USA 103, 2257–2261 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yu, S. L. et al. MicroRNA signature predicts survival and relapse in lung cancer. Cancer Cell 13, 48–57 (2008).

    Article  CAS  PubMed  Google Scholar 

  26. Dvinge, H. et al. The shaping and functional consequences of the microRNA landscape in breast cancer. Nature 497, 378–382 (2013).

    Article  CAS  PubMed  Google Scholar 

  27. Mitchell, P. S. et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc. Natl Acad. Sci. USA 105, 10513–10518 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Arroyo, J. D. et al. Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc. Natl Acad. Sci. USA 108, 5003–5008 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Kroh, E. M., Parkin, R. K., Mitchell, P. S. & Tewari, M. Analysis of circulating microRNA biomarkers in plasma and serum using quantitative reverse transcription-PCR (qRT-PCR). Methods 50, 298–301 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Turchinovich, A., Weiz, L., Langheinz, A. & Burwinkel, B. Characterization of extracellular circulating microRNA. Nucleic Acids Res. 39, 7223–7233 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Pritchard, C. C. et al. Blood cell origin of circulating microRNAs: a cautionary note for cancer biomarker studies. Cancer Prev. Res. (Phila.) 5, 492–497 (2012).

    Article  CAS  Google Scholar 

  32. Chen, C. et al. Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res. 33, e179 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ell, B. et al. Tumor-induced osteoclast miRNA changes as regulators and biomarkers of osteolytic bone metastasis. Cancer Cell 24, 542–556 (2013).

    Article  CAS  PubMed  Google Scholar 

  34. Dong, H. et al. MicroRNA: function, detection, and bioanalysis. Chem. Rev. (2013).

  35. Castoldi, M. et al. A sensitive array for microRNA expression profiling (miChip) based on locked nucleic acids (LNA). RNA 12, 913–920 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Shendure, J. & Ji, H. Next-generation DNA sequencing. Nat. Biotechnol. 26, 1135–1145 (2008).

    Article  CAS  PubMed  Google Scholar 

  37. Ryan, B. M., Robles, A. I. & Harris, C. C. Genetic variation in microRNA networks: the implications for cancer research. Nat. Rev. Cancer 10, 389–402 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chang, H. T. et al. Comprehensive analysis of microRNAs in breast cancer. BMC Genomics 13 (Suppl. 7), S18 (2012).

    PubMed  PubMed Central  Google Scholar 

  39. Li, S. C. et al. miRNA arm selection and isomiR distribution in gastric cancer. BMC Genomics 13 (Suppl. 1), S13 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Williams, Z. et al. Comprehensive profiling of circulating microRNA via small RNA sequencing of cDNA libraries reveals biomarker potential and limitations. Proc. Natl Acad. Sci. USA 110, 4255–4260 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Hafner, M. et al. RNA-ligase-dependent biases in miRNA representation in deep-sequenced small RNA cDNA libraries. RNA 17, 1697–1712 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lawrie, C. H. et al. Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large B-cell lymphoma. Br. J. Haematol. 141, 672–675 (2008).

    Article  PubMed  Google Scholar 

  43. Shen, J. et al. Diagnosis of lung cancer in individuals with solitary pulmonary nodules by plasma microRNA biomarkers. BMC Cancer 11, 374 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Roth, C., Kasimir-Bauer, S., Pantel, K. & Schwarzenbach, H. Screening for circulating nucleic acids and caspase activity in the peripheral blood as potential diagnostic tools in lung cancer. Mol. Oncol. 5, 281–291 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Roth, C. et al. Low levels of cell-free circulating miR-361-3p and miR-625* as blood-based markers for discriminating malignant from benign lung tumors. PLoS ONE 7, e38248 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Cui, E. H. et al. Serum microRNA 125b as a diagnostic or prognostic biomarker for advanced NSCLC patients receiving cisplatin-based chemotherapy. Acta Pharmacol. Sin. 34, 309–313 (2013).

    Article  CAS  PubMed  Google Scholar 

  47. Wang, Y. et al. Pathway-based serum microRNA profiling and survival in patients with advanced stage non-small cell lung cancer. Cancer Res. 73, 4801–4809 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hu, Z. et al. Serum microRNA signatures identified in a genome-wide serum microRNA expression profiling predict survival of non-small-cell lung cancer. J. Clin. Oncol. 28, 1721–1726 (2010).

    Article  PubMed  Google Scholar 

  49. Yuxia, M., Zhennan, T. & Wei, Z. Circulating miR-125b is a novel biomarker for screening non-small-cell lung cancer and predicts poor prognosis. J. Cancer Res. Clin. Oncol. 138, 2045–2050 (2012).

    Article  CAS  PubMed  Google Scholar 

  50. Huang, Y. et al. MicroRNA-21 gene and cancer. Med. Oncol. 30, 376 (2013).

    Article  CAS  PubMed  Google Scholar 

  51. Liu, X. G. et al. High expression of serum miR-21 and tumor miR-200c associated with poor prognosis in patients with lung cancer. Med. Oncol. 29, 618–626 (2012).

    Article  CAS  PubMed  Google Scholar 

  52. Sanfiorenzo, C. et al. Two panels of plasma microRNAs as non-invasive biomarkers for prediction of recurrence in resectable NSCLC. PLoS ONE 8, e54596 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Pepek, J. M. et al. How well does the new lung cancer staging system predict for local/regional recurrence after surgery?: a comparison of the TNM 6 and 7 systems. J. Thorac. Oncol. 6, 757–761 (2011).

    Article  PubMed  Google Scholar 

  54. Kaduthanam, S. et al. Serum miR-142-3p is associated with early relapse in operable lung adenocarcinoma patients. Lung Cancer 80, 223–227 (2013).

    Article  PubMed  Google Scholar 

  55. Silva, J. et al. Vesicle-related microRNAs in plasma of nonsmall cell lung cancer patients and correlation with survival. Eur. Respir. J. 37, 617–623 (2011).

    Article  CAS  PubMed  Google Scholar 

  56. Wang, T. et al. Cell-free microRNA expression profiles in malignant effusion associated with patient survival in non-small cell lung cancer. PLoS ONE 7, e43268 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Chen, W., Cai, F., Zhang, B., Barekati, Z. & Zhong, X. Y. The level of circulating miRNA-10b and miRNA-373 in detecting lymph node metastasis of breast cancer: potential biomarkers. Tumour Biol. 34, 455–462 (2013).

    Article  CAS  PubMed  Google Scholar 

  58. Eichelser, C., Flesch-Janys, D., Chang-Claude, J., Pantel, K. & Schwarzenbach, H. Deregulated serum concentrations of circulating cell-free microRNAs miR-17, miR-34a, miR-155, and miR-373 in human breast cancer development and progression. Clin. Chem. 59, 1489–1496 (2013).

  59. Wang, F., Zheng, Z., Guo, J. & Ding, X. Correlation and quantitation of microRNA aberrant expression in tissues and sera from patients with breast tumor. Gynecol. Oncol. 119, 586–593 (2010).

    Article  CAS  PubMed  Google Scholar 

  60. Roth, C. et al. Circulating microRNAs as blood-based markers for patients with primary and metastatic breast cancer. Breast Cancer Res. 12, R90 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Schwarzenbach, H., Milde-Langosch, K., Steinbach, B., Muller, V. & Pantel, K. Diagnostic potential of PTEN-targeting miR-214 in the blood of breast cancer patients. Breast Cancer Res. Treat. 134, 933–941 (2012).

    Article  CAS  PubMed  Google Scholar 

  62. Asaga, S. et al. Direct serum assay for microRNA-21 concentrations in early and advanced breast cancer. Clin. Chem. 57, 84–91 (2011).

    Article  CAS  PubMed  Google Scholar 

  63. Schwarzenbach, H., Hoon, D. S. & Pantel, K. Cell-free nucleic acids as biomarkers in cancer patients. Nat. Rev. Cancer 11, 426–437 (2011).

    Article  CAS  PubMed  Google Scholar 

  64. Gorges, T. M. & Pantel, K. Circulating tumor cells as therapy-related biomarkers in cancer patients. Cancer Immunol. Immunother. 62, 931–939 (2013).

    Article  CAS  PubMed  Google Scholar 

  65. Kang, Y. & Pantel, K. Tumor cell dissemination: emerging biological insights from animal models and cancer patients. Cancer Cell 23, 573–581 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Zhang, L. et al. Meta-analysis of the prognostic value of circulating tumor cells in breast cancer. Clin. Cancer Res. 18, 5701–5710 (2012).

    Article  PubMed  Google Scholar 

  67. Madhavan, D. et al. Circulating miRNAs as surrogate markers for circulating tumor cells and prognostic markers in metastatic breast cancer. Clin. Cancer Res. 18, 5972–5982 (2012).

    Article  CAS  PubMed  Google Scholar 

  68. Roth, C., Kasimir-Bauer, S., Heubner, M., Pantel, K. & Schwarzenbach, H. in Circulating nucleic acids in plasma and serum (ed. Gahan, P. B.) 63–71 (Springer, 2011).

    Google Scholar 

  69. Hong, F., Li, Y., Xu, Y. & Zhu, L. Prognostic significance of serum microRNA-221 expression in human epithelial ovarian cancer. J. Int. Med. Res. 41, 64–71 (2013).

    Article  CAS  PubMed  Google Scholar 

  70. Xu, Y. Z., Xi, Q. H., Ge, W. L. & Zhang, X. Q. Identification of serum MicroRNA-21 as a biomarker for early detection and prognosis in human epithelial ovarian cancer. Asian Pac. J. Cancer Prev. 14, 1057–1060 (2013).

    Article  PubMed  Google Scholar 

  71. Yu, J. et al. Circulating microRNA-218 was reduced in cervical cancer and correlated with tumor invasion. J. Cancer Res. Clin. Oncol. 138, 671–674 (2012).

    Article  CAS  PubMed  Google Scholar 

  72. Chen, J. et al. Serum microRNA expression levels can predict lymph node metastasis in patients with early-stage cervical squamous cell carcinoma. Int. J. Mol. Med. 32, 557–567 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Zhao, S., Yao, D., Chen, J. & Ding, N. Circulating miRNA-20a and miRNA-203 for screening lymph node metastasis in early stage cervical cancer. Genet. Test. Mol. Biomarkers 17, 631–636 (2013).

    CAS  Google Scholar 

  74. Yaman Agaoglu, F. et al. Investigation of miR-21, miR-141, and miR-221 in blood circulation of patients with prostate cancer. Tumour Biol. 32, 583–588 (2011).

    Article  CAS  PubMed  Google Scholar 

  75. Nguyen, H. C. et al. Expression differences of circulating microRNAs in metastatic castration resistant prostate cancer and low-risk, localized prostate cancer. Prostate 73, 346–354 (2012).

    Google Scholar 

  76. Zhang, H. L. et al. Serum miRNA-21: elevated levels in patients with metastatic hormone-refractory prostate cancer and potential predictive factor for the efficacy of docetaxel-based chemotherapy. Prostate 71, 326–331 (2011).

    Article  CAS  PubMed  Google Scholar 

  77. Shen, J. et al. Dysregulation of circulating microRNAs and prediction of aggressive prostate cancer. Prostate 72, 1469–1477 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Brase, J. C. et al. Circulating miRNAs are correlated with tumor progression in prostate cancer. Int. J. Cancer 128, 608–616 (2011).

    Article  CAS  PubMed  Google Scholar 

  79. Selth, L. A. et al. Circulating microRNAs predict biochemical recurrence in prostate cancer patients. Br. J. Cancer 109, 641–650 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Bryant, R. J. et al. Changes in circulating microRNA levels associated with prostate cancer. Br. J. Cancer 106, 768–774 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Shah, M. A. & Kurtz, R. C. Upper gastrointestinal cancer predisposition syndromes. Hematol. Oncol. Clin. North Am. 24, 815–835 (2010).

    Article  PubMed  Google Scholar 

  82. Han, M. et al. Re-expression of miR-21 contributes to migration and invasion by inducing epithelial-mesenchymal transition consistent with cancer stem cell characteristics in MCF-7 cells. Mol. Cell Biochem. 363, 427–436 (2012).

    Article  CAS  PubMed  Google Scholar 

  83. Komatsu, S. et al. Circulating microRNAs in plasma of patients with oesophageal squamous cell carcinoma. Br. J. Cancer 105, 104–111 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Takeshita, N. et al. Serum microRNA expression profile: miR-1246 as a novel diagnostic and prognostic biomarker for oesophageal squamous cell carcinoma. Br. J. Cancer 108, 644–652 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Liu, R. et al. Circulating miR-155 expression in plasma: a potential biomarker for early diagnosis of esophageal cancer in humans. J. Toxicol. Environ. Health A 75, 1154–1162 (2012).

    Article  CAS  PubMed  Google Scholar 

  86. Cheng, H. et al. Circulating plasma MiR-141 is a novel biomarker for metastatic colon cancer and predicts poor prognosis. PLoS ONE 6, e17745 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Wang, L. G. & Gu, J. Serum microRNA-29a is a promising novel marker for early detection of colorectal liver metastasis. Cancer Epidemiol. 36, e61–e67 (2012).

    Article  CAS  PubMed  Google Scholar 

  88. Kuo, T. Y. et al. Computational analysis of mRNA expression profiles identifies microRNA-29a/c as predictor of colorectal cancer early recurrence. PLoS ONE 7, e31587 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Ng, E. K. et al. Differential expression of microRNAs in plasma of patients with colorectal cancer: a potential marker for colorectal cancer screening. Gut 58, 1375–1381 (2009).

    Article  CAS  PubMed  Google Scholar 

  90. Tsai, K. W. et al. Aberrant expression of miR-196a in gastric cancers and correlation with recurrence. Genes Chromosomes Cancer 51, 394–401 (2012).

    Article  CAS  PubMed  Google Scholar 

  91. Valladares-Ayerbes, M. et al. Circulating miR-200c as a diagnostic and prognostic biomarker for gastric cancer. J. Transl. Med. 10, 186 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Komatsu, S. et al. Prognostic impact of circulating miR-21 in the plasma of patients with gastric carcinoma. Anticancer Res. 33, 271–276 (2013).

    PubMed  Google Scholar 

  93. Zhou, H. et al. Detection of circulating tumor cells in peripheral blood from patients with gastric cancer using microRNA as a marker. J. Mol. Med. (Berl.) 88, 709–717 (2010).

    Article  CAS  Google Scholar 

  94. Yamamoto, Y. et al. MicroRNA-500 as a potential diagnostic marker for hepatocellular carcinoma. Biomarkers 14, 529–538 (2009).

    Article  CAS  PubMed  Google Scholar 

  95. Zhou, J. et al. Plasma microRNA panel to diagnose hepatitis B virus-related hepatocellular carcinoma. J. Clin. Oncol. 29, 4781–4788 (2011).

    Article  CAS  PubMed  Google Scholar 

  96. Koberle, V. et al. Serum microRNA-1 and microRNA-122 are prognostic markers in patients with hepatocellular carcinoma. Eur. J. Cancer 49, 3442–3449 (2013).

    Article  CAS  PubMed  Google Scholar 

  97. Tomimaru, Y. et al. Circulating microRNA-21 as a novel biomarker for hepatocellular carcinoma. J. Hepatol. 56, 167–175 (2012).

    Article  CAS  PubMed  Google Scholar 

  98. Liu, J. et al. Combination of plasma microRNAs with serum CA19–19 for early detection of pancreatic cancer. Int. J. Cancer 131, 683–691 (2012).

    Article  CAS  PubMed  Google Scholar 

  99. Liu, R. et al. Serum microRNA expression profile as a biomarker in the diagnosis and prognosis of pancreatic cancer. Clin. Chem. 58, 610–618 (2012).

    Article  CAS  PubMed  Google Scholar 

  100. Hanash, S. M., Baik, C. S. & Kallioniemi, O. Emerging molecular biomarkers--blood-based strategies to detect and monitor cancer. Nat. Rev. Clin. Oncol. 8, 142–150 (2011).

    Article  PubMed  Google Scholar 

  101. Gilad, S. et al. Serum microRNAs are promising novel biomarkers. PLoS ONE 3, e3148 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Chim, S. S. et al. Detection and characterization of placental microRNAs in maternal plasma. Clin. Chem. 54, 482–490 (2008).

    Article  CAS  PubMed  Google Scholar 

  103. Le, H. B. et al. Evaluation of dynamic change of serum miR-21 and miR-24 in pre- and post-operative lung carcinoma patients. Med. Oncol. 29, 3190–3197 (2012).

    Article  CAS  PubMed  Google Scholar 

  104. Jung, E. J. et al. Plasma microRNA 210 levels correlate with sensitivity to trastuzumab and tumor presence in breast cancer patients. Cancer 118, 2603–2614 (2012).

    Article  CAS  PubMed  Google Scholar 

  105. Zheng, D. et al. Plasma microRNAs as novel biomarkers for early detection of lung cancer. Int. J. Clin. Exp. Pathol. 4, 575–586 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Sun, Y. et al. Serum microRNA-155 as a potential biomarker to track disease in breast cancer. PLoS ONE 7, e47003 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Ohyashiki, K. et al. Clinical impact of down-regulated plasma miR-92a levels in non-Hodgkin's lymphoma. PLoS ONE 6, e16408 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Wei, J. et al. Identification of plasma microRNA-21 as a biomarker for early detection and chemosensitivity of non-small cell lung cancer. Chin. J. Cancer 30, 407–414 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Kurashige, J. et al. Serum microRNA-21 is a novel biomarker in patients with esophageal squamous cell carcinoma. J. Surg. Oncol. 106, 188–192 (2012).

    Article  CAS  PubMed  Google Scholar 

  110. Wang, P. et al. The serum miR-21 level serves as a predictor for the chemosensitivity of advanced pancreatic cancer, and miR-21 expression confers chemoresistance by targeting FasL. Mol. Oncol. 7, 334–345 (2013).

    Article  CAS  PubMed  Google Scholar 

  111. Zhou, M. et al. MicroRNA-125b confers the resistance of breast cancer cells to paclitaxel through suppression of pro-apoptotic Bcl-2 antagonist killer 1 (Bak1) expression. J. Biol. Chem. 285, 21496–21507 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Wang, H. et al. Circulating MiR-125b as a marker predicting chemoresistance in breast cancer. PLoS ONE 7, e34210 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Lee, L. W. et al. Complexity of the microRNA repertoire revealed by next-generation sequencing. RNA 16, 2170–2180 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Madhavan, D., Cuk, K., Burwinkel, B. & Yang, R. Cancer diagnosis and prognosis decoded by blood-based circulating microRNA signatures. Front. Genet. 4, 116 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Garzon, R., Marcucci, G. & Croce, C. M. Targeting microRNAs in cancer: rationale, strategies and challenges. Nat. Rev. Drug Discov. 9, 775–789 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Janssen, H. L. et al. Treatment of HCV infection by targeting microRNA. N. Engl. J. Med. 368, 1685–1694 (2013).

    Article  CAS  PubMed  Google Scholar 

  117. Kalluri, R. & Zeisberg, M. Fibroblasts in cancer. Nat. Rev. Cancer 6, 392–401 (2006).

    Article  CAS  PubMed  Google Scholar 

  118. Fabbri, M. et al. MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. Proc. Natl Acad. Sci. USA 109, E2110–E2116 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Chen, X. et al. Identification of ten serum microRNAs from a genome-wide serum microRNA expression profile as novel noninvasive biomarkers for nonsmall cell lung cancer diagnosis. Int. J. Cancer 130, 1620–1628 (2012).

    Article  CAS  PubMed  Google Scholar 

  120. Yu, J. et al. Circulating microRNA-218 was reduced in cervical cancer and correlated with tumor invasion. J. Cancer Res. Clin. Oncol. 138, 671–674 (2012).

    Article  CAS  PubMed  Google Scholar 

  121. Redova, M. et al. Circulating miR-378 and miR-451 in serum are potential biomarkers for renal cell carcinoma. J. Transl. Med. 10, 55 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Wang, S. et al. A plasma microRNA panel for early detection of colorectal cancer. Int. J. Cancer http://dx.doi.org/10.1002/ijc.28136 (2013).

  123. Liu, R. et al. A five-microRNA signature identified from genome-wide serum microRNA expression profiling serves as a fingerprint for gastric cancer diagnosis. Eur. J. Cancer 47, 784–791 (2011).

    Article  CAS  PubMed  Google Scholar 

  124. Zhang, C. et al. Expression profile of microRNAs in serum: a fingerprint for esophageal squamous cell carcinoma. Clin. Chem. 56, 1871–1879 (2010).

    Article  CAS  PubMed  Google Scholar 

  125. Hsu, C. M. et al. Circulating miRNA is a novel marker for head and neck squamous cell carcinoma. Tumour Biol. 33, 1933–1942 (2012).

    Article  CAS  PubMed  Google Scholar 

  126. Yu, S. et al. Circulating microRNA profiles as potential biomarkers for diagnosis of papillary thyroid carcinoma. J. Clin. Endocrinol. Metab. 97, 2084–2092 (2012).

    Article  CAS  PubMed  Google Scholar 

  127. Yang, C. et al. Identification of seven serum microRNAs from a genome-wide serum microRNA expression profile as potential noninvasive biomarkers for malignant astrocytomas. Int. J. Cancer 132, 116–127 (2013).

    Article  CAS  PubMed  Google Scholar 

  128. Kanemaru, H. et al. The circulating microRNA-221 level in patients with malignant melanoma as a new tumor marker. J. Dermatol. Sci. 61, 187–193 (2011).

    Article  CAS  PubMed  Google Scholar 

  129. Zuo, Z. et al. Circulating microRNAs let-7a and miR-16 predict progression-free survival and overall survival in patients with myelodysplastic syndrome. Blood 118, 413–415 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Guo, H. Q., Huang, G. L., Guo, C. C., Pu, X. X. & Lin, T. Y. Diagnostic and prognostic value of circulating miR-221 for extranodal natural killer/T-cell lymphoma. Dis. Markers 29, 251–258 (2010).

    Article  CAS  PubMed  Google Scholar 

  131. Ferrajoli, A. et al. Prognostic value of miR-155 in individuals with monoclonal B-cell lymphocytosis and patients with B-chronic lymphocytic leukemia. Blood 122, 1891–1899 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Tanaka, K. et al. Circulating miR-200c levels significantly predict response to chemotherapy and prognosis of patients undergoing neoadjuvant chemotherapy for esophageal Cancer. Ann. Surg. Oncol. 20 (Suppl. 3), 670–615 (2013).

    Google Scholar 

Download references

Acknowledgements

G.A.C. is The Alan M. Gewirtz Leukemia & Lymphoma Society Scholar. He was also supported as a Fellow at The University of Texas MD Anderson Research Trust, as a University of Texas System Regents Research Scholar. Work in G.A.C.'s laboratory is supported in part by the US National Institutes of Health (NIH)/US National Cancer Institute (NCI) grants 1UH2TR00943-01 and 1R01 CA182905-01; a US Department of Defence Breast Cancer Idea Award; Developmental Research Awards in breast cancer, ovarian cancer, brain cancer, prostate cancer, multiple myeloma and leukaemia (P50 CA100632) as well as head and neck cancer (P50 CA097007) from the Specialized Programs of Research Excellence (SPOREs); by the CLL Global Research Foundation; a Sister Institution Network Fund (SINF) grant from the MD Anderson Cancer Centre and the German Cancer Research Centre (DKFZ) in chronic lymphocytic leukaemia; a SINF grant in colorectal cancer, the Laura and John Arnold Foundation; the RGK Foundation; and The Estate of C. G. Johnson Jr. K.P. is recipient of the European Research Council Advanced Investigator grant “DISSECT” (no. 269,081), and his work is supported by grants of the Deutsche Forschungsgemeinschaft (DFG), Federal Minister of Education and Science (BMBF) and Deutsche Krebshilfe. The authors apologize to all colleagues whose work was not cited because of space restrictions.

Author information

Authors and Affiliations

Authors

Contributions

All authors researched data for article, contributed substantially to discussion of content, wrote, and reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Klaus Pantel.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Table 1

Diagnostic and prognostic value of circulating miRs in patients with different cancer entities) and 100 references (DOC 505 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Schwarzenbach, H., Nishida, N., Calin, G. et al. Clinical relevance of circulating cell-free microRNAs in cancer. Nat Rev Clin Oncol 11, 145–156 (2014). https://doi.org/10.1038/nrclinonc.2014.5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrclinonc.2014.5

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing