Miroculus

Highly sensitive biomarkers for different types of conditions



MicroRNAs as biomarkers

MicroRNAs are small RNA molecules, whose primary role is to regulate the expression of our genes (genetic material) in the cells [1]. We find great potential in the fact that they can be found in body fluids such as blood plasma and serum [2], where they give clues about the patho-physiological status of a person.


In other words, microRNAs reflect a person’s health status and can therefore be used as biomarkers for various diseases, including cancer.

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Cancer is a major public health problem with over 12 million of new cancer cases diagnosed and over 7 million cancer-related deaths each year [3]. The major challenges of this disease are (i) early detection, (ii) patient stratification and (iii) therapy response prediction. Improvements in these areas hold promise to lead in a more favorable outcome for the patients. Therefore, a lot of attention is turning towards the investigation of novel and minimally invasive biomarkers, such as circulating microRNAs, which can complement the existing cancer detection techniques as well as aid in clinical decision-making and disease-monitoring [4].

One of the first scientific articles describing circulating microRNAs as potential diagnostic biomarkers for cancer reported elevated miR-21, miR-155 and miR-210 levels in the serum of lymphoma patients when compared to healthy individuals [5]. The investigation of circulating microRNAs in various types of cancer followed and a myriad of microRNAs with diagnostic, prognostic and predictive capabilities were identified [6]. For example, a panel of seven circulating microRNAs was found to be able to distinguish between plasma samples from healthy women and those with breast cancer [7]. These circulating microRNAs even showed promise for the detection of benign and early stage breast tumors [7]. Similarly, for lung cancer a plasma microRNA signature has been devised with the capability of detecting cancer even in asymptomatic patients before clinically evident disease onset [8].

In the metastatic breast cancer setting, plasma levels of the miR-200 family, as well as a few other circulating microRNAs, were highly correlated with the counts of circulating tumor cells (CTC) in blood (an FDA-approved prognostic marker for metastatic breast cancer [9]) and showed great potential in predicting the survival of these patients [10]. Similarly, an investigation of serum samples from metastatic prostate cancer patients and healthy individuals found miR-141 levels to be elevated in the patients [2]. Later on, the predictive value of the same circulating microRNA was found comparable if not superior to established clinically-used biomarkers, i.e. circulating tumor cell (CTC) counts, prostate- specific antigen (PSA) and lactate dehydrogenase (LDH) levels [11] for therapy response in prostate cancer patients.

Circulating microRNAs have several advantages over some other biomarker types. MicroRNAs are highly stable in body fluids, even in non-ideal sample handling conditions, under which most other molecules would degrade [2, 12, 13]. Further, circulating microRNAs are easily accessible and can be measured repeatedly over a period of time in an essentially non-invasive manner (blood-based test). Finally, considering that there are over 2000 different microRNAs in the human genome, it is highly probable that researchers will be able to identify circulating microRNA signatures, which can be used as “fingerprints” of various pathological conditions.

Superior and less invasive tools for cancer detection and prognosis can be developed through the identification of novel microRNA biomarkers in the circulation and further clarification of their association to tumor development and pathology. Because of the continuous methodological advances it will be possible to measure them in a simple, cost-effective and rapid manner in the near future. This will allow the utilization of circulating microRNAs as a novel type of disease biomarkers for personalized medicine.



References

1. Bartel DP: MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004, 116(2): 281-297.

2. Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, Peterson A, Noteboom J, O'Briant KC, Allen A et al: Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A 2008, 105(30):10513-10518.

3. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin 2011, 61(2):69-90.

4. Cortez MA, Bueso-Ramos C, Ferdin J, Lopez-Berestein G, Sood AK, Calin GA: MicroRNAs in body fluids--the mix of hormones and biomarkers. Nat Rev Clin Oncol 2011, 8(8):467-477.

5. Lawrie CH, Gal S, Dunlop HM, Pushkaran B, Liggins AP, Pulford K, Banham AH, Pezzella F, Boultwood J, Wainscoat JS et al: Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large B-cell lymphoma. Br J Haematol 2008, 141(5):672-675.

6. Schwarzenbach H, Nishida N, Calin GA, Pantel K: Clinical relevance of circulating cell-free microRNAs in cancer. Nat Rev Clin Oncol 2014, 11(3):145-156.

7. Cuk K, Zucknick M, Madhavan D, Schott S, Golatta M, Heil J, Marme F, Turchinovich A, Sinn P, Sohn C et al: Plasma microRNA panel for minimally invasive detection of breast cancer. PLoS One 2013, 8(10):e76729.

8. Boeri M, Verri C, Conte D, Roz L, Modena P, Facchinetti F, Calabro E, Croce CM, Pastorino U, Sozzi G: MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer. Proc Natl Acad Sci U S A 2011, 108(9):3713-3718.

9. Riethdorf S, Fritsche H, Muller V, Rau T, Schindlbeck C, Rack B, Janni W, Coith C, Beck K, Janicke F et al: Detection of circulating tumor cells in peripheral blood of patients with metastatic breast cancer: a validation study of the CellSearch system. Clin Cancer Res 2007, 13(3):920-928.

10. Madhavan D, Zucknick M, Wallwiener M, Cuk K, Modugno C, Scharpff M, Schott S, Heil J, Turchinovich A, Yang R et al: Circulating miRNAs as surrogate markers for circulating tumor cells and prognostic markers in metastatic breast cancer. Clin Cancer Res 2012, 18(21):5972-5982.

11. Gonzales JC, Fink LM, Goodman OB, Jr., Symanowski JT, Vogelzang NJ, Ward DC: Comparison of circulating MicroRNA 141 to circulating tumor cells, lactate dehydrogenase, and prostate- specific antigen for determining treatment response in patients with metastatic prostate cancer. Clin Genitourin Cancer 2011, 9(1):39-45.

12. Chen X, Ba Y, Ma L, Cai X, Yin Y, Wang K, Guo J, Zhang Y, Chen J, Guo X et al: Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res 2008, 18(10):997-1006.

13. Turchinovich A, Weiz L, Langheinz A, Burwinkel B: Characterization of extracellular circulating microRNA. Nucleic Acids Res 2011, 39(16):7223-7233.