microRNA Biomarkers as Potential Diagnostic Markers for Cancer - Genomic Biomarkers for Pharmaceutical Development - page 104

4. They eliminate the radiation exposure risk associated with the use of CT scans.
5. Unlike CT scans, they may allow the distinction of indolent from more aggressive lesions.
In addition, circulating biofluids offer yet another advantage of enabling cost-effective
monitoring.
In 2008, the detection of circulating miRNAs in serum from diffuse large B-cell lymphoma
[116] provided a new class of potential biomarkers for cancer and other diseases. In the same
year, Mitchell et al. [117] showed that miRNAs were present in plasma, and that serum miR-
NAs could enable the distinguishing of prostate cancer patients from healthy controls. Since
then, several studies have shown that circulating miRNAs have great potential to serve as
diagnostic markers for various cancer types including breast, colon, ovarian, pancreatic and
lung cancer (reviewed in [118] ).
In general, circulating nucleic acids are believed to exist in two types of cell-derived lipid
vesicles: micro-vesicles of ~100 nm - 1 µm in diameter, and exosomes of ~30-100 nm [119-122] .
Because blood is enriched with enzymes that degrade RNA [123] , it is suggested that the vesi-
cles / exosomes protect circulating miRNA from degradation [124,125] . Evidence indicates that
circulating miRNAs could function in cell-to-cell communication [126] ; however, the specific
functions and mechanisms of circulating miRNAs remain largely elusive. In spite of that, cir-
culating miRNAs have recently emerged as potential biomarkers for cancer diagnostics and
prognostics (for review see [127] ). In fact, miRNAs have been further proposed as tools for
cancer monitoring and treatment of several cancer types, through miRNA replacement similar
to gene therapy. In this chapter, we discuss the potential utility of miRNAs from blood, serum,
plasma, and urine as diagnostic biomarkers in several human cancer types. We also discuss
the challenges that must be overcome in order to bring circulating miRNAs into clinical prac-
tice. This discussion will focus on cancers in which circulating miRNAs have been implicated.
Circulating miRNAs have also been reported in other cancers such as renal, ovarian and head
and neck cancer; however, these cancers have not been reviewed in this chapter due to the
limited number of studies which have been carried out.
5.3.2.1 Leukemia
The ability of miRNA to distinguish cancer from normal tissues was first demonstrated in
chronic lymphocytic leukemia (CLL), in which miR-15a and -16 were both shown to be down-
regulated in CLL patients relative to cancer-free subjects, indicating that both miRNAs may
act as tumor suppressors [128] . The presence of both miR-15 and -16 on chromosome 13q14,
which is deleted in the majority of CLL cases, further supported the role of the two miRNAs.
In 2004, Calin et al. showed that several miRNAs including miR-10b, 181b and others were
de-regulated in CLL [129] . Further evidence showed that reduced expression of miR-29b and
miR-181b was associated with poor prognosis in CLL [125] , suggesting that like miR-15b and
miR-16, miR-29b and miR-181b also act as tumor suppressors. In 2006, Pekarsky et al. showed
that oncogene T cell leukemia / lymphoma 1 (TCL1) is regulated by miR-29b, and that TCL1
expression was inversely proportional to that of miR-29b, and further that high TCL1 levels
were correlated with high ZAP-70 [130] .
The discovery that miRNAs were differentially expressed in CLL set the stage for the
study of miRNAs in other forms of leukemia, including acute lymphoblastic leukemia (ALL)
and acute myeloid leukemia (AML). Similarly to CLL, miR-15b and miR-16 were found to be