The Application of MicroRNAs in Cancer Diagnostics - RNA Interference from Biology to Therapeutics - page 277

miRNAs, while the origin of miRNA signal in the remaining studies was not exam-
ined. In the pioneering study by Mitchell et al . , miR-141 levels were increased in
serum from 25 patients with metastatic prostate cancer compared to 25 healthy
controls. In a subsequent study, miR-141 was found to predict the clinical outcome
of prostate cancer patients with a hazard ratio of 8.3 as well as to correlate with PSA
levels under longitudinal evaluations [ 227 ]. More recently, circulating miR-141 has
been reported as an independent adverse prognostic factor for patients with meta-
static colon cancer [ 228 ]. The combination of miR-141 and the widely used col-
orectal marker carcinoembryogenic antigen (CEA) further improved the accuracy
of detection. In the study by Chen et al . in 2008, miR-25 and miR-223 were found
to be deregulated in serum samples from lung cancer patients, and the two miRNAs
were validated as noninvasive diagnostic markers among additional 152 cases [ 156 ] .
Several of the circulating miRNAs identified by Chen et al . for colorectal cancer
overlapped with those identified for lung cancer. This suggests that specific circulat-
ing miRNAs may exist in cancer disease in general. This would be in agreement
with data reported from profiling of solid tumor tissue, showing a general upregula-
tion of oncogenic miR-21 and downregulation of tumor suppressor miR-145 [ 123,
229 ] .
Several studies indicate that circulating miRNAs have potential as diagnostic
markers for lung cancer (reviewed in [ 230 ]). In one study, a fivefold difference in
expression was detected for 11 serum miRNAs between long- and short-term survi-
vors, and the levels of four miRNAs (miR-486, miR-30d, miR-1, and miR-499)
were significantly associated with overall survival [ 215 ]. Early stages of lung cancer
have also been associated with changes in serum miRNAs [ 231 ] . Concordantly, a
diagnostic test of 34 circulating miRNAs has been developed for detection of early
non-small cell lung cancer (NSCLC) [ 232 ]. This test was able to identify NSCLC
cases among asymptomatic high-risk individuals with 80% accuracy and could dis-
criminate between benign and malignant lesions. Rabinowits et al . examined epi-
thelial exosome concentration by size-exclusion chromatography and magnetic
activated cell sorting using an anti-EpCAM antibody [ 197 ]. Here, an increase in
exosome concentration from 0.77 mg/ml for the control group to 2.85 mg/ml for the
lung adenocarcinoma group was observed. Small RNA extraction from the epithe-
lial-derived exosomes (=carcinoma-derived) was profiled for miRNAs using
microarray hybridization. Twelve specific miRNAs elevated in NSCLC tumor tis-
sue were mirrored in the circulating exosomes. For the control samples, the total
levels of miRNAs were low, and the level of the 12 miRNAs was below the detec-
tion limit. The results were recently supported by the finding that a combination of
miR-21, miR-210, and miR-486-5p detection was shown to identify lung cancer
patients with malignant solitary pulmonary nodules (SPN), compared to benign
SPN or healthy controls, with a sensitivity of 75% and specificity of 85% [ 233 ] .
This holds promise for improvement of the pre-operative diagnosis based on SPN
status presently conducted.
Several studies have addressed whether changes in circulating miRNAs is
directly related to the presence of a tumor. The upregulated plasma concentrations
of miR-17-5p, miR-21, miR-106a, and miR-106b in gastric cancer [ 206 ] , miR-184