Researchers centered at Nagoya University develop a nanowire device able to detect microscopic levels of urinary markers potentially implicated in cancer
press released on December 25, 2017
Video 1: MicroRNA extraction using nanowires
After introducing a urine sample onto the device, extracellular vesicles are captured by a nanowire substrate via electrostatic forces. MicroRNAs can then be directly extracted from the substrate. ©Takao Yasui
Nagoya, Japan - Cells communicate with each other through a number of different mechanisms. Some of these mechanisms are well-known: in animals, for example, predatory threats can drive the release of norepinephrine, a hormone that travels through the bloodstream and triggers heart and muscle cells to initiate a "fight-or-flight" response.
A far less familiar mode of cellular transport is the extracellular vesicle (EV). EVs can be thought of as small "chunks" of a cell that are able to pinch off and circulate throughout the body to deliver messenger cargo to other cells. These messengers have become increasingly recognized as crucial mediators of cell-to-cell communication.
In a new study reported in Science Advances, researchers centered at Nagoya University have developed a novel medical device that can efficiently capture these EVs, and potentially use them to screen for cancer.
"EVs are potentially useful as clinical markers. The composition of the molecules contained in an EV may provide a diagnostic signature for certain diseases," lead author Takao Yasui explains. "The ongoing challenge for physicians in any field is to find a non-invasive diagnostic tool that allows them to monitor their patients on a regular basis--for example, a simple urine test."
Among the many molecules EVs have been found to harbor are microRNAs, which are short pieces of ribonucleic acid that play diverse roles in normal cellular biology. Critically, the presence of certain microRNAs in urine might serve as a red flag for serious conditions such as bladder and prostate cancer. While this important cargo could therefore theoretically aid physicians in cancer diagnoses, there are still many technological hurdles that need to be overcome. One such hurdle: finding a feasible method to capture EVs in sufficient quantities to analyze them in a routine clinical setting.
"The content of EVs in urine is extremely low, at less than 0.01% of the total fluid volume. This is a major barrier to their diagnostic utility," Yasui notes. Our solution was to embed zinc oxide nanowires into a specialized polymer to create a material that we believed would be highly efficient at capturing these vesicles. Our findings suggest that the device is indeed quite efficient. We obtained a collection rate of over 99%, surpassing ultracentrifugation as well as other methods that are currently being used in the field."
(a) Scatterplot comparing normalized intensities of microRNAs extracted with the nanowire device versus conventional collection by ultracentrifugation. (b) Histogram showing the frequency of microRNA species at different fluorescent intensities collected by nanowires (red) and ultracentrifugation (blue). Both the scatterplot and histogram analyses show a notably greater abundance of extracted microRNAs using the nanowire technology. © Takao Yasui
To test the practicality of their device, the research team compared the microRNAs of EVs isolated from healthy patients with those isolated from patients who were already diagnosed with bladder, prostate, and other forms of cancer. Notably, their technique required only 1 milliliter of urine--far more than the typical "deposit" provided during a routine checkup--and found a substantially greater number and different types of microRNAs compared with the standard ultracentrifugation approach.
Figure 2: Identification of distinct microRNA patterns in healthy donors and cancer patients
Nanowire extraction allowed many microRNAs to be compared at once using urine samples collected from patients. Expression of each microRNA is shown as low/downregulated (blue), intermediate (black), or high/upregulated (yellow). The analysis reveals unique patterns of expression for groups of microRNAs when comparing healthy donors (−) with cancer patients (+). © Takao Yasui
"Finding a specific, reproducible marker to help confirm a cancer diagnosis is difficult. This is especially true for microRNAs, which are a relatively new class of markers in the field," co-author Yoshinobu Baba explains. "Sometimes finding just one reliable microRNA is considered a success. Using this approach, we were surprised to find that not just one, but whole combinations of microRNAs might be associated with different types of cancers. The findings are preliminary, of course, but we hope our device can help to lay the groundwork for easier ways to diagnose life-threatening diseases as early as possible."
The article, "Unveiling massive numbers of cancer-related urinary-microRNA candidates via nanowires" was published in Science Advances at DOI: 10.1126/sciadv.1701133
Authors: Takao Yasui 1,2,3, Takeshi Yanagida 4,5, Satoru Ito 1, Yuki Konakade 1, Daiki Takeshita 1, Tsuyoshi Naganawa 1, Kazuki Nagashima 4, Taisuke Shimada 1, Noritada Kaji 1,2,3, Yuta Nakamura 1, Ivan Adiyasa Thiodorus 1, Yong He 4, Sakon Rahong 2,6, Masaki Kanai 4, Hiroshi Yukawa 1,2, Takahiro Ochiya 7, Tomoji Kawai 5, Yoshinobu Baba 1,2,8,9
1 Department of Biomolecular Engineering, Graduate School of Engineering, Nagoya University
2 ImPACT Research Center for Advanced Nanobiodevices, Nagoya University
3 Japan Science and Technology Agency, PRESTO
4 Institute of Materials Chemistry and Engineering, Kyushu University
5 Institute of Scientific and Industrial Research, Osaka University
6 College of Nanotechnology, King Mongkut's Institute of Technology Ladkrabang
7 Division of Molecular and Cellular Medicine, National Cancer Center Research Institute
8 Health Research Institute, National Institute of Advanced Industrial Science and Technology
9 College of Pharmacy, Kaohsiung Medical University
Baba Lab.(Japanese), Graduate School of Engineering, Nagoya University
Biomolecular Engineering, Graduate School of Engineering, Nagoya University
"Artificial hyper-nanospace for mechanism elucidation of cancer metastasis", PRESTO, Japan Science and Technology Agency
"Development of Diagnostic Technology for Detection of miRNA in Body Fluids", the Japan Agency for Medical Research and Development and New Energy and Industrial Technology Development Organization (Japanese)
"Japanese Team Develops Nanowire Technology for Detecting Cancer Biomakers in Urine", by Justin Petrone, genomeweb (Dec 18, 2017)
Bisiness Standard(Washington D.C.)
New Kerala(Washington D.C.)
Funding: This research was supported by PRESTO (JPMJPR151B); the Japan Science and Technology Agency; the "Development of Diagnostic Technology for Detection of miRNA in Body Fluids" grant from the Japan Agency for Medical Research and Development and New Energy and Industrial Technology Development Organization; the ImPACT Program of the Council for Science, Technology and Innovation (Cabinet Office, Government of Japan); the Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research (A) 16H02091; the Nanotechnology Platform Program (Molecule and Material Synthesis) of the Ministry of Education, Culture, Sports, Science and Technology (MEXT); and the Cooperative Research Program of "Network Joint Research Center for Materials and Devices."