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The Light Has Turned on for Cancer Detection
Fluorescence proves a noteworthy boon for clinicians in the hide-and-seek game of cancer detection, and its future implications may lead to less invasive and more effective methods for screening and prognosis.
Hang Hubert Yin, PhD, Associate Professor of Chemistry and Biochemistry, Investigator at the Biofrontier Institute at the University of Colorado Boulder, and Neil Renwick, MD, PhD, Howard Hughes Medical Institute, Laboratory of RNA Molecular Biology, The Rockefeller University, are currently pursuing different ways of using fluorescence to detect, identify type and characteristics such as chemoresistance of, and accurately stage the disease.
For Better Detection
“One of our interests is in using novel, fluorescence-based techniques to detect not only cancer — [but], particularly, really dangerous and harmful cancers,” Yin says.
Recently published studies of ovarian and prostate cancer screening processes show traditional methods have not only proven largely ineffective at early detection, but have often led to harmful preventive measures, such as surgery, chemotherapy or radiation, that likely were unnecessary.
“We believe that we face not only a diagnostic challenge, but a prognostic one as well,” Yin says. “We need to be able to evaluate whether or not cancer cells will become metastatic and travel to other parts of the body, such as the brain.”
Yin’s research has led him and his team to examine the utility of noninvasive cancer biomarkers — substances found in the body that enable clinicians to track biological processes, such as diseases, and predict potential outcomes — to more effectively detect and stage cancer without a series of painful and invasive tests or inconvenient screening methods. To do so, Yin turned to submicroscopic particles.
Attaching a Target
From their surfaces, cells shed extremely small nanoparticles called microvesicles, which then circulate in the blood. Although everyone produces microvesicles, these tiny cellular effluvia are found in higher numbers when cancer begins to metastasize.
“When cancer becomes metastatic, the number of shed microvesicles increases, and [they] can be found in the blood, urine and other biological fluids,” Yin explains. “We thought it would be beneficial to try to track these because they correlate with the propensity of cancer to metastasize to another site.”
But microvesicles are nanoparticles — which have diameters of less than 100 nanometers — and cannot be seen even with an optical microscope. So, Yin and his team had to devise a way to illuminate these submicroscopic particles.
Light It Up
Yin’s research team focused on binding protein probes called fluorophores to microvesicles in already-drawn blood samples, shining a spotlight on the presence of cancer cells.
“These protein probes bind to the microvesicle’s characteristically highly curved surface,” Yin says. “After they bind, the fluorophore’s environment changes, causing it to glow. When there is an elevated [level] of microvesicles in the fluid, the fluorescence would enhance.”
Defining Tumor Type
While liquid-based microvesicle research continues, developments in fluorescent, tissue-based methodologies are being researched as well — possibly leading to pathological techniques that will more effectively identify tumor type and origin.
Dr. Renwick recently published a study in the Journal for Clinical Investigation, in which he and his co-authors examine multicolor microRNA (miRNA) fluorescent in situ hybridization (FISH) techniques to identify tumor type by tackling a common pathological problem.
“Merkel cell carcinoma can look like basal cell carcinoma,” Dr. Renwick says. “I looked at the problem and found that each cancer has a unique miRNA, so we could use this to identify the tumor type. This is a great system for using FISH, and you know you’ve got the assay right when it comes up as one tumor and not the other.”
The key is cell-type specificity, and miRNAs are only expressed in specific cell lines, according to Dr. Renwick. For example, miRNA-375 is exclusively found in neuroendocrine cells, and miRNA-205 in skin cells. These are particularly effective biomarkers because miRNAs are highly expressed, and therefore easy to detect.
Using the same formalin-fixed paraffin-embedded (FFPE) tissues employed as standard practice by pathologists, Dr. Renwick introduced miRNA FISH techniques in place of commonly utilized immunohistochemistry methodology to detect cancer.
“The present state of pathological practice is to use immunohistochemistry for diagnosis and prognosis of disease,” Dr. Renwick says. “This means using antibody reagents that target proteins. The problem with this is that it’s expensive and slow to develop an antibody, and you can’t look at multiple antibodies at once. It’s a good system, but slow and expensive.”
Using miRNA FISH methodology, Dr. Renwick reduces the cost and avails pathologists the opportunity to multitask.
“Clinicians may want to know the type or subtype of the disease or cancer, its prognosis, and whether or not it is chemoresistant,” Dr. Renwick says. “Using miRNA FISH protocols enables clinicians to design multiple markers that will provide answers to these questions and put them together into one giant cocktail that will provide much more information than using immunohistochemistry.”
After removing the tissue sample from the test cocktail after approximately 16 hours to allow for hybridization, clinicians examine it under a microscope. If the targeted miRNA is present in the sample, it will fluoresce.
What to Expect
While full utilization of these methods is years away — Dr. Renwick expects that of miRNA FISH to take about five years, depending on funding and multi-institutional participation — the principles of fluorescence are already finding utility in various disciplines. Yin notes that surgeons are studying ways of fluorescing tumors for more complete resection.
Further development of these methods presents the possibility of more effective diagnostic and prognostic screening and testing methods that may eventually eliminate multimodal imaging studies and repeated painful biopsies.