Scientists have developed a molecular probe that finds and illuminates cancer stem cells in human cancer cell lines and live mice. The ability to identify and track these elusive cells, which can spread and cause recurrent, treatment-resistant tumors, in the body could potentially be useful in clinical imaging.
“It’s really the first time to be able to look at cancer stem cells in the complicated environment where they live — not only in cell cultures or artificial tumor environments,” Jefferson Chan, PhD, a chemistry professor at the University of Illinois who led the study, said in a press release. “Seeing them is the first step toward understanding them. Now we can see where they’re hiding out, how they change as the disease is progressing or how they respond when you apply treatment.”
Findings were reported in the study, “Surveillance of Cancer Stem Cell Plasticity Using an Isoform-Selective Fluorescent Probe for Aldehyde Dehydrogenase 1A1,” published in ACS Central Science.
Lighting up cancer stem cells with fluorescent dyes is not a new concept, and researchers have already developed molecular approaches for this purpose, but their use is limited.
The most common are what is known as antibody-dye conjugates. The general principle behind these is that an antibody targeting a specific marker on cancer stem cells is also bound to a fluorescent dye. When the antibody binds to the cell, the cell becomes fluorescent.
The problem with antibody-dye conjugates is their large size, since cancer stem cells are often found in small, difficult-to-reach spaces. Other disadvantages include the possibility that these antibodies might identify the wrong cellular targets, or they may light up both dead and live cancer stem cells.
In addition, these approaches are all created to be used in lab-grown cell cultures or artificial tumor environments, which do not replicate the body’s full biological complexity.
There is a great need for methods that can be used to not only detect cancer stem cells but also to report on specific whole, living organism properties.
A team from the University of Illinois set out to develop a highly selective fluorescent probe to target cancer stem cells with elevated levels of aldehyde dehydrogenase 1A1 (ALDH1A1) in various human cancer cell cultures and mice.
The enzyme ALDH1A1 is related to stemness in cancer stem cells, i.e., the ability of a cell to perpetuate its lineage and give rise to different types of cells. It is also a marker of cancer stem cells across many cancer types, including prostate, lung, breast, esophageal, and ovarian cancers.
Evidence suggests that ALDH1A1 levels increase in response to therapy, promoting chemotherapy resistance and survival mechanisms in cancer stem cells.
Researchers developed AlDeSense, a small molecule that enters cancer stem cells, binds to ALDH1A1, and causes the cells to emit a fluorescent signal. The probe only activates when it reaches its target and only works in viable cancer stem cells since ALDH1A1 depends on the availability of NADH, a molecule involved in cellular respiration.
Scientists identified cancer stem cells at the cellular level via flow cytometry and confocal imaging — two imaging techniques that detect fluorescence. Results support ALDH1A1 as a marker of stemness in several types of cancer, indicating that this new molecular technology has the potential to be useful in clinical imaging.
Researchers then tested the method by identifying and monitoring cancer stem cells in biopsy tissue from mice and in live mice with metastatic melanoma tumors. They were able to track the cells from the time they injected them into the animals until the tumor state.
“Prior to this study, nobody knew what happens between injection of cancer stem cells and removal of a tumor. There are a lot of models that hypothesize about how cancer stem cells differentiate and grow, but limited experimental data,” Chan said. “Through this study, we can see that the stemness properties are maintained in the population, even after they metastasize. There’s something about the environment in the body that supports stem cell characteristics. With AlDeSense, now we can profile that environment.”
The team now plans to investigate if tracking cancer stem cells in tumors with AlDeSense can predict prognosis in dogs with lymphoma.
“Another thing we’re pursuing is screening for inhibitors or drugs that can kill cancer stem cells by targeting this enzyme,” Chan said. “Since we know that our probe only interacts with that one target, we can use the probe to look for a drug that can inhibit this enzyme and verify it in cells and in live animals. The multiscale utility of the molecule makes it unique.”
