Microfluidic chip helps track cancer cells circulating in blood
A microfluidic device developed by scientist Mehmet Toner and his colleagues is helping researchers isolate rare circulating tumor cells from blood, offering a minimally invasive way to study cancer metastasis, monitor treatment response and investigate drug resistance
Tehran (ISNA) - A blood sample holds a wealth of information about what’s happening inside our bodies. This is why blood tests are a common and crucial method for monitoring overall health or diagnosing diseases. If you have ever had a blood test, you’ve likely noticed that a significant amount of blood is drawn, and processing the results takes considerable time. Behind the scenes, various reagents and materials are used to analyze the blood all of which eventually end up as waste
Is there a way to optimize this entire process? Imagine conducting cholesterol, triglyceride, uric acid, and glucose tests with a very small volume of blood and in a short time, not in a lab, but at home! The microfluidic chip will help us achieve these capabilities.
Microfluidic chips work with very small fluid volumes, mainly in the nanoliter to microliter range. To be considered microfluidic, at least one dimension of the channel must be in the range of about 1 to 1000 micrometers. Microfluidics can be regarded both as a science (the study of fluid behavior in microchannels) and as a technology (the fabrication of microfluidic devices for performing laboratory tests on a chip). Fluids at the micrometer scale exhibit behaviors that are entirely different from what we observe in everyday life; for instance, at these scales, the internal viscosity of the fluid dominates over inertial forces, and flows move smoothly (predominantly laminar) rather than turbulently. Moreover, mixing fluids becomes challenging, and the dominant phenomenon capable of combining liquids at these scales is molecular diffusion. As a result, two fluid streams can flow side by side for several minutes without completely mixing. This enables the creation of multiple distinct environments within a single channel. Imagine a tiny plate that has the potential to replace an entire laboratory with this cutting-edge technology.
Microfluidic chips are small plates that contain a network of microchannels molded into materials like as glass, silicon, or polymer. These microchannels are interconnected to provide properties such as mixing, pumping, sorting, or controlling the biochemical environment for the substances inside them (liquids and gases). The network of microchannels within the chip is connected to the outside world through inputs/outputs integrated into the chip, serving as a link between the macro- and micro- scales. Liquids and gases flow into, are examined within, and exit the chip through these inlets/outlets; Similarly to an X-ray machine, a designated pathway is established for samples/fluids to enter, undergo processing, and then exit the chip. Indeed, in microfluidics, isolation is based on surface interactions and physical properties, not imaging.
Today, researchers are still exploring the fascinating subject of microfluidics and its applications in medicine and biology. One of these applications is cancer diagnosis. Cancer is a name that each of us has heard at least once, and we may even know one or more patients diagnosed with it. This disease is a condition that arises from the uncontrolled division of cells, and if cancer cells detach from their primary tumor and enter the bloodstream or lymphatic system, metastasis occurs. Most metastatic cancers, however, are not treatable. To understand the importance of studying the processes that drive metastasis and exploring potential therapeutic solutions, it is worth noting that metastasis is the main cause of mortality in cancer patients, and a large proportion (over 90% in some statistics) of cancer-related deaths are attributed to it. With this background in mind, if we can use microfluidic chips to detect the effects of cancer in the blood, we can implement more precise and suitable treatment strategies for patients.
Fugitive Criminals in the Blood
CTCs are tumor-derived cells found in the blood of cancer patients and are likely the source of incurable metastatic disease. The impact of cancer in the blood can also be tracked using circulating tumor cells, or CTCs. Most distant metastases are mediated by CTCs, as circulating tumor cells are the main route for cancer cells to spread through the bloodstream. CTCs can also aid in better diagnosis, monitoring response to treatment, and even developing new treatments, making them an important tool in cancer research. They are recognized as key biomarkers in solid tumors, and their presence in the blood can provide valuable information about cancer progression and response to therapy. They are also effective in predicting disease recurrence, metastasis, and resistance to treatment.
These metastatic cells are like criminals moving through the bloodstream, attempting to travel between different parts of the body, as if upon entering an airport, they intend to flee the area. If the investigators cannot detect the metastatic cell, the criminal will escape, and another place will be contaminated by its presence. However, if we can apprehend it, we will obtain valuable information that can help prevent other crimes. Could we build a device with a function similar to airport X-ray scanners that, through inspection, can detect metastatic cells?
Rare but Impactful
Isolation of CTCs is challenging because they are extremely rare; depending on the type and stage of cancer and the isolation method, there may be only about one CTC among ten million white blood cells per milliliter of blood. Existing methods for CTC isolation, depending on the platform and marker they use, often have low yield, low purity, and limited sensitivity. If previous methods have shortcomings, then we need to reconsider our inspection framework.
One prominent researcher in the field of microfluidic chips is Mehmet Toner, a scientist who uses these chips to capture and study metastatic cancer cells. Toner and his colleagues, combining biology with microfluidic chip technology, designed a microfluidic chip called the CTC-chip. The number of CTCs isolated by this chip in various studies has ranged from a few cells to hundreds of cells per milliliter, and its purity shows a significant improvement over previous technologies.
In this method, Toner exploited a distinctive feature of cancer cells compared to blood cells. This feature is the overexpression of the EpCAM gene in carcinomas of the lung, colon, breast, prostate, head and neck, and liver, which is absent in blood cells, thereby enabling selective capture of CTCs. Carcinoma is the most common type of cancer and accounts for the majority of adult cancers. This type of cancer develops in epithelial tissue, the same tissue that covers organs, internal body passages, and the skin.
Molecular Lock and Key
The EpCAM gene encodes instructions for producing a protein called epithelial cell adhesion molecule (EpCAM). This protein is present in epithelial cells, where it is located in the cell membrane and aids in cell adhesion, helping cells stick together.
EpCAM is widely and frequently expressed in most carcinomas, but its intensity and abundance is heterogeneous and depend on the type and stage of the disease. For this reason, EpCAM has great potential as a marker for prognosis and treatment in cancers as well as during cancer progression and metastasis formation. EpCAM is thus referred to as the surface antigen of these cells. If we can find a complementary molecule (called an antibody) that is complementary in terms of geometry and chemical properties to the antigen, a specific interaction (antibody-antigen binding) occurs between them, making the recognition of the antigens possible. The example of a lock and key is often used to describe the antigen-antibody reaction, illustrating the high specificity of this interaction. Just like a lock and key, each key only fits a specific lock.
This biological theory was utilized in an innovative manner by Toner and colleagues. By employing an anti-EpCAM antibody on the chip, they were able to successfully identify circulating tumor cells (CTCs) in the blood of patients with metastatic lung, prostate, pancreatic, breast, and colon cancer in a significant portion of patient samples.
This chip is also important for monitoring the response to cancer treatment. Temporal changes in CTC numbers were reasonably correlated with the clinical course of the disease in treated patients, indicating the potential of the CTC-chip for this purpose.
Today, with the advancement of CTC technologies, it is possible to examine the phenotypic characteristics of cancer and their likelihood of responding to treatment. Since CTCs contain the tumor genome, isolating viable CTC cells during treatment helps to examine the mutational signature of drug resistance (a set of genetic mutations in cancer cells that make them resistant to anticancer drugs). This allows scientists to find new ways to combat cancer resistance to treatment. The identification, characterization, and molecular analysis of CTCs elevate liquid biopsy (a non-invasive method that allows cancer to be examined through blood) to a new level, meeting the needs of 21st-century medicine.
These are just a few important aspects of isolating live circulating tumor cells (CTCs) from blood. Toner and his colleagues’ research has yielded remarkable achievements in this field. Sometimes, we simply need to change our perspective in order to advance science! Perhaps, hidden within these common tools, lies the potential for medical and biological innovation that will guide us towards the future.
