Cancerous tumors are formidable enemies, recruiting blood vessels to aid their voracious growth, damaging nearby tissues, and deploying numerous strategies to evade the body’s defense systems. But even more malicious are the circulating tumor cells (CTCs) that tumors release, which travel stealthily through the bloodstream and take up residence in other parts of the body, a process known as metastasis. While dangerous, their presence is also a valuable indicator of the stage of a patient’s disease, making CTCs an attractive new approach to cancer diagnostics. Unfortunately, finding the relative handful of CTCs among the trillions of healthy blood cells in the human body is like playing the ultimate game of needle-in-a-haystack: CTCs can make up as few as one in ten thousand of the cells in the blood of a cancer patient. This is made even more difficult by the lack of broad-spectrum CTC capture agents, as the most commonly used antibodies fail to recognize many types of cancer cells.
To address this problem, a group of researchers at the Wyss Institute at Harvard University has adapted an engineered human blood opsonin protein known as FcMBL, which was originally developed as a broad-spectrum pathogen capture agent, to target CTCs instead. Using magnetic beads coated with FcMBL, they were able to capture >90% of seven different types of cancer cells. “We were able to rapidly isolate CTCs both in vitro and from blood, including some which are not bound by today’s standard CTC-targeting technologies,” says Michael Super, Ph.D., Lead Senior Staff Scientist at the Wyss Institute and co-author of the paper. “This new technique could become useful in cancer diagnostics.” The technology is described today in Advanced Biosystems.
Current CTC diagnostic systems frequently make use of a cancer cell marker, the epithelial cell adhesion molecule (EpCAM), which is highly expressed on the surface of tumor cells. However, EpCAM expression on cancer cells decreases when tumor cells transform into CTCs, ironically making EpCAM-based tests less useful precisely when it is most crucial to know that a patient’s cancer has metastasized.
The Wyss Institute capture technology takes advantage of a protein naturally found in the body, mannose-binding lectin (MBL), which recognizes and binds to carbohydrates present on the surfaces of bacteria and other pathogens, marking them for destruction by the immune system. Healthy human cells have different carbohydrate patterns and are immune to MBL, but many cancer cells have aberrant carbohydrates that are similar to those found on pathogens and, therefore, are vulnerable to MBL binding.
The team previously developed a genetically engineered version of MBL in which the binding portion is fused to an antibody Fc fragment (FcMBL) to stabilize the molecule. Past studies showed that when tiny magnetic beads are coated with FcMBL and added to various pathogens, the FcMBL-coated beads attach to the surfaces of these cells like flies on flypaper so that, when a magnetic field is applied, the beads drag their bound cells along with them toward the magnet.