- Circulating tumor cells (CTCs) represent cancer cells that have
detached from the main cancer and are spreading to other tissues via the
- Current study has modified a naturally occurring opsonin,
mannose-binding lectin (MBL) by fusing it to a Fc antibody fragment
- FcMBL when coated with magnetic beads binds to the circulating
tumor cells and marks them for destruction by host immunity.
modified opsonin bound to antibody (FcMBL) could become a broad-spectrum potent
tool in the treatment of several cancer types by binding to carbohydrate
ligands on the surface of cancer cells, according to a recent study conducted
at the Wyss Institute at Harvard University.
New Target In the War Against Cancer -
The Reason Behind This Study
Several studies and research projects are
still continuing to work at finding the elusive cure against cancer although
giant strides have been made and several new immunotherapies
have been developed to keep cancer in check and improve the
quality of the patient's life and prolong survival.
When the tumor cells detach from a primary malignancy, they gain access to the
blood stream (circulating tumor cells or CTCs)
and spread to other parts of
the body forming metastases; they then signify a stage in the cancer which has
a graver prognosis and one that is more difficult to treat.
‘The FcMBL (mannose binding lectin fused to antibody Fc fragment) opsonin shows broad-spectrum activity against several types of CTCs with promising applications in the future.’
research team aims to target these CTCs and eliminate them, offering an
attractive and exciting approach to cancer diagnosis and treatment
Currently, there are not many effective agents that target these circulating cells which probably
make up 1 out of ten thousands of cells in the blood
making it all the more difficult to recognize and capture them.
Modified FcMBL Opsonin To Capture Circulating Tumor Cells
To overcome the existing gap, scientists
at the Wyss Institute adapted the FcMBL
, originally engineered to act as a
broad-spectrum microbial capturing agent
, to target these CTCs
- Most of the cancer cells express
aberrant sugar molecules on their surface similar to pathogens and are
therefore vulnerable to capture by the MBL opsonin.
- The carbohydrate molecules expressed
by healthy body cells are not bound by the MBL opsonin.
- The mannose binding lectin was fused
with the Fc antibody fragment to stabilize it. This combination was termed
- When magnetic beads coated with
FcMBL were added to a suspension of pathogens, the opsonin bound the
pathogens like flies to flypaper.
- When a magnetic field was then
applied, the beads dragged the bound cells towards the magnet.
- The team tested the activity of the
FcMBL against cancer cells by implanting fluorescent-labeled breast cancer
cells in mice and 4 weeks later, tested the blood of the mice for the
presence of CTCs by adding the FcMBL opsonin coated magnetic beads and
applying a magnetic field.
- It was seen that CTCs bound to the
opsonin were moving rapidly compared to normal cells. The concentrations
of CTCs in blood was shown to be reduced by more than 93%.
beads are unlikely to be bound to normal cells, and so when we measured the
movement of cancer cells versus normal cells, the cancer cells moved much
faster because they were being dragged to the magnet by the beads
explains first author Joo Kang, Ph.D., who was a Technology Development Fellow
at the Wyss Institute while completing this study and is now an Assistant
Professor at the Ulsan National Institute of Science and Technology.
- The scientists then tested the FcMBL
coated beads against six additional cancer cell types, including lung
carcinoma, human non-small cell lung cancer, and glioblastoma. The
FcMBL-coated beads bound all six types of tumor cells with >90% efficiency,
similar to epithelial cell adhesion molecule (EpCAM) targeting methods.
Additionally they were also able to target two cancer types that are not
successfully captured by anti-EpCAM antibodies (lung carcinoma and
What are Opsonins?
A molecule that aids recognition and
promotes engulfment of the target cell (microbe, tumor cell) by the immune cell
is called an opsonin
. Examples include mannose binding lectin
(MBL), IgG antibody and C3b. MBL binds to a range of sugars such as N-acetyl-D-glucosamine,
mannose, N-acetyl-mannosamine, glucose and fucose. This allows the protein to
interact with a wide selection of viruses, bacteria, yeasts, fungi and protozoa
decorated with such sugars on their surfaces.
is FcMBL Superior to EpCAM in Capturing CTCs?
Current CTC binding methods mostly employ
a cancer cell marker, the epithelial cell adhesion moleculeEpCAM, which is highly expressed on the surface of tumor cells.
However, interestingly, EpCAM expression
on cancer cells reduces when tumor cells become CTCs
, making EpCAM-based
tests irrelevant especially when it is most important to know if a patient's
cancer has metastasized.
"Our results suggest that while the
EpCAM marker can be useful for some tumors, it becomes less and less useful over
time as EpCAM expression decreases and the cell becomes metastatic," says
Michael Super, Ph.D., Lead Senior Staff Scientist at the Wyss Institute and
co-author of the paper. "Our FcMBL system can either be used as an
alternative to EpCAM-based diagnostics, or as a follow-up method once EpCAM
ceases to be expressed."
The team plans to expand the current research and
determine exactly which sugar molecules on the CTCs are targeted by the FcMBL
opsonin to improve efficiency of capture.
To conclude in the words of senior author
of the study and Wyss Founding Director Donald Ingber, who is also the Judah
Folkman Professor of Vascular Biology at Harvard Medical School (HMS), as well
as a Professor of Bioengineering at Harvard's School of Engineering and Applied
Sciences, "The FcMBL opsonin technology has already been shown to be an
extremely broad-spectrum capture agent for pathogens; this new finding that it
has similar broad-spectrum binding activity for many different types of circulating
cancer cells is equally exciting, and once again demonstrates the power of
leveraging biological design principles when developing new medical
- Joo H. Kang, Harry Driscoll, Akiko Mammoto, Alexander L. Watters, Bissrat Melakeberhan, Alexander Diaz, Michael Super, Donald E. Ingber. An Engineered Human Fc-Mannose-Binding-Lectin Captures Circulating Tumor Cells. Advanced Biosystems, 2017; 1700094
- The role of mannose-binding lectin in health and disease. - (https://www.ncbi.nlm.nih.gov/pubmed/14568388)