Michael King, Professor of Biomedical Engineering at the University of Rochester, has successfully demonstrated that implants coated with selectins are able to harvest adult stem cells while simultaneously triggering apoptotic signals in circulating cancer cells.
When King was working at the University of Pennsylvania from 1999 to 2001, one of his labmates discovered that bone marrow stem cells stick to adhesive proteins called selectins more strongly than other cells — including blood cells — stick to selectins. When King came to the University of Rochester in early 2002, he started studying the adhesion of blood cells to the vascular wall, the inner lining of the blood vessels. During inflammation, the vascular wall presents surface selectins that adhere specifically to white blood cells. These selectins cause the white blood cells to roll slowly along the vascular wall, seeking signals that tell them to crawl out of the bloodstream. This is how white blood cells migrate to bacterial infections and tissue injuries. King set out to find a way to duplicate this natural process.
First, he noted that the selectins form bonds with the white blood cells within fractions of a second, then immediately release the cells back into the bloodstream. He also realized that selectin is the adhesive mechanism by which bone marrow stem cells leave the bloodstream and find their way back into bone marrow. This is how bone marrow transplantation works. Finally, he learned that when a cancer cell breaks free of a primary tumor and enters circulation, it flow through the bloodstream to a remote organ, then leaves the bloodstream and forms a secondary tumor. This is how cancer spreads. He put these facts together with one more, very important fact: the selectins grab onto a specific carbohydrate on the surfaces of white blood cells, stem cells, and cancer cells. Associate Professor King decided to capture stem and cancer cells before the selectins release them.
Harvesting Stem Cells
Because bone marrow stem cells stick to selectin surfaces more strongly than other cells, King’s group coated a slender plastic tube with selectin. They then did a series of lab experiments, both in vitro and in vivo using rats, with this selectin-coated tube to filter the bloodstream for stem cells. It worked, and the King Lab discovered that they could attract a large number of cells to the wall of their selectin-coated device, and that 38% of these captured cells were stem cells. King envisioned a system by which doctors could remove stem cells from the bloodstream by flowing the cells through a device, and make a more concentrated mixture containing, say, 20-40 percent stem cells. These stem cells could then be used for tissue engineering or bone marrow transplantation.
This is a non-controversial way of obtaining stem cells that can be differentiated into other, useful cells.
Killing Cancer Cells
Another exciting application of King’s invention is filtering the blood for cancer cells and triggering their death, an innovative, new method to prevent the spread of cancer. When someone has a primary cancer tumor, a small number of cancer cells circulates through the bloodstream. In a process called metastasis, these cells are transmitted from the primary tumor to other locations in the body, where they form secondary, cancerous growths.
As a cancer cell flows along the implanted surface, King’s device captures it and delivers an apoptosis signal, a biochemical way of telling the cancer cell to kill itself. Within two days, that cancer cell is dead. Normal cells are left totally unharmed because the device selectively targets cancer cells.
The apoptosis signal is delivered by a molecule called TRAIL that coats the cancer-killing device. Cancer cells have five types of proteins that recognize and bind to TRAIL, but only two trigger cell death. The other three are called decoy receptors. Healthy cells contain a lot of decoy receptors, giving them a natural protection against TRAIL, whereas cancer cells mainly express the two receptors that signal cell death.
During the death of the cancer cells, TRAIL is not depleted or used up in any way, and in fact, it stays active for many weeks or months. The same TRAIL molecules can kill enormous numbers of cancer cells.
Picture caption: “Each Y indicates the presence of selectin, which slows down white blood cells (bl), stem cells, and cancer cells (ca) to promote close, sustained contact. The blue triangles represent TRAIL molecules, which kill cancer cells within 2-4 days, yet does not affect normal cells. Here, TRAIL has attracted the cancer cells, which are then killed by the apoptosis assay.”
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