Cancer Cell as Hijacker
Research team probes how tumor cells commandeer an otherwise helpful biological process to grow and spread
Cancer cells are one of nature’s most sinister predators. They prey on the body’s otherwise healthy systems, using what they need to feed their growth and ravaging whatever gets in their way.
The body’s clotting system seems to be one of cancer’s favorite means of growing and spreading. Joseph Palumbo, MD, a researcher in the Division of Hematology / Oncology at Cincinnati Children’s, is working to understand just how this is so.
Joseph Palumbo, MD, wants to know how cancer uses the clotting mechanism to spread.
It’s long been recognized that people with cancer often have blood clotting problems. French physician Armand Trousseau identified the connection more than a century ago. “He observed that cancer patients have hemostatic derangements,” Dr. Palumbo says. “They either develop a lot of clots, or they bleed abnormally.”
More Than Just Bystanders
Only in the last several decades, however, have researchers recognized that hemostatic factors actively participate in cancer’s spread. How actively is what Dr. Palumbo and his teamare focusing on.
They use genetically modified mice with specific clotting factor defects, then analyze tumor growth and metastases in the mice.“What we’ve found is that hemostatic factors are major determinants of metastatic potential,” he says.
One of these hemostatic factors is tissue factor (TF), the protein responsible for initiating the clotting cascade. Tissue factor appears to play a big role in metastasis. “Without tissue factor, the tumor cell is nearly incapable of metastasizing,” Dr. Palumbo explains. “This correlates with a significant amount of clinical data showing that patients whose cancers express high levels of tissue factor have more advanced disease and tend to do worse.”
Desperately Seeking Platelets
His research team has studied several possibilities to understand this connection, but the most compelling is a process in which the tumor cell deliberately seeks out platelets as it begins to spread.
“If a newly-formed, micrometastatic tumor cell can engage platelets, it’s protected from the innate immune surveillance mechanisms, particularly natural killer cells,” Dr. Palumbo explains. “The tumor cell can presumably prevent the natural killer cells from killing it by commandeering platelets.”
We all have natural “killer cells,” the cytotoxic white blood cells that allow us to fight infections and other onslaughts.€ese killer cells can also kill cancer cells. But in cases where cancer spreads, the process gets turned upside-down.
“The fact that people get cancer and die of cancer tells us that cancer cells are capable of evolving ways to evade these natural killer cells,” Dr. Palumbo says.
One way cancer cells can evolve to do this, he points out, is by forming a bond with the body’s clotting system in the early stages of metastasis.
“This is a time when the tumor cells disengage from the primary tumor and travel to some distant organ. So now they’re separated from their ‘friends’ and particularly vulnerable to natural killer cells,” he says. “If they can engage platelets and fibrinogen [the primary components of a blood clot], they’re protected from those killer cells.”
Disarmed and Dangerous
To understand how this linkup disarms the killer cells, Dr. Palumbo’s team is focusing on what cancer cells do to engage one particular platelet-derived factor, TGF Beta-1, to regulate the downstream function of killer cells and inhibit their ability to kill intended targets. TGF Beta-1 circulates throughout our systems in the platelets, making it a ready source of ammunition for tumor cells looking to attack and neutralize killer cells.
“Our hemostatic system has evolved to deal with all sorts of challenges, such as wounds, so down-regulating natural killer cell function may be a good thing in certain circumstances because it can help minimize your chances of developing autoimmunity, for example,” Dr. Palumbo says. “But in the context of cancer, the tumor cells have evolved a way to take over these mechanisms to make themselves more metastatic.”
What might seem like evil intent on the part of tumor cells may be pure evolutionary chance, says Dr. Palumbo. “These tumor cells have become genetically unstable, so they’re capable of mutations that normal cells would never express.”
Dr. Palumbo believes his work is a number of years from having direct clinical applications. But he points to studies with adults in which their cancers improved when treated with anti-coagulants. And he’s begun a collaboration with Nationwide Children’s Hospital in Columbus to study clotting factor’s effect on tumors in children. Ultimately, his team’s research could lead to more precisely-targeted, effective treatments.
“If we better understood the mechanisms that link the clotting system to tumor progression,” he says, “we could treat metastatic disease by targeting hemostatic system components, but without the potential bleeding side effects of anti-coagulants.”
