Anticoagulant drugs may not only prevent blood clots in cancer patients — they may also help prevent the spread of tumors, according to the first in vivo experiment of its kind.
In an article published March 4 in Blood, researchers from Heidelberg University Hospital in Germany used advanced microscope technology to track live cancer cells in mice and see how common anticoagulant drugs including dabigatran and tinzaparin, a type of heparin, inhibit their ability to metastasize. Many cancer patients have a higher risk of developing blood clots, and physicians commonly administer these drugs to prevent them.
"There have been a lot of clinical trials that show this may be connected, but it's all retrospective," said lead author and doctoral student Manuel Feinauer of Heidelberg University Hospital. "If you look at the data of tumor patients you can see when they are anticoagulated, normally they survive longer, but the mechanism behind that is not well understood — why tumors need blood coagulation for metastasis."
To investigate, Feinauer injected human breast cancer and melanoma cells into lab mice through their hearts. He then examined what happened to these cells before and after giving the mice an anticoagulant, or blood thinner, viewing them with a high-powered multiphoton laser-scanning microscope.
With this technology, he could follow the journey of each individual cancer cell in real time. Feinauer had participated in prior research analyzing in vitro samples of lung and liver tissue that could only show metastases at one point in time, without the advantage of tracking and watching the cells metastasize.
In many cases, anticoagulant treatment significantly reduced each cancer's ability to form clots and effectively breach the small capillaries that lead to brain tissue, which is a crucial step for these cells to take before they can form a tumor. Feinauer estimates that the anticoagulant treatment cut breast cancer cells' ability to successfully metastasize by about half, and melanoma cells' by about 25%. The cells that couldn't form a clot in capillaries inside the brain were not able to grow new tumors.
"They were able to enter but they were unable to stay there; they just got washed away with the blood flow," Feinauer said in an interview with The Academic Times. "None of these cells were able to stay in the brain."
According to Feinauer, forming a successful clot requires a clump of cancer cells to stick inside capillary vessels for several hours, but anticoagulants seem to weaken this ability.
"There was always a clot around these tumor cells that actually survived in the end, and that was very surprising, that no tumor cell without a clot survived," said Feinauer. "They need something to stay there in the capillary system. [The clot] is the glue that makes them stay."
This clotting mechanism is similar to the immune system's, which deploys clots of white blood cells that stick to inflamed areas. It is also possible that cancer cells hijack the immune system this way to spread metastases, but more research is needed to determine how that may work.
Feinauer says he would like to use this study as a jumping-off point for anticoagulant research in melanoma patients. In future studies, he and his colleagues would treat a portion of the patient group with anticoagulants, leaving the rest as a control group and observing which patients develop metastases over time. He would also like to expand this research to study other forms of cancer, though he believes that they probably all use clotting in similar ways, with anticoagulants having a similar effect on them as well.
"There are hints that tumor patients actually benefit from anticoagulation, but to say something like that for sure you would need a prospective study," Feinauer said. "We just want to hint that there is probably a benefit for tumor patients to get anticoagulants without any major side effects in these treatments, which are well tolerable by all patients."
The study, "Local blood coagulation drives cancer cell arrest and brain metastasis in a mouse model," published March 4 in Blood, was authored by Manuel J. Feinauer, Cedric Tehranian, Matthia A. Karreman, Julia Katharina Grosch, Katharina Gunkel, Bogdana Kovalchuk, Wolfgang Wick, Frank Winkler, Anna S. Berghoff, Manuel Fischer, Michael O. Breckwoldt and Maik Brune, University Hospital Heidelberg; Stefan W. Schneider, Jose Ramon Robador and Alexander T. Bauer, University Hospital Hamburg-Eppendorf; Varun Venkataramani, Heidelberg University Hospital and Heidelberg University; Gergely Solecki, Heidelberg University Hospital and Zeiss Microscopy GmbH; Frank Thomas Mayer, University of Heidelberg; and Yannick Schwab, European Molecular Biology Laboratory.