Blood-Clotting Protein Linked to Cancer and Septicemia

ScienceDaily (Feb. 4, 2011) — Scientists in a collaboration between EMBL Heidelberg and the University of Heidelberg Medical Centre have discovered how stressed cells boost the production of the key blood-clotting factor, thrombin. Their work shows how cancer cells may be taking advantage of this process, and opens new possibilities for fighting back against cancer and septicemia.

In our not-so-distant evolutionary past, stress often meant imminent danger, and the risk of blood loss, so part of our body's stress response is to stock-pile blood-clotting factors. Scientists in the Molecular Medicine Partnership Unit (MMPU), a collaboration between the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, and the University of Heidelberg Medical Centre, have discovered how stressed cells boost the production of the key blood-clotting factor, thrombin. Their work, published February 4 in Molecular Cell, shows how cancer cells may be taking advantage of this process, and opens new possibilities for fighting back, not only against cancer but also against septicemia, where increased blood clotting is still one of the leading causes of death.

Blood clots tend to form more often in the veins of people with cancer, a syndrome first described almost 150 years ago by French physician Armand Trousseau. In recent years, doctors have also come to realise that people with activated blood coagulation are more likely to develop cancer. Accordingly, recent studies have shown that anti-coagulants may help treat and prevent cancer, but exactly how blood-clotting and cancer progression are linked was unclear -- until now.

"For the 1st time, we have something in hand that might explain this enigmatic relationship between enhanced pro-coagulatory activities and the outcome of cancer," says Sven Danckwardt, who carried out the research within the MMPU.

The amount of thrombin our cells produce is controlled by two sets of proteins: proteins that slow thrombin production, and proteins that speed it up. Both types of protein act by binding to the cellular machinery that synthesises thrombin, and, under normal conditions, the production-slowing proteins keep thrombin levels low. But Danckwardt and colleagues discovered that, when our cells come under stress from inflammation, another protein, called p38 MAPK, reacts by adding a chemical tag to those production-slowing proteins. That tag makes it harder for the production-slowing proteins to bind to the thrombin-synthesising machinery, allowing the proteins that speed up production to take over. So inflammation caused by cancer could lead to increased thrombin levels and, as thrombin is a blood-clotting agent, this could explain why cancer patients are more likely to suffer from blood-clots. The scientists believe this new mechanism of gene regulation may apply to other genes, too.

"Knowing the exact molecules involved, and how they act, has implications for treatment, especially as drugs that inhibit p38 MAPK are already being tested in clinical studies for other conditions," says Matthias Hentze, Associate Director of EMBL and co-director of MMPU, adding: "those drugs could be good candidates for potential cancer or septicemia therapies."

The Heidelberg scientists found that p38 MAPK also influences thrombin production during septicemia. Also known as blood poisoning, septicemia occurs when bacteria or other pathogens enter the bloodstream, leading to widespread infection and to blood-clotting problems. When they analysed liver samples taken from septicaemic mice and from cancer patients, the scientists discovered that thrombin production increases in response both to widespread inflammation during septicemia and to localized inflammation at the tumour's invasion front, where cancer cells are spreading into nearby tissue.

Aside from its role as a blood-clotting agent, thrombin is also involved in creating new blood vessels, and it is able to degrade the extracellular matrix that keeps cells together. So it's possible that the cancer cells are increasing thrombin production to help the tumour spread, by making it easier to invade healthy tissue and creating blood vessels to supply the new tumour cells. This, the researchers believe, could explain why people with blood-clotting problems seem to have a higher risk of developing cancer.

"This study shows the benefits of partnerships like the MMPU, which bridge the gap between clinical and basic research," Andreas Kulozik from the University of Heidelberg Medical Centre, co-director of MMPU, concludes.

New Induced Stem Cells May Unmask Cancer at Earliest Stage

ScienceDaily (Feb. 4, 2011) — By coaxing healthy and diseased human bone marrow to become embryonic-like stem cells, a team of Wisconsin scientists has laid the groundwork for observing the onset of the blood cancer leukemia in the laboratory dish.

"This is the first successful reprogramming of blood cells obtained from a patient with leukemia," says University of Wisconsin-Madison stem cell researcher Igor Slukvin, who directed a study aimed at generating all-purpose stem cells from bone marrow and umbilical cord blood. "We were able to turn the diseased cells back into pluripotent stem cells. This is important because it provides a new model for the study of cancer cells."

The research was reported Feb. 4 in the journal Blood by Slukvin and colleagues from the WiCell Research Institute and the Morgridge Institute for Research, private research centers in Madison.

Slukvin's group, using banked healthy and diseased bone marrow and cord blood, employed a technique developed in 2009 by Wisconsin stem cell pioneer James Thomson that sidesteps the problems posed by the genes and viral vectors used to induce mature cells to regress to a stem cell state.

According to the new study, which was funded by the National Institutes of Health and The Charlotte Geyer Foundation, reprogramming blood cells to become induced stem cells is many times more efficient than the reprogramming of skin cells, which were the first mature cells to be guided back to an embryonic stem cell-like state.

The new work could open to science vast repositories of banked tissue, both healthy and diseased, such as bone marrow, the soft tissue in bones that helps make blood, and umbilical cord blood. The work could underpin insightful models capable of unmasking the cellular events that go awry and cause cancers such as leukemia, and could aid the development of new stem cell-based therapies, according to Slukvin.

Of particular note in the new study, says Slukvin, is the reprogramming of marrow cells from a patient with chronic myeloid leukemia, a cancer of the blood that kills about 1,500 people a year in the United States. The disease, like all leukemias, starts in the cells that produce white blood cells in bone marrow.

According to Slukvin, the induced stem cells generated from the diseased tissue retain the exact same complex of genetic abnormalities found in the mature cancer cells. That means that when the induced cells are turned back into blood, scientists could, in theory, watch cancer develop from scratch as cells bearing cancer mutations become cancer stem cells.

"When we differentiate induced stem cells back to blood, we can identify the stages when the abnormality that leads to cancer manifests itself," Slukvin explains.

The ability to pinpoint the very earliest stages of cancer is a major focus of biomedical science.

"This is very important for developing new leukemia drugs," says Slukvin. "A major focus of leukemia research is to find ways to try and eliminate the most immature leukemia cells -- cancer stem cells."

The work by Slukvin and his team may represent the first step in a new understanding of the cascade of events that results in blood diseases such as leukemia.

Employing the reprogramming technique developed by Thomson and his colleagues, Slukvin emphasizes, is important because it eliminates the exotic reprogramming genes, some of which are cancer-related genes, from the induced stem cell equation. In the case of chronic myeloid leukemia and other blood diseases, obtaining stem cells that do not have the genetic reprogramming factors is very important.

"When you use viruses (to ferry genes into a cell) you have chromosomal integration," the Wisconsin researcher notes. "Some of the reprogramming factors are oncogenes and would interfere with a study of chronic myeloid leukemia" whose abnormalities are also encoded on the chromosome.

In addition to Slukvin, an investigator at the Wisconsin National Primate Research Center (WNPRC) and an associate professor of pathology at the UW-Madison School of Medicine and Public Health, authors of the new study include Kejin Hu, Junying Yu and Kyung-Dal Choi of the WNPRC; Kran Suknuntha of the UW-Madison School of Medicine and Public Health; Shulan Tian, Ron Stewart and James A. Thomson of the Morgridge Institute for Research; and Karen Montgomery of the WiCell Research Institute.