(All fields required)
Please enter a valid email.
Please enter your name.
Joseph Palumbo, MD, has taken his research a few significant steps backward.
After years of studying what fuels the aggressive spread of tumors, says the cancer researcher, “We’ve wound the pathogenesis clock backwards.”
So far backwards, in fact, that his latest findings seem to offer a way to prevent certain tumors from starting at all.
Palumbo, currently acting director of the Division of Hematology, has spent most of his career studying the role of the hemostatic system in cancer metastasis. These days, he is also looking at how the clotting system causes tumors to start in the first place.
Much of his work has been based on the pioneering studies of Harold Dvorak, who in the 1980s proposed that the tumor’s environment is like a wound that does not heal.
“We used to think of tumors as just a collection of tumor cells,” says Palumbo, “but they represent a pathologic organ. And like any organ, they have a blood supply and multiple supportive stromal cells. Dvorak noticed that the stromal elements in the tumor resembled stromal elements in a healing wound, and hypothesized that tumor cells could hijack this normal reparative system and use it to promote their own growth and survival.”
Although Palumbo saw the wisdom in Dvorak’s hypothesis, he did not find evidence of a connection to the hemostatic system, a key system in wound repair, when he studied tumor growth using highly transformed transplantable tumor models. While these experimental systems were very informative for dissecting the mechanisms coupling hemostatic factors to metastasis, an end stage in cancer progression, they were far less informative regarding early tumor development.
“By focusing on the later stages of tumor progression, we were missing key earlier steps in cancer pathogenesis – the evolution from a normal cell to a highly malignant cell,” he says. “I started thinking, could it be that the hemostatic system has a role to play in tumor growth, but it’s happening earlier in the process than we’re studying? We’re missing it because at the stage where the tumor is capable of metastatic spread, the tumor cells have already evolved to a point where they can generate everything needed to maintain a supportive stroma, including the ability to manipulate inflammatory cells in the tumor microenvironment.”
From Healthy – to Haywire
So he returned to early tumor development, in search of the fine line where the body’s healing mechanism goes haywire and becomes chronic inflammation.
“The first things that happen after a wound has occurred are the activation of the hemostatic and the inflammatory systems, both of which require tight regulation,” Palumbo says. “But in the case of chronic inflammation, you have a pathologic setting where this normal reparative process is not being turned off and healing never occurs. You have a chronic problem that developing tumor cells can use to nurture their own growth and development.”
This view is consistent with studies showing that chronic inflammation drives the development of multiple cancers, including cancers of the lung, pancreas and colon. Recent evidence has also shown that hemostatic factors are fundamental regulators of the inflammatory response in conditions that include bacterial infection and arthritis. Based on the dual importance of the clotting system in both cancer biology and regulation of inflammation, Palumbo reasoned that inflammation-driven cancers are likely to represent an important context where hemostatic factors play a role in early stages of tumor development and growth.
Looking for the source
So he and his team began to study colitis-associated colon cancer in mouse models. They found what they believe is the culprit in one of the clotting and healing cascade’s starting lineup, the clotting protein prothrombin.
“If we genetically dialed down prothrombin by just 50 percent, we got a major decrease in the number of inflammation-driven adenomas that formed in the colon,” Palumbo says. “In fact, a significant portion of mice with low levels of prothrombin developed no tumors whatsoever. “
Less prothrombin, less cancer. But why?
To understand this, Palumbo’s team focused on one of prothrombin’s “downstream targets,” fibrinogen. They found that fibrinogen also played a role in inflammation driven colon cancer progression, but surprisingly this role had nothing do with clot formation.
Stopping Inflammation – and Cancer
The discovery came about as a team effort. Fellow researchers Matthew Flick, PhD, and Jay Degen, PhD, had developed a mouse with a genetically modified fibrinogen. The mutant fibrinogen was designed so that it would clot normally, but would not bind with the leukocyte integrin receptor mac-1. Integrins regulate how a cell interacts with surrounding tissues; mac-1 is present on many immune cells and when it binds with fibrinogen, it drives inflammatory events. Disabling fibrin from binding with mac-1 stopped the inflammatory process.
“The mice were significantly protected from inflammation driven colon cancer. The majority developed no adenomas whatsoever,” says Palumbo. “And the adenomas that did form were smaller and less proliferative.”
Palumbo, who is also in the early stages of exploring the hemostatic system’s influence on prostate cancer, believes these findings have powerful potential for not just treating, but preventing inflammation-driven cancers.
“What we’ve found would suggest that therapies targeting hemostatic system components could possibly prevent cancer development in some individuals,” Palumbo says. “For example, if you had patients at high risk for colon cancer, targeting these interactions could prevent them from developing the disease. Given that inflammation is such a crucial factor in the development of numerous cancers, this paradigm is likely to be relevant beyond just colon cancer.
Palumbo and his laboratory team.
3333 Burnet Avenue, Cincinnati, Ohio 45229-3026 | 1-513-636-4200 | 1-800-344-2462 | TTY: 1-513-636-4900
New to Cincinnati Children’s or live outside of the Tristate area? 1-877-881-8479
© 1999-2015 Cincinnati Children's Hospital Medical Center