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Doing the math
While Eder, Heymach, and others study angiogenesis inhibitors in patients, other scientists are looking into the basic mechanics of blood vessel growth. Among this latter group is Dana-Farber's Philip Hahnfeldt, PhD, a mathematician by training who belongs to what might be called the "Big Picture" school of molecular research, which includes his longtime colleague Lynn Hlatky, PhD. Rather than seeing cancer as an isolated event, a slip-up that happens within individual cells, these investigators work from the premise that tumors grow by interacting with healthy, surrounding tissue. A scaffold of supporting cells and blood vessel components known as endothelial cells, this tissue (called the stroma) is hardly an innocent bystander to tumor growth.
Philip Hahnfeldt, PhD, and his colleagues are developing mathematical models to better understand tumor growth.
"In 1993, William Black and H. Gilbert Welch of Dartmouth Medical School published a study showing that 99 percent of adults ages 50—70 have tiny cancers of the thyroid gland. But the actual incidence of thyroid cancer in that age group is less than 1 percent," Hahnfeldt observes. "Similar results were found in both the breast and prostate.
"This suggests that the initiation of cancer may not be what we need to focus on as much as the status of tumors: Are they small and likely to stay that way, or are they growing and likely to continue doing so?" If tumor status is what counts, then the area to study is the "cross talk" between tumor cells and their normal neighbors — the exchange of signals that influences whether tumors grow, and how rapidly.
"The new thinking is that this cross talk doesn't just accompany cancer, it determines whether people actually get clinical cancer," Hahnfeldt says. "The crucial step may not be the change of a normal cell into a cancerous one, but the signal imbalance that pushes a tumor to grow.
"This is a paradigm shift in the way we understand cancer," he continues. "Simply having cancer cells in your body doesn't necessarily mean there's a clinical problem. If we can control the communication between cancer cells and their surroundings, including blood vessels, we may be able to prevent tumors from becoming dangerous."
Scientists may not have to parse each and every aspect of this cellular conversation. Hahnfeldt is developing mathematical models that can describe the interchange in broad but precise ways. "The models will help us understand tumor cell-stromal cell communication as a complete system, which, hopefully, will let us predict how alterations to the system will affect tumor growth," he says.
He compares his work to physicists' formulas for explaining how water acts under various conditions. Rather than having to account for each water molecule's interactions with the others, physicists use such formulas to describe water's properties as a liquid, solid, and vapor.
To design mathematical models of cell systems, Hahnfeldt focuses on the aspects of cell signaling that limit how large and fast tumors can grow. Because there are so many kinds of tumors, and so many cell types within each one, he looks for signal-sending and -receiving systems shared by a variety of cells. These may serve as attack points for future therapies.
Although Hahnfeldt's work may seem theoretical, its purpose is practical. "The goal is to attack cancer at several areas of vulnerability," he says. "Therapies that slow or prevent tumor growth by disrupting their cross talk with nearby tissue — including blood vessel tissue — have an important place in the future of cancer treatment."
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