A simulation has been built to show how cancerous tumors manipulate blood-vessel growth for their own benefit. Since the ability to stop tumors through anti-angiogenesis is one goal of cancer therapy, this new work should help researchers quickly test strategies with sophisticated computer models.
Like all cells, those in tumors need access to the body’s fine network of blood vessels to bring them oxygen and carry away waste. Tumors have learned to game the process called angiogenesis in which new vessels sprout from existing ones, like branches from a tree.
The research team created a detailed model of how proteins involved in angiogenesis communicate with each other and how tumors take charge of the protein signaling chain that controls vessel growth. They were led by theoretical physicists José Onuchic, PhD, and Eshel Ben-Jacob, PhD, both at Rice University in Houston, Texas.
A key finding in the work, published in the Proceedings of the National Academy of Sciences (2015; doi: 10.1073/pnas.1511814112), showed that ligands known as “jagged” play a major role in the chaotic vessel growth observed around tumors.
In normal growth, an endothelial cell sprouts from an existing vessel as a tip, while others that follow the tip cell become the stalk cells that ultimately form vessel walls. The cell-to-cell notch signaling pathway directs the endothelial cell’s decision to become a tip or stalk.
Notch receptors are proteins that bind with delta ligand or jagged ligand molecules produced by cells. How they interact determines the cell’s fate. When notch and delta bind, they prompt a few cells to be tips and adjacent ones to be stalks; how this happens was the subject of an earlier study.
The new model has uncovered the role of jagged ligands. Because jagged is overexpressed in the tumor environment, notch-jagged binding overpowers notch-delta and results in a new kind of cell, a tip/stalk hybrid. While such cells can still form new vessels, these vessels rarely mature.
“You get blood vessels that send out many branches, but very few of them are as well-developed as seen during normal angiogenesis,” said coauthor Mohit Kumar Jolly, a Rice University bioengineering graduate student.
“High levels of jagged in the environment can trigger the formation of blood vessels that are useful to the tumor: fast-developing, leaky, and spread chaotically all over the tumor mass,” added lead author Marcelo Boareto, a postdoctoral fellow at the Swiss Federal Institute of Technology in Zurich, Switzerland.
“Tumors don’t have to wait for the vessels to develop,” Onuchic said. “They take advantage of the leakiness of the structure.”
The notch-delta pathway has been heavily studied and is the target of many anti-angiogenesis drugs now in use, according to the researchers. “We wondered exactly what notch-jagged signaling does that is not done in notch-delta signaling,” Boareto said. “We find that when the cells communicate mostly via jagged, we see a new kind of cell that is not exactly tip and not exactly stalk, but somewhere in between.
“This compromised cell is the major difference between normal and tumor angiogenesis and suggests that if notch-jagged signaling can be somehow suppressed without affecting notch-delta, we can probably disrupt tumor angiogenesis,” he said.