Angiogenesis Factors: Tracking down the suspects in blood vessel growth near tumors

Cancerous growths rely on a surrounding tangle of blood vessels to support their reckless expansion, and scientists have spent decades hunting for the compounds that promote the development of such vessels. Although tumors are known to generate proteins that do the job, researchers have recently implicated bone marrow cells in the process too.

A new study in mice finds that a protein called Bv8 promotes vessel growth around tumors both directly and by inducing certain marrow cells to migrate out of bone and help tumors form a vessel network. Neutralizing Bv8, or preventing cells from making it, curbs such proliferation, scientists at Genentech in South San Francisco report in the Dec. 6 Nature.

The notion of thwarting angiogenesis to shut off a tumor’s supply of nutrients has dazzled scientists ever since researchers suggested the approach 20 years ago. Since then, scientists have tested dozens of compounds in hopes of neutralizing pivotal factors in angiogenesis.

“Now Bv8 is another target,” says Shahin Rafii, a hematology-oncologist at the Howard Hughes Medical Institute and Weill-Cornell Medical College in New York City. “Blocking its activity could abrogate the growth of certain tumors.”

Bv8 joins two other proteins clearly implicated in angiogenesis that scientists are seeking to neutralize.

In a raft of experiments, Genentech biochemist Napoleone Ferrara and his team identified a signaling protein that tumors release. They established that this signaler induces certain immature immune cells in the bone marrow to overproduce Bv8. These changes also prompted the marrow cells to venture out of the bone and produce Bv8 elsewhere, including tumor sites, the researchers found.

In tests on mice with cancer, the researchers found that excess Bv8 in tumors increased nearby vessel growth. Bv8 apparently triggers cells lining blood vessels to replicate, Ferrara says.

Treating tumors with antibodies to Bv8 suppressed vessel growth. Anti-Bv8 treatment also kept the marrow cells cooped up in the bone, where they couldn’t promote vessel-cell replication.

The Bv8 findings bolster the concept that certain bone marrow cells can contribute to cancer by aiding angiogenesis. That notion met with much skepticism only 10 years ago, Rafii says. “This is exciting. The whole concept that a tumor is a self-sufficient entity is being challenged now.”

The migration of marrow cells out of the bone to a tumor represents “a form of inflammation,” says immunologist Kyle C. McKenna of the University of Pittsburgh School of Medicine. Many studies have linked inflammation with cancer, in part because nascent immune cells often show up near tumors. The presence of immature immune cells may limit mature immune cells from properly attacking cancer, he says.

The new study shows that Bv8 “is clearly involved in promoting this inflammatory microenvironment around a tumor,” McKenna says.

Earlier work had established that nascent immune cells, when in contact with tumors, secrete a protein called matrix metallopeptidase-9 that facilitates new vessel growth, says P. Charles Lin, a vascular biologist at Vanderbilt University Medical Center, in Nashville. Tumors have multiple systems by which they promote angiogenesis, and a reliable therapy would need to address all of them. The Bv8 finding offers a specific protein to target as part of such an all-encompassing strategy, Lin says.

Not all marrow cells boost vessel growth. Some curb it, Rafii says. “We’re finding that there is a subset of these cells that contribute to tumor angiogenesis.”