WASHINGTONThe relation between tumor cell proliferation and
angiogenesis is well known: Tumors need a supply of blood in order to
grow beyond a depth of 1 mm. Discovering how angiogenesis works has
been the focus of research by Harold Dvorak, MD, Mallinckrodt
Professor of Pathology, Harvard Medical School.
Specifically, he is studying how tumor vessels become hyperpermeable,
allowing fibrin, a key molecule in the process of angiogenesis, to
get out of existing blood vessels and into tumor stroma.
To do that, two things have to happen. First, vessels have to
be leaky so that fibrin can escape and, second, clotting has to take
place. Both of these things happen regularly in tumors, Dr.
Dvorak said at a basic science symposium sponsored by the National
Foundation for Cancer Research, which supports his work.
Normally, adult human tissues are in balance with regard to blood
supply; this balance discour-ages the growth of new blood vessels,
Dr. Dvorak said. However, anything that causes vessel
permeabilitysuch as wound healing or a tumorcan lead to
fibrin leakage. Such leakage induces the formation of fibrin clots
that encourage the development of new blood vessels.
Fibrin serves as a provisional matrix, imposing cell structure,
regulating cell migration, and inducing formation of mature
stroma, he said.
Dr. Dvorak reported finding a substance he calls vascular
permeability factor (VPF), also known as vascular endothelial growth
factor (VEGF), that can induce vessel permeability (see box ). Tumors
have the ability to make and secrete VPF/VEGF, thus causing blood
vessels to leak fibrin. Increased vascular permeability to
circulating fibrin macromolecules converts the ordinarily neutral
extracellular matrix to one that is proangiogenic, he said.
VPF/VEGF Shown to Promote Angiogenesis In Human Tissue
In order to study factors involved in tumor angiogenesis, Dr. Harold
When the virus carrying VPF/VEGF is injected into muscle fibers,
With VPF/VEGF alone, he said, we can generate the
Wound healing also induces production of VPF/VEGF. However, tumors
differ from healing wounds in one important respect. As soon as a
wound is healed, VPF/VEGF production is turned off abruptly. Tumors,
however, continue to make large amounts of VPF/VEGF because they are
growing rapidly and need a new blood supply.
How do circulating macromolecules like fibrin get out of blood
vessels? Dr. Dvorak said that various explanations have been
proposed. The most popular explanation is that they pass through
interendothelial spaces or junctions. Alternatively, a small lipid
may dissolve the endothelial membrane. Or perhaps a fenestrated type
of endothelium forms, one with a thin membranea pattern
characteristic of endocrine tissues, he said.
In the 1950s, Dr. Dvorak noted, George Palade described a structure
called a caveola, which forms a small pocket in the endothelium and
then migrates across the vessel wall to discharge its contents.
Although the vast majority of tumor endothelium is continuous, Dr.
Dvorak described grape-like clusters of interconnecting vessels and
vacuoles of varying size, which he calls vesiculo-vacuole organelles
(VVOs). They form very large structures, occupying 20% of the
endothelial cytoplasm. These VVOs are joined by diaphragms and span
the entire thickness of the endothelial lumen, with multiple openings
to each surface. Dr. Dvorak believes they play an important role in
transmitting fibrin molecules across the endothelium to begin angiogenesis.