 |
The histopathological images show
angiotropism of tumor cells (A) some
distance from the primary melanoma
in a melanoma patient. At higher
magnification (B), one can observe
dark-purple melanoma cells cuffing
the external surface of the vessel
(V). The diagrams describe how
angiotropic melanoma cells spread
from the main primary-tumor mass
and migrate progressively along
the external surfaces of vessels
without entering the bloodstream,
defining pericytic mimicry (C) and
EVMM (D). During EVMM, once a
solid tumor becomes invasive, cells
at the advancing front of the tumor
acquire migratory properties, migrate
away from the primary tumor and
embark upon an extensive continuous
migration to reach their metastatic
secondary sites. |
It is well-known that melanoma cells from an initial tumor can travel through the bloodstream to other parts of the body to form new tumors. Through such metastasis, a small skin cancer can become lifethreatening by spreading to the brain, lungs, liver or other organs. Fifteen years ago, Claire Lugassy, MD, and Raymond Barnhill, MD, both professors of pathology at UCLA’s Jonsson Comprehensive Cancer Center, discovered and described an alternative metastatic process, which they called extravascular migratory metastasis (EVMM), by which melanoma cells move along the outside surface of blood vessels by way of angiotropism — a biological interaction between the cancer cells and the blood vessel cells. Since then, Drs. Lugassy and Barnhill have continued this line of research to confirm the existence of this metastatic pathway of cancer cells.
With angiotropism and EVMM, the cancer cells may replace tendril-like cells called pericytes, which are normally found on the outsides of blood vessels. Imitating the pericytes, the melanoma cells creep along the length of blood vessels until they reach an organ or other point where they accumulate to form new tumors, the researchers say. “At first our idea was controversial,” Dr. Lugassy says. “But mounting evidence confirming angiotropism and EVMM has revolutionized the knowledge of how cancer spreads through the body; other scientists have confirmed the process in other solid-tumor cell types, such as pancreatic cancer.”
The scientists observed the process in a genetically engineered mouse model of melanoma. The researchers also found that the immune systems of mice exposed to ultraviolet radiation responded with inflammation that accelerated the angiotropism, increasing the level of EVMM and leading to more lung metastases than among the mice not exposed to UV light.
“We have known for a long time that UV radiation is a factor in the development of melanoma,” Dr. Barnhill says. “But in this study, the melanoma was already present in the mice.”
Their colleague, Thomas Tüting, of the Laboratory of Experimental Dermatology at the University of Bonn (Germany), observed that UV light provoked inflammation at the site of the tumor, which caused the mouse immune system to attract a type of common white blood cells known as neutrophils, which, in turn, promoted angiotropism. With this new knowledge — and the confirmation of Drs. Lugassy and Barnhill’s research on angiotropism and EVMM — researchers in the scientific community can now begin looking for a drug target that will interfere with this EVMM process.
Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma,” Nature, March 6, 2014
