New research indicates that tumor blood vessels contain a protein sensor that detects minute changes in oxygen levels in tissues. These tumor vessels respond to the changes by becoming either more or less porous, which significantly influences the ability of cancer cells to escape through capillary walls and spread as metastases to distant organs. The findings are published in the March 6 issue of the journal Cell.

Massimiliano Mazzone and his colleagues, under the direction of Dr. Peter Carmeliet, at Katholieke Universiteit Leuven, Belgium, have shown that reducing activity of the oxygen sensor PHD2, which is normally increased in times of oxygen shortage (hypoxia), leads to the formation of a close-fitting, smooth, cobblestone-like lining of endothelial cells inside blood vessels. This contiguous row of cells resembles a 'phalanx'—the Greek military formation in which soldiers stand shoulder-to-shoulder with shields touching. This phalanx streamlines blood vessels, which improves the delivery of chemotherapy and other drugs into the tumor.

The researchers used mice genetically modified to have reduced levels of PHD2 and implanted them with different types of tumors. Compared to normal, wild-type mice, the tumor vasculature of the mice with reduced PHD2 expression had more normalized endothelial cells marked by tighter cell junctions. This change in architecture resulted in a significantly reduced propensity for metastasis and invasion.

The discovery of this protein function could lead to new angiogenesis-based treatments for cancer. As tumors grow they produce growth factors that stimulate the growth of new blood vessels to increase oxygen supply. These new tumor blood vessels have an abnormal structure, so tumors become hypoxic, which increases production of PHD2, loosening the phalanx and making the vessels more easy for cancer cells to escape from and metastasize to distant organs. In addition, the abnormal shape of the blood vessels restricts the delivery and effectiveness of chemotherapeutic agents.

PHD2-blockers may therefore offer new possibilities to combat cancer. By converting the abnormal endothelial layer into a phalanx of tightly aligned and impermeable cells, cancer drugs can penetrate the tumor more effectively. In addition, such a phalanx barrier may reduce metasases.

This research might also open new methods of treatment for other angiogenesis-dependent diseases such as wet age-related macular degeneration.

By Roderick Smith, M.S.

References: Mazzone M, Dettori D, de Oliveira RL, et al. Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell 2009;136:839-851.