Science Editor

"Clinically, there has been an observation for almost a century that inflammation and cancer are linked," Thomas Schall told Bioworld Today. "And people have been looking for the molecular links for a long time."

Schall is president and CEO of biotech company ChemoCentryx Inc. and senior author of a paper in the Oct. 2, 2007, issue of the Proceedings of the National Academy of Sciences. In that paper, he and his colleagues at ChemoCentryx and the University of Michigan, Iowa State University and Yorktown Technologies report one such molecular link - the chemokine receptor CXCR7, which is expressed on both tumor cells themselves and the endothelial cells of tumor-associated vasculature.

Chemokines, or chemoattractant cytokines, are proinflammatory molecules that attract white blood cells to the site of injuries or diseases. They are the focus of Mountain View, Calif.-based ChemoCentryx. The company has clinical programs targeting chemokine receptors for the treatment of Crohn's disease and multiple sclerosis, and preclinical programs in cancer, rheumatoid arthritis and lupus.

In previous papers, the scientists had shown that CXCR7, whose function was previously unknown, is a chemokine receptor, and that it affected tumor growth in several model systems. But it was not clear whether CXCR7 played a significant role in the normal course of cancer.

In the work described in PNAS, the researchers first did a series of studies implanting or injecting breast and lung tumor cells whose expression levels of CXCR7 had been manipulated to be higher or lower than normal.

In the experiments, cells overexpressing CXCR7 formed larger tumors than control cells, while dialing down CXCR7 via RNA interference "resulted in a spectacular diminution of tumor growth" in mice, Schall said. Reducing CXCR7 expression also resulted in fewer lung metastases of breast tumor cells, again in mice.

Importantly, the tumor cells did not express another chemokine receptor: CXCR4, which, like CXCR7, binds the chemokine CXCL12. CXCR4 already has been implicated in both breast and lung cancer, and Schall said that the idea that other chemokine receptors also might play a role in cancer initially "got quite a lot of pushback" in the scientific community. For that reason, it was important to avoid potential confounding effects of interactions between CXCL12 and CXCR4.

The researchers used breast and lung tumors because they are well worked out models of epithelial tumors, which make up the majority of tumor types. But Schall noted that when ChemoCentryx scientists tested human tumor tissues, they found them "in virtually every tumor type we looked at."

Furthermore, a series of immunohistochemistry experiments on human tissues showed that the receptor appears to be very specific for tumor tissues - and tumor blood vessels. When the researchers stained biopsies of normal and tumor tissues, and the blood vessels supplying both tissue types, CXCR7 was expressed on roughly 30 percent of tumor cells but undetectable in biopsies of normal tissues. The same situation prevailed in the blood vessel supply: CXCR7 was expressed on tumor but not normal vasculature.

CXCR7 also appears to play an important role for blood vessel formation during normal development, when the scientists knocked down the expression of CXCR7 in zebrafish, the fish "basically form without a blood vessel supply," Schall said.

And, he added, the effects of CXCR7 seem to be independent of the VEGF and EGFR pathways targeted by such blockbusters as Avastin (bevacizumab) and Erbitux (cetuximab). "It's a very powerful new way to think about anti-angiogenic therapy," he said. "We're hoping for a knockout punch."