Blocking Growth Factor Halts Tumor Advance, Spread In Mice

Drs. Ann Marie Schmidt and David Stern, from the Department of Surgery, and their colleagues at the College of Physicians and Surgeons along with researchers from the Osaka University School of Medicine and the Kanazawa University School of Medicine, are investigating the receptor for advanced glycation endproducts (RAGE). This receptor, found on the surface of many types of cells, interacts with several different molecules (termed ligands) that play a role in both health and disease. Some of these molecules are involved in development, maintenance of normal cellular functions, and inflammation, while others have been implicated in diabetes and Alzheimer's disease.

Drs. Schmidt and Stern and their colleagues investigated one ligand in particular, amphoterin. Normally, when RAGE and amphoterin interact they trigger intracellular processes likely to be involved in normal development. But sustained RAGE-amphoterin interaction in the context of tumors is shown to promote rapid proliferation, cell migration and invasion. The researchers studied whether blocking RAGE and amphoterin from interaction would have any effect on tumor behavior.

They employed several different strategies for blocking this interaction using tumor models in laboratory mice. The first model used local injection of glioma cells, derived from a tumor of the nervous system, to develop tumors on the backs of mice. Blockade of RAGE-amphoterin interaction by several methods strikingly decreased tumor size. The second model was one of distant tumor spread, or metastasis. In this model, blocking RAGE strongly suppressed lung metastasis. The third model used genetically manipulated mice prone to the development of skin tumors called papillomas. Preventing access of ligands to RAGE in these mice decreased the number and size of the papillomas.

Inhibition of RAGE-amphoterin interaction appeared to exert its effect on the tumor cells by decreasing tumor cell growth, migration and invasion. This inhibition did not kill tumor cells, nor did it affect the growth of blood vessels into the tumor, which is known as angiogenesis. Thus, Drs. Schmidt and Stern suspect that combining RAGE blockade with cell-destroying and anti-angiogenic therapies might provide even more potent anti-tumor therapy. However, the authors point out that it is essential to interpret their data cautiously in the broader context of tumor behavior in humans, since the studies to date have only been performed in selected mouse models.