By David N. Leff
Until fairly recent decades, physicians and relatives used to call cancer by discreet code words - "Ca" or "C." Malignancy was regarded as somehow shameful, almost like a curse, and patients were shielded from the knowledge that their disease was indeed cancer.
Nowadays, of course, in most countries that prudery seems quaint as well as counterproductive. The global war on cancer is beginning to show results, in terms of lowering mortality statistics and heightened understanding of the molecular mechanisms of malignancy.
One such insight is the fact that - whatever the initial cause - the start, invasion and spread of tumor cells is an inside job. They arise in a healthy body by hijacking normal molecular processes, often those by which that body begins to grow during embryonic and fetal development.
Take the future nervous system, for instance. As the new neurons begin to proliferate, and put out their connective axons and dendrites, two interacting molecules move that growth forward. One is a receptor called RAGE, which stands for "receptor for advanced glycation end products." Its protein partner is a ligand called amphoterin.
At Columbia University's College of Physicians & Surgeons, pioneer cancer researchers Anne Marie Schmidt and David Stern reasoned that if they could find some means to inhibit or block the growth-promoting propensity of the RAGE-amphoterin duo in tumor cells, this might put a crimp in their malignant proliferation, migration and invasion.
Their speculation has begun to pay off, as evinced by a paper in today's issue of Nature, dated May 18, 2000, of which Schmidt and Stern are co-senior authors. Their report bears the title: "Blockade of RAGE-amphoterin signaling suppresses tumor growth and metastases." An accompanying commentary by cancer scientist Lance Liotta at the National Cancer Institute (NCI) in Bethesda, Md., is titled: "Checkpoint for invasion."
Liotta told BioWorld Today how the RAGE-blocking strategy evolved: "RAGE was originally discovered in 1992 by Columbia's Schmidt and Stern," he recounted, "as a receptor related to disease in diabetes. That is, as a glycation factor that binds sugar-coated molecules, which are augmented in diabetes because of high glucose levels in the blood of diabetic patients. But RAGE didn't bind those molecules really tightly.
"Then they found," Liotta continued, "that RAGE did bind a specific factor, their amphoterin protein, very tightly. That seemed to be associated with the migration of nerve cells - their neurite outgrowth. When the brain is getting wired up in embryology," Liotta explained, "the nerve cells migrate all over the body, go right where they're supposed to, and then connect up. Schmidt and her colleagues found this at the limiting edge of that migration.
"Then their thought was that if migrating neurites have to invade - essentially penetrate - tissue to go where they're supposed to go, then maybe tumor cells might use this mechanism. That led Schmidt's group to study RAGE to see if it could block the invasion-migration of the tumor cells. They found that they could, as reported in this experimental study in Nature. They have taken this all the way from diabetes to cancer," Liotta pointed out.
Schmidt's overall neoplasm-shrinking results required experiments in three sets of mouse models:
First, she and her co-authors seeded brain tumor glioma cells from rats onto the backs of nude mice, where they grew, until dosage with the RAGE-blocking treatment strikingly reduced their volume.
In their second experiment, the RAGE treatment suppressed distant metastases in the lungs, a favorite target tissue of tumor spread.
Thirdly, the co-authors shifted from implanting foreign tumor cells into mice to tackling the rodents' own spontaneously homegrown papillomas - benign skin cancers. Here, too, RAGE-amphoterin treatment decreased the size and number of those wart-like growths.
To administer their RAGE-amphoterin blockade in vivo, the co-authors designed not one but four alternative formulations:
1. Soluble, ligand-binding RAGE;
2. Blocking antibodies, or antibody fragments, against RAGE or amphoterin;
3. A transfected glioma gene expressing a RAGE mutant that negates RAGE signaling;
4. A transfected glioma gene expressing soluble RAGE.
"What the receptor does downstream, when it's engaged," Liotta pointed out, "is stimulate at least three signaling pathways. These can be involved in cell proliferation and growth - which is necessary for a cancer cell to grow, for a tumor to expand. RAGE also stimulates pathways that may promote invasion by proteases - enzymes that may help the cell chew its way through the barriers that it's invading.
"A third pathway," the NCI researcher added, "stimulates movement - migration, locomotion - of the cell by rearranging its cytoskeleton and protruding its pseudopods, the cell's feet. These cause it to step forward, crawl and migrate. So the receptor-ligand stimulates three pathways that affect all those functions," Liotta summed up. "Hence, when you block RAGE, it blocks all those pathways."
Edging Toward Anti-RAGE Clinical Therapies
Liotta also proposed, "You could make a biological treatment that looks like the amphoterin protein ligand to RAGE, or is a piece of it. So it's a potential therapeutic candidate. And it can have an application in diabetes, too."
But in all three of the co-author's preclinical experiments, inhibition of RAGE-amphoterin didn't kill the target tumor cells outright. Neither did they arrest angiogenesis - the penetration and expansion of blood vessels to nourish the growing tumors. Schmidt suggests that a three-pronged strategy - anti-angiogenesis plus direct tumor-cell destruction plus RAGE blockade - might provide even more potent anticancer therapy.
Columbia's chairman of surgery, Eric Rose, told BioWorld Today, "We have a collaboration with a biotech firm called Transtech Pharma, located in Greensboro, N.C., to develop small molecules that inhibit RAGE and its various agonists."
That firm's CEO, Adnan Mjalli, told BioWorld Today, "We have two major breakthroughs, one demonstrating high-throughput assays for RAGE interaction with its ligands, and we already have several small molecules, which we hope to start testing orally in animal tumor models by mid-summer."