People owe a debt of gratitude to a mouse born into the world totallybald. The nude mouse's nakedness comes about because of geneticmutations, which also leave the beast devoid of a thymus, thuslacking immune defenses. This weakness is its strength as an animalmodel for mimicking human diseases.

Research oncologists inject suspensions of human tumor cells underthe skin of a nude mouse, knowing that it can't reject the foreigntissue. They then observe the cancer's growth, and test it for responseto potential anti-cancer drugs and other therapies.

This is all very well, but only up to a point. That point is where atypical solid tumor, after growing bigger and bigger in place, beginsto send out malignant cells to colonize distance organs. Such tumormetastases travel to their remote target tissues by way of thebloodstream and lymphatic network, neither of which is very handyto a subcutaneously implanted cancer.

That's why AntiCancer Inc. (ACI), of San Diego, Calif., invented andpatented its MetaMouse, as an animal model closer to the humancancer condition. The U.S. Patent Office, ACI's president, RobertHoffman, told BioWorld Today, has just notified it of allowance onits pending application.

"This mouse model and the patent for it," Hoffman said, "involvetumor transplant technology developed at AntiCancer, such that ahuman or xenograft cancer can be transplanted orthotopically _literally, to the correct place _ from a patient to the animal'scorresponding organ. These models are the first in which animal-implanted human tissues closely replicate the complex behavior ofthe original tumor while still in its human host. It allows the tumor togrow and spread, and then metastasize, as it does in patients." (SeeBioWorld Today, March 11, 1993, p. 3.)

Hoffman pointed out that "this contrasts with the usual nude-mousesubcutaneous mode, which very rarely metastasizes, and even morerarely to the proper target organ."

In human colon cancer, this metastatic target is almost invariably theliver, Hoffman observed. "In this country, 150,000 people a year getcolon cancer, and at least half are fatal over five years or so. Surelythe vast majority of these die from liver metastases."

ACI's president, who also is a professor of surgery at the Universityof California's San Diego (UCSD) campus, is senior author of apaper in last month's Proceedings of the National Academy ofSciences (PNAS) dated Dec. 19, 1995. Its title: "Liver colonizationcompetence governs colon cancer metastasis."

That paper tests in vivo its co-authors' concept that some coloncancer strains are predestined to metastasize, and others not. AtTokyo's University of Keio, Hoffman joined Japanese cancersurgeons intermittently over the past two years in orthotopicallyimplanting a series of eight human colon cancer strains into "maybe100 nude MetaMice, as a ballpark figure," he said.

As these malignancies, stitched to the surface of the animal's ownguts, rather than under their skins, duly increased in size, theinvestigators transplanted aliquots of the tumors to their livers. Someof the samples "took;" others did not.

"The colonization step is what distinguishes metastatic from non-metastatic cancer," Hoffman said.

To show that only orthotopic tumors, conditioned by growing oncolon tissue, could strike out for the liver, the team tried planting onestrain on stomach and colon surfaces alike. "There was a vastdifference," Hoffman said, "On the stomach it grew ratherextensively, but only on colon could it progress and metastasize tothe liver. This showed how important the originating, or primary,organ is."

For the past year at UCSD, Hoffman, wearing his academic hat as acancer surgeon, has been "transplanting all the colon cancers intoMetaMice. We're going to correlate metastasis with the patients andmice, and see if the direct liver assay will correlate with the patients'tumors. If that's the case," he continued, "then we have at least theliver tumor assay to determine if they are going to be metastatic."

He said that "Liver metastases, as the main cause of death in coloncancer, are a great target to attack. And that is what this is all aboutwith regard to reduction to clinical practice."

He and his colleagues "are now setting up the orthotopic transplantassay" to demonstrate if it is practical in patient prognosis. At thesame time, he added, "We're busily at work comparing the non-livercolonizers _ that is, the non-metastasizers _ with the colonizers,trying to see what the basic physiological and molecular differencesare."

Moving Up From Mice To Molecules

Hoffman speculated that "If we can from our mouse studies identify amolecule, a receptor or growth factor, we would do it. But I'm notsure it's so simple."

He regards molecular oncologist Lance Liotta at the National CancerInstitute (NCI) as "the maven in this field." Liotta heads the NCI'stumor invasion and metastasis section. Having read the PNAS paper,he told BioWorld Today: "If they follow that up, and find a cytokineand a receptor that cause the difference, then I would say that thatcytokine receptor could be such a marker."

Liotta added that, "One potential cytokine and receptor, which fulfillall the criteria from their model, is hepatocyte growth factor and itsmetastatic oncogene receptor. I don't know if that's the right one, butit would fit with everything they have reported in their study." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.