By David N. Leff

A philosopher-poet once wrote that "the proper study of man is man."

Physicians who diagnose and treat prostate cancer wish they could study an animal model that precisely simulated the onset and course of this men-only malignancy. The lack of such a mammal, standing in for cancer of the prostate (CaP), is not for lack of trying.

"TRAMP" is the acronym for one such surrogate animal. It stands for "transgenic adenocarcinoma mouse prostate model." Molecular biologist Jeffrey Gordon said of TRAMP and its ilk: "In this and the other transgenic models, the onset of neoplasia is delayed as much as several months after transgene expression begins. Moreover, only a subset of the [CaP] luminal secretory cells is transformed."

Gordon, a faculty member at Washington University, in St. Louis, has created a novel, and reportedly more faithful, mouse model of CaP. He reports it in the current Proceedings of the National Academy of Sciences (PNAS), dated Dec. 22, 1998. His paper's title is "A transgenic mouse model of metastatic prostate cancer originating from neuroendocrine cells."

"The prostate contains three epithelial cell types," Gordon told BioWorld Today. "The most abundant are the luminal cells, which secrete a variety of factors into the prostatic fluid. Basal cells are the cells that proliferate in the prostatic epithelium. They are thought to give rise to the luminal cells, and also to the very rare neuroendocrine cells. These comprise less than 1 percent of the total prostate cell types. Neuroendocrine cells elaborate a variety of factors, including hormones that affect cell growth.

"In patients with adenocarcinoma of the prostate, their cells start to secrete some of the products that are normally found in neuroendocrine cells," he observed. "They also exist in a variety of other organs, including the lung. There, when transformed, they produce small-cell carcinoma, a very aggressively metastatic malignancy. People with small-cell lung cancer are typically diagnosed only at a very late stage, when their tumor has already metastasized."

Gordon observed that the prostate-specific antigen (PSA) test "has been terrific in identifying patients with carcinoma in situ. For most individuals the disease is relatively indolent, and doesn't require aggressive treatment. But we just don't have molecular markers to distinguish or predict those individuals with positive PSA tests who on biopsy have carcinoma in situ from those who will go on to aggressively metastatic disease.

Tool To ID Patients Who Can Avoid Drastic Therapies

"What makes our new mouse model of CaP so intriguing," Gordon said, "is the stereotyped pattern of rapid invasion and metastatic spread. It will be useful for characterizing molecular mediators of invasion at early stages of neuroendocrine cancer. This may be shared by neuroendocrine cells transformed in other tissues, such as the lung."

Lung cancer, he noted, is the leading cause of cancer-related mortality in Americans. Prostate is second -- and first in men -- with about 35,000 deaths a year.

"Patients who have surgical or chemical androgen-ablation therapy," Gordon observed, "will eventually escape the protective effects of removing the hormone, and go on to develop aggressive metastatic disease that doesn't depend on androgen. Why should that be? How can we predict which individuals will be at risk for that? And what gene products -- that might be shared by neuroendocrine cells normally, and adenocarcinoma when they are transformed -- might be responsible for that sort of androgen-independent aggressive behavior?"

For answers to these life-and-death clinical questions, he and his co-authors look to their new mouse.

"We have a small-animal model now that offers us an opportunity for looking at a normally rare cell, that is now vastly amplified, and determining what gene products that neuroendocrine cell normally expresses," Gordon said. "And we can do that using a variety of modern genomic approaches. The model's utility would be to understand how growth can occur in the absence of androgens, and perhaps to identify certain neuroendocrine features exhibited late in the course of prostate cancers that may be amenable to therapeutic manipulation.

"We have a large colony of these mice," he said. "They could certainly be used to test a variety of drugs that might affect neuroendocrine cell growth arising in the prostate, but perhaps applicable to other tissues, as targets for gene therapy."

What led Gordon and his co-authors to their model "was a fortuitous observation. We study epithelial cells in the gut, and had made transgenic mice designed to explore the effects of introducing certain cancer-causing oncoproteins into one particular intestinal cell, called the Paneth cell. (See BioWorld Today, April 13, 1998, p. 1.)

Gift From Gut Enabled Prostate Mouse Model

"We used the regulatory elements from a gene normally expressed in these Paneth cells to express the oncoprotein," Gordon said. "These elements also function in neuroendocrine cells of the prostate. We found that expression of this oncoprotein in the intestine of these mice had little effect. Females who expressed the oncoprotein were perfectly healthy. But the male mice began dying at five to six months of age of metastatic cancer, which originated in the prostate's neuroendocrine cells. They went to transformation into malignant cells within a week after the gene was first turned on.

"Cryptin genes, expressed in Paneth cells, are silent in prostate," Gordon continued. "But we just excised a portion of the gene's regulatory elements, and exposed its capacity to express foreign gene products -- including oncoproteins -- in the neuroendocrine cells of the prostate, with very rapid and predictable invasion and metastases.

"There are few mouse models of metastatic cancer," he said. "So, this was an interesting and unexpected finding that allows us to explore the behavior of neuroendocrine cells at very early stages of transformation. Our animal model of CaP displays the stereotyped pattern of rapid invasion and metastatic spread that makes these mice intriguing.

"There are two ways of thinking of our new transgenic mouse," Gordon concluded. "One is as a model of CaP arising in neuroendocrine cells. The other is a neuroendocrine cell cancer arising in the prostate." *