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The Scientific Mechanics of Cancer

New research illuminates the role of genetic mutations in the diagnosis of cancer. This research has resulted in some promising treatments.

Published June 1, 2002

By Fred Moreno, Dana Van Atta, Jill Stolarik, and Jennifer Tang
Academy Contributors

Cancer researchers are getting ever closer to “understanding the molecular events that underwrite the transformation of a normal cell” into one capable of causing the deaths of millions of people around the world each year, Harold Varmus, MD, recently told a filled auditorium at Hunter College in New York City.

A Nobel laureate, former Director of the National Institutes of Health, and current President of Memorial Sloan Kettering Cancer Center, Dr. Varmus spoke at a mid-March gathering sponsored by The New York Academy of Sciences’ (the Academy’s) Microbiology Forum. “We are working toward understanding the molecular and genetic underpinnings of cancer,” he said.

Armed with this knowledge, physicians will be able to “assess the risk that an individual will develop cancer, prevent disease, diagnose it at the molecular level and, most importantly, treat it with new therapies that are much more precise than in the past.”

Varmus described a series of events in cancer research that have contributed to the understanding of oncogenesis, the changes that turn a normal cell into a malignant one. He spoke first about early events in the history of molecular oncology; next how some of this knowledge has been applied to the development of a specific cancer therapy. He concluded with a description of recent work, development models using mice, conducted in his own lab.

Cancer and Genetic Mutations

Cancer has its roots in genetic mutations — either changes to the genetic code of non-germ cells (somatic mutations), which may occur spontaneously or in response to environmental agents, or mutations inherited through germ cells. The latter happens much less frequently, Varmus noted. Singular mutations may be the first step in the process of oncogenesis, but many other cellular processes must subsequently occur for cancer to develop, he explained. Initiation is the moment normal gene expression is altered as a result of the mutation. If this altered cell fails to maintain normal cellular discipline, tumor maintenance begins. If the altered cell increases in oncogenecity, it is called progression.

Cancer cells then undergo a loss of growth control — an exaggerated response to growth signals or a failure to respond to inhibitory signals, and they escape from the signals that induce apoptosis, or cell death. Cancer cell growth is dependent on specific interactions between these cells and the host, such as angiogenesis, the induction of blood vessels to the tumor. Genetic instability gives rise to additional mutations and the cancer cell becomes more oncogenic, and may finally develop the capacity to colonize, to break away and travel to distant sites in the body.

In considering potential targets of cancer therapies, Varmus said many researchers have directed their efforts at tumor maintenance, the cellular functions necessary for cancer cells to remain in an oncogenic state. He noted that Steve Martin, a researcher at UC Berkeley, published in 1970 the results of a series of experiments conducted with avian cells.

The Impact of Temperature on Tumor Cells

The cells were infected with a virus that was capable of converting normal cells to those with a heightened potential for division or growth (the src mutant of the rous sarcoma virus). Dr. Martin induced many mutations in the virus stock and found a particular mutant form that would transform to an altered state only when the ambient temperature was 35 degrees F. or lower. When he took tumor isolates and raised the temperature above 35 degrees, he found that they returned to normal.

“With this work, Martin demonstrated that tumor cells require something — in this case temperature — to initiate and maintain the tumor state,” Varmus said. “This experiment defined the maintenance function.” The mutations in function allowed researchers to make the first genetic probe for a vertebrate gene.

Since 1970 researchers have made many fundamental discoveries about the role that genes play in cancer. They have identified specific genes — many of them encoding enzymes — that, when mutated, contribute to cellular transformation and tumor maintenance, as well as other genes that govern the integrity of the genetic code. Through this, they have discovered that the development of cancer depends on many kinds of mutations — inherited, somatic and multiple mutations. They also have discovered the biochemistry and physiologic properties of cancer gene products.

In addition, researchers have explored transgenes — foreign genes introduced into an organism in the laboratory — and have targeted mutations in mouse gene lines. And some of this genetic information is now used, in a limited way, in patient care, Varmus said. An understanding of genetic information was central to the development of one recently heralded new cancer therapy, Gleevec, a signal transduction inhibitor for patients with chronic myelogenous leukemia (CML). This is a common adult leukemia, with 6,000 new cases a year in the United States.

The Philadelphia Chromosome

Patients may remain in the early chronic phase, the phase in which the disease progresses slowly, for about five years. When the disease enters blast crisis, Varmus said patients survive about six months, on average.

Virtually all patients with CML have a mutation called the Philadelphia chromosome, in which a piece of chromosome 9 is joined to chromosome 22. At the point where the two chromosomes make contact, the abl oncogene fuses onto the bcr gene. “This fusion gene, bcr-abl, encodes an enzyme (an activated tyrosine kinase) that drives normal myeloid cells into the leukemic state and keeps them there,” he explained.

Gleevec fits in the active site in the enzyme and has a powerful inhibitory effect on the action of not only the enzyme encoded by the bcr-abl fusions gene, but also on two other oncogenes: the kit oncogene and the platelet-derived growth factor (PDGF) receptor. Nearly all patients in the early phase of CML respond when treated with Gleevec. It has produced striking remissions in patients with both CML and another cancer, gastrointestinal stromal cancer.

A Promising Treatment

After 10 days of treatment with Gleevec, patients with CML who had had evidence of disease throughout the bone marrow have marrow that has returned to normal, with no evidence of the Philadelphia chromosome. Patients can develop resistance to the drug, especially those with late-phase CML. It’s believed that this resistance is mediated by further mutations in the bcr-abl gene. “Patients’ responses to Gleevec demonstrate that bcr-abl activity is key to tumor maintenance, and that maintenance functions in general are potential therapeutic targets,” Varmus said.

“This success has emboldened those of us who work with mouse models to define tumor maintenance functions,” said Varmus. “In my lab we are working with a gene, ras, that is involved in a large number of non-small-cell lung cancers, which are a very common cause of cancer mortality.”

Members of Varmus’s lab are working with mutant mice that have a transgene, a mutant k-ras gene in a specific type of lung cells (the type 2 alveolar epithelium cells). The mutated gene was fused with a genetic unit called a tet operon, which turns the mutated gene on in the presence of the antibiotic doxycycline.

Using these techniques, researchers in Varmus’s lab are able to incite a proliferation of type 2 pneumocytes — tumors — in mice when Doxycyclineis administered. “If doxycycline is stopped after a few days, the tumor disappears, and there is little evidence of previous cell proliferation,” he said. These experiments suggest that this type of tumor grows in response to mutations in the ras gene, he concluded.

Also read: Cancer Metabolism and Signaling in the Tumor Microenvironment


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