Cutter Lecture: Why Don't More People Develop Cancer

George Klein

Many researchers view cancer as an aberration of normal biology and ask what goes wrong. Researcher George Klein makes no such presumption. On the contrary, he has spent 60 years hypothesizing that mutant cells are an inevitable consequence of complex biology. He asks what protects most people from cancer for so long.

Klein gave the 147th Cutter Lecture on Preventive Medicine at HSPH on December 17. His talk addressed a question he posed in the title of a recent review article, "Why do we not all die of cancer at an early age?", published in Volume 98 of Advances in Cancer Research. Klein, professor emeritus at the Microbiology and Tumor Biology Center at the Karolinska Institute discussed what scientists know so far about tumor defense mechanisms. He previewed a new project in his lab to investigate the possibility of cancer-resistant genotypes.

In an introduction, Dean Barry Bloom called Klein the "father of tumor immunology." Fifty years ago, Klein showed that the immune system had the power to kill a cancer cell and that it targeted the tumor and not normal cells. Later he found that immunological protection largely applied to virally-induced cancers, whose cells have foreign viral antigens that conveniently distinguish them from a person's normal cells. Klein also made the connection between Epstein-Barr virus and lymphomas and several other cancers.

In his talk, Klein credited the basic idea about the body's defenses against cancer to Nobel laureate Paul Ehrlich. In 1909, Ehrlich wrote that the extraordinarily complicated process of fetal and postfetal development must continuously generate mutated cells and that only the defenses of the organism prevent cancer from arising with enormous frequency.

In the 1950s and 1960s, Lewis Thomas and McFarlane Burnet formulated the theory of immunosurveillance, where the immune system cleans up tumor cells. But immunology is not the whole story, Klein said. It cannot explain why the majority of heavy smokers do not get lung cancer or why many men who die of other causes seem to have lesions in their prostates that have not progressed into threatening cancers.

Klein encouraged researchers investigating cancers not caused by viruses to consider nonimmunological weapons with which to do battle. These weapons include DNA repair and related mechanisms. Genetic variations in certain DNA repair mechanisms have been associated with a higher and lower risk of tobacco cancers.

Epigenetic mechanisms are another kind of anti-cancer measure. Epigenetics refers to changes in gene activity not encoded by the DNA sequence that can be passed from cell to cell or that can be inherited from parent to child. For example, inactivated tumor suppressor genes have been implicated in the genesis of all major cancers.

Another type of surveillance is intracellular, or within the cell itself. This approach includes the programmed cell death pathway known as apoptosis and other mechanisms that arrest the growth of the mutated cells.

Intercellular surveillance, which occurs between cells, may be equally important, Klein said. Other researchers have found that normal neighbors can exert a "peer pressure" to defuse tumor cells.

"Tumor cells can still be regulated to behave as normal cells," said Klein. "Normal neighbors can act as important microenvironmental controls."

In his next research project, Klein is planning to investigate differences in peoples' abilities to inhibit prostate cancer using phenotypic differences in tissue collected from study participants.

—Carol Cruzan Morton. Photo by Suzanne Camarata.