Cancer and the Immune System: The Oncogene: A Key Factor

Cancer and the Immune System: The oncogene: A Key Factor in the Development of Cancer

 

1.2 The progress of cancer within the body
Every cancer starts with a single cell that has been unleashed from the growth restraints placed on all normal cells. Because the changes that took place within the cancer cell were directed by the cell’s DNA (the molecular basis of heredity), they are passed on to each of the daughter cells arising from the original cancer cell. As these cells continue to divide, collections of abnormal cells accumulate. Except in the case of leukemia, these cells form a mass or tumor.

The cells of the tumor then push outward from their boundaries, infiltrating surrounding normal tissues. Small clumps of cells may then dislodge from the tumor (primary site) and migrate to distant (secondary) sites, often by piggybacking on the circulatory system of the blood or lymph. After traveling to a new organ, the cancer cells burrow out of the blood or lymph vessels and invade the surrounding tissues, where they continue to multiply and form secondary tumors. This process of spreading to a distant site is called metastasis. Eventually, either local invasion or metastasis disrupts the body’s normal function and often leads to death.

The oncogene: A Key Factor in the Development of Cancer

In the 1980s, the American government declared war on cancer. That war is still raging and the latest report from the frontline is a mixed bag of good and bad news. According to the latest figures from the American Cancer Society, more than half a million Americans will die at the hands of this scourge in this year alone. This makes cancer second only to heart disease as the leading cause of death among Americans. The cost of cancer to the American economy was estimated at almost $200 billion for the year 2000 alone. According to the latest projections, one out of every four Americans alive today will eventually die of cancer in the absence of major breakthroughs in prevention and control.

In terms of mortality rate, lung cancer is by far the most frequent killer among all Americans, followed distantly by cancer of the colon and rectum, the breast, and the prostate. Even when men and women are considered separately, lung cancer is still the biggest killer, although the mortality rate is much higher for men than for women. After lung cancer, prostate and colorectal cancers kill men the most often. Among women, breast cancer is by far the most prevalent form, followed by colorectal and uterine cancers. The next most common killer for men is cancer of the pancreas and for women is ovarian cancer. A recent and disturbing development is the increasing evidence that suggests that obesity increases the likelihood of colon and prostate cancers in men and breast, ovarian, and gall-bladder cancers in women. With an estimated 97 million American adults classified as obese, this new link does not bode well for the battle against cancer.

1.3 Cancer incidence and mortality rates in the United States

The good news is that the rate of new cancer cases and deaths for all cancers combined, as well as for most of the top 10 cancers in the United States has been declining. The report shows that the incidence rate—the number of new cancer cases per 100,000 persons per year—for all cancers combined declined by an average of 0.8 percent per year between 1990 and 1997. The greatest decline in cancer incidence rates has been among men, who overall have higher rates of cancer than women. The reduction in deaths from cancer has been attributed to better screening and advances in treatment. These uplifting findings reflect the considerable progress that Americans have made against cancer. This decline in cancer deaths is all the more remarkable if we consider the fact that the size of the American population has been increasing while deaths from cancer have been declining.

1.4 The connection between cancer and the immune system
In 1909, a scientist by the name of Paul Ehrlich proposed that the incidence of cancer would be much greater were it not for the vigilance of our immune defense system in identifying and eliminating nascent tumor cells. This suggestion gave birth to the generally accepted concept that the immune system plays a vital role in the identification and elimination of transformed cells. About 50 years later, two scientists, Lewis Thomas and Frank MacFarlane Burnet, took Paul Ehrlich’s original idea a step further and proposed that a special type of immune cell called a T cell was the pivotal sentinel in the immune system’s response against cancer. This elaboration led to the coinage of the term “immune surveillance or immunosurveillance” to describe the concept whereby the immune system is on perpetual alert against transformed cells.

As dictated by the scientific method, theories must in the course of time either withstand rigorous experimental testing, crumble and be discarded or be improved upon. This basic requirement brought the theory of immunosurveillance under severe attack and great controversy when scientists like Osías Stutman showed in the 1970s that mice supposedly lacking an intact immune system (so-called nude mice) did not become more susceptible to tumor growth as predicted by the theory.

Thus, the theory of immunosurveillance remained controversial until an important scientific article entitled “IFN-gamma and lymphocytes prevent primary tumor development and shape tumor immunogenicity” was published in the journal Nature on April 26, 2001. This breakthrough article was authored by Robert D. Schreiber, Ph.D., and his colleagues at Washington University School of Medicine, St. Louis, MO, in collaboration with Lloyd J. Old, M.D., of the Ludwig Institute for Cancer Research and Memorial Sloan-Kettering Cancer Center, New York, NY. The experimental evidence presented in their paper unambiguously showed that the immune system can and often does prevent tumors from developing, and thus plays a strong protective role against cancer. These researchers also uncovered important new insights regarding the immune system and tumor development that they dubbed “immunoediting.”

Utilizing genetically engineered mice that lacked a functional immune system, the authors showed that lymphocytes and the immune stimulator, IFN-gamma, cooperate to inhibit the development of both spontaneous and carcinogen-induced tumors. Unfortunately, this natural body defense is imperfect, and some tumor cells escape identification and go on to cause cancer. These renegade tumors are less immunogenic, having undergone a process of immunoselection triggered by the actions of the immune system. Conceptually, in much the same way as bacteria can become resistant to antibiotic treatment and lead to more potent and harmful strains, so too can the body’s own tumor defense system lead to tumors that escape elimination.

Importantly, these researchers went on to demonstrate that there are ways to overcome the “camouflage” of such renegade tumors by increasing their antigen ｅxpression and making them visible to the immune system. This suggests that even tumors that have escaped recognition can be turned into targets for an immune response. Further experimentation is underway to test how these results can be used to develop cancer immunotherapies. The Cancer Research Institute (CRI) sponsored this research with a grant to Dr. Schreiber’s lab and provided further funding through its pre- and post-doctoral training programs to two graduate students, one of whom was the first author of the paper, and a postdoctoral fellow.

Despite the tremendous scientific progress (such as that described above) that has been made over the years, a complete and precise understanding of the immune system’s response to cancer remains elusive. The continued exploration of these questions is the province of cancer immunology; the scientific discipline to which CRI is dedicated to supporting and nourishing.

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