From Chimney Sweeps to Oncogenes
The publication of this first issue of the journal Molecular Carcinogenesis is a salutatory event since it symbolizes the fruition of an exciting new phase in cancer research, the systematic elucidation of the molecular mechanisms by which normal cells evolve into malignant tumors.
It is generally acknowledged that the first major insights into cancer causation occurred in the eighteenth century, with Percival Pott's astute association of scrota1 cancer in chimney sweeps with an occupational exposure and Bernardino Ramazzini's perception that the occurrence of breast cancer is related to life-style factors. The nineteenth century was notable for the application of microscopic pathology to the study of cancer and the emergence of the concept of cellular pathology. Curiously, the field of cancer causation was relatively dormant during most of that century. The twentieth century, however, has been rich with discoveries related to cancer etiology. The field of experimental chemical carcinogenesis was launched with the development, by Katsusaburo Yamagiwa and Koichi lchikawa in 1918, of an experimental model for skin tumor induction by chemicals. The 1930s revealed the structures of the first chemically pure carcinogens, the polycyclic aromatic hydrocarbons, by Ernest L. Kennaway and James W. Cooke, who isolated these compounds from combustion products similar to the soot originally implicated in cancer causation by Percival Pott. This was followed by the discovery of several other chemical classes of carcinogens, including azo dyes, aromatic amines, nitrosamines, various alkylating agents, and halogenated organic compounds. In the late 1930s and 1940s the multistage nature of the carcinogenic process and the phenomenon of tumor promotion were revealed by Peyton Rous and Isaac Berenblum, and further major insights on tumor promotions were provided by Roswell Boutwell and his colleagues. Studies by Jacob Furth and C. Huggins indicated that hormones, acting at the epigenetic level, play major roles in tumor development. Major achievements in the 1950s and 1960s included the discovery of the biochemical mechanisms by which carcinogens undergo metabolism and activation to yield highly reactive electrophiles that bind covalently to cellular DNA and other macromolecules, by Elizabeth B. and James A. Miller, Phillip Lawley, Peter Brookes, Peter Simms, and others. Carcinogen-induced changes in the structure of DNA, DNA repair mechanisms, and molecular mechanisms of mutagenesis also emerged as important themes in carcinogenesis research. The development of cell culture transformation systems by L. Sachs, C. Heidelberger, and others opened the field to an analysis of the cellular and molecular mechanisms of action of chemical carcinogens, radiation and tumor promoters. Epidemiologic and experimental studies performed during the past few decades have identified at least 23 specific chemicals or chemical processes as human carcinogens, and have also provided evidence that dietary and life-style factors play important roles in the causation of certain major human cancer (e.g., colon and breast cancer). The carcinogenic effects of radiation were first observed in the early decades of this century. The tragic atomic bomb explosions over Hiroshima and Nagasaki led to fundamental studies on radiation dosimetry and radiation biology. Recent concern over potential hazards of nuclear energy plants and radon exposure from natural sources has reawakened interest in radiation carcinogenesis.
The field of cancer genetics had its beginnings with the prophetic concept of Theodor Boveri, in 1910, that the fundamental defect in cancer cells resides in the chromosomes. The development of inbred strains of mice and studies on cancer transmission in these strains of mice, which were begun during the early decades of this century by Ernest E. Tyzzer, Leonell C. Strong, Clarence C. Little, John J. Bittner, and others, laid the groundwork for subsequent advances in tumor immunology and the study of mammalian tumor viruses. More recently the genetic defects in cancer cells have been revealed at the chromosomal and DNA levels by the development of high resolution cytogenetic methods, powerful gene transfer methods, and DNA cloning and sequencing methods. Clinical studies of hereditary tumors, coupled with these new methods, are now giving us our first glimpses of tumor suppressor genes.
For general reviews of these subjects see: