In prior articles we have discussed the role of oncogenes (cancer-causing genes) in carcinogenesis as well as the role of tumor suppressor genes. The former promote the expression of the cancer phenotype (makeup), while the latter suppress it. The changes in these two types of genes, which are normally balanced in normal cells, are the backbone to how carcinogenesis occurs, in the transformation of a normal cell to a malignant cell. Along with the changes in these two types of genes, multiple other associated metabolic and cellular changes are also occurring in parallel in the cell’s proteins and membrane and literally every part of the cell’s physiology.
But how do all these changes interact, interdigitate and integrate to ultimately incur the truly profound change that the malignant phenotype (makeup) represents relative to the original normal phenotype? It is understood that carcinogenesis is a multi-step process that takes place over years, indeed often decades, and that it is a dynamic, fluid process with changes occurring throughout that time frame in an inexorable progression to the endpoint. I do not mean to imply that this progression is unstoppable—only that it is likely to be sequential with the accumulation of changes leading to closer and closer proximity to the ultimately transformed (malignant) cell.
Bert Vogelstein was born in Baltimore in 1949; he is the 14th-generation descendant of rabbis on his mother’s side. He went into medicine, became a pediatrician, and went into the study of the molecular genetics of cancer, primarily at Johns Hopkins University in Baltimore. He chose as his model or paradigm for study colorectal cancer, which offered several unique advantages. Because of the widespread availability of fiberoptic endoscopy (colonoscopy) since the 1970s, it has been relatively easy to collect tissue from the lumen of the colon. Colon cancer has long been understood to evolve as a progression from normal cells to colorectal adenomatous polyps, the precursor lesion for the malignant invasive colon cancer. This concept is what has led to the success of colon cancer screening, primarily with colonoscopy, by removing these polyps so they do not have the opportunity to progress to full-blown invasive carcinoma.
Vogelstein and his collaborators were able to collect samples of normal colon tissue as well as polyp specimens ranging in size from very small and increasing in size to very large. Along with the increase in size, as the polyps grew, they also developed histologic changes that increasingly resembled neoplastic tissue—mild dysplasia, moderate dysplasia, severe dysplasia, carcinoma in-situ. And finally they also obtained multiple specimens of actual invasive colon carcinoma.
These investigators meticulously went through these various colon stages and cataloged the presence or absence of each of the known molecular genetic abnormalities that had been described in the cancer sequence. In this way, they were able to document the precise sequence of events that occurs in the cellular genome as the normal colon cell progresses from normal through adenomatous polyps through dysplasia through carcinoma in-situ, until it becomes fully transformed or malignant.
This full sequence was published in 1990 in the journal Cell. It became widely accepted, and as new information is accrued from genomics and genetics, it is updated. For example, the model shows that the tumor suppressor gene APC is inactivated at a very early stage in the multi-stage process. Activation of the KRAS oncogene is associated with the transition from small to intermediate size adenomas. The loss or inactivation of the tumor suppressor gene p53 is a late stage event that occurs in the final step prior to invasive cancer.
The model also shows where environmental and lifestyle factors may have the opportunity to interact with the molecular and chromosomal changes that are occurring and either causing or accelerating this progression. Many of these markers also have significance in clinical colon cancer management.
The Vogelgram for colon cancer has served as a model for other tumors. Similar models have been constructed for head and neck cancer, lung cancer and other malignancies.
It is good to bear in mind that cancer etiology, like the etiology of all diseases, represents a gene-environment interaction. Lifestyle and environmental factors can and do have significant, sometimes even profound, influences on the risk and etiology of cancer. This may be by influencing changes in the genes or by affecting the rate of growth of partially abnormal cells in the carcinogenesis pathway or by other means. But neither the genes nor the environment are responsible for carcinogenesis independently of each other. The Vogelgram provides us with a map to where such environmental influences may exert their effects and, conversely, where preventive measures may be similarly effective.
Alfred I. Neugut, MD, PhD, is a medical oncologist and cancer epidemiologist at Columbia University Irving Medical Center/New York Presbyterian and Mailman School of Public Health in New York.
This article is for educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment, and does not constitute medical or other professional advice. Always seek the advice of your qualified health provider with any questions you may have regarding a medical condition or treatment.
