Tumor progression: a brief historical perspective

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Abstract

It has long been known that tumors become more clinically and biologically aggressive over time. This has been termed ‘tumor progression’ and includes, among other properties invasion and metastasis, as well as more efficient escape from host immune regulation. Since 1960, first cytogenetics and then molecular techniques have shown that tumors expand as a clone from a single altered cell, and that clinical ‘progression’ is the result of sequential somatic genetic changes, generating increasingly aggressive subpopulations within the expanding clone. Multiple types of genes have been identified, and they differ in different tumors, but they provide potential specific targets for important new therapies.

Introduction

This paper is a brief review of our developing knowledge and understanding of the phenomenon of tumor progression, with emphasis on areas of personal interest during a career of more than four decades in cancer research.

The biology of tumor progression will be summarized, including comment on evasion of host immunity. I will then note the contributions of cytogenetics in the 1960s and 1970s to the concept of ‘clonal evolution’ in tumors as a basis for understanding tumor progression. Finally, I will consider superficially the enormous amount of emerging evidence in the 1980s and 1990s concerning the specific genes involved in this process in different tumors, the multiple complex pathways in which the products of these genes are important, and the remarkable clinical implications of these findings.

Section snippets

The biology of tumor progression

It has been recognized for more than a century that most tumors tend to become more aggressive in clinical behavior and more ‘malignant’ in their characteristics over time, although this time course may be quite variable. This phenomenon has been termed ‘tumor progression’, and Foulds is generally credited with first pointing out, in the 1950s, that the process appears to develop in a stepwise fashion through qualitatively different stages.1 Other workers, both before and after, have also

Cytogenetics of tumor progression

My own studies relevant to the initiation and progression of tumors began in the 1960s and 1970s as I became involved in cytogenetic studies of human leukemias. In 1960, I described, with David Hungerford, an abnormal small chromosome in the cells of chronic myelogenous leukemia (CML).17 Subsequently called the Philadelphia (Ph) chromosome, this abnormality was present in essentially every typical case of CML, indicating that it was an important contributor to the pathogenesis of the disease.

Molecular genetics of tumor progression

Through the 1980s and 1990s, increasingly sophisticated methods for isolating and characterizing specific genes and their products greatly extended our understanding of tumor progression, including the remarkable complexity of this phenomenon. In general, the clonal evolution model has been widely confirmed at the molecular level, with the recognition that at least three major types of genes are involved in the full development of common human cancers.

The first group of genes, which has been

Conclusion

Thus, over the past four decades, the biomedical community has acquired an increasing understanding of the phenomenon of tumor progression, including escape from immune regulation. The concept of clonal evolution, with sequential genetic alterations, has been extensively confirmed as the basis for the clinical and biological aspects of tumor progression. It has also become clear that the genes involved cover a variety of functions, and that in most instances the genes are different in one type

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