What Significant Events Have Happened In Cancer Research In The Last 25 Years

As I was beginning to gather my thoughts for the fourth edition of Cancer Biology, one of my colleagues mentioned that he thought it would be of interest to describe the significant things that have happened in cancer biology in the 25 years since the first edition was published (1981). Many things have happened since then, of course, and everyone has their favorite list. But looking back at the table of contents for the first edition and at the outline for this edition, several things struck me, as listed below.

1. Cancer susceptibility genes. In 1981 we knew that familial clustering of some cancers occurred, for example, with colon cancer, but the genes involved in this hadn't been determined. The APC, BRCA-1, BRCA-2, and p53 inherited mutations, for example, were not known at that time. Research in this area has identified a number of genes involved in cancer susceptibility, and with modern cloning techniques, more are identified every few months.

2. The techniques of modern molecular biology were in their infancy at that time. Polymerase chain reaction (PCR), DNA

microarrays, protein chips, and bioin-formatics were not terms in anybody's dictionary.

3. Genes involved in cancer initiation and promotion were very poorly defined. Although we knew that chemicals and irradiation could damage DNA and initiate cancer in animals and humans, the specific genes altered were almost completely unknown. We now know a lot about the genes involved at various stages of a number of cancers. For example, the work of Bert Vogelstein and colleagues has defined a pathway sometimes called the "Vogelgram" for the progression of colon cancer (see Chapter 5). We knew that DNA repair was important and that heritable conditions of defective DNA repair (e.g., xeroderma pigmentosum) could lead to cancer, but the ideas about the mechanisms of DNA repair were primitive.

4. The identification of oncogenes didn't really start until the early 1980s. The src gene was identified in 1976 by Stehelin et al., and erb, myc, and myb oncogenes were identified in the late 1970s, but this was about the limit of our knowledge (see Chapter 5).

5. The term tumor suppressor gene wasn't even coined until the early 1980s, although their existence had been implied from the cell fusion experiments of Henry Harris, (Chapter 5) who showed that if a normal cell was fused with a malignant cell, the phenotype was usually nonmalignant. The RB gene was the first one cloned, in 1983 by Cavenee et al. (Chapter 5) p53 was originally thought of as an oncogene. It wasn't realized until 1989 that wild-type p53 could actually suppress malignant transformation. A number of tumor suppressor genes have, of course, been identified since then.

6. Starting in the 1970s, cell cycle checkpoints were identified in yeast by Lee Hartwell and colleagues, but the identification of human homologs of these genes didn't occur until the late 1980s (see Chapter 4).

7. Tumor immunology was still poorly understood in 1981—both the mechanism of the immune response and the ability to manipulate it with cytokines, activated dendritic cells, and vaccines. Such manipulation was not in the treatment armamentarium.

8. The first treatment of a patient with gene therapy occurred in 1990. Several gene therapy clinical trials for cancer are under way and some gene therapy modalities will likely be approved in the next few years.

9. The viral etiology of cancer was still being widely debated in 1981. The involvement of Epstein-Barr virus in Burkitt's lymphoma and of hepatitis B virus in liver cancer was becoming accepted, but the role of viruses in these diseases and in cervical cancer, Kaposis' sarcoma, and in certain T-cell lymphomas became clearer much later.

10. Although some growth factors that affect cancer cell replication, such as IGF-1 and IGF-2, FGF, NGF, PDGF, and EGF, were known in 1981, knowledge about their receptors and signal trans-duction mechanisms was primitive indeed. Tumor growth factor a was known as sarcoma growth factor (SGF), and the existence of its partner, TGF-p, was only implied from what was thought to be a contaminating HPLC peak from the purification procedure. The explosion of knowledge about signal transduction mechanisms and how these pathways interact has been a tremendous boon to our understanding of how cells respond to signals in their environment and communicate with each other.

11. Knowledge about the regulation of gene expression has greatly increased in the past 25 years, on the basis of our current information on the packaging of chro-matin, transcription factors, coinducers and corepressors, and inhibitory RNA (siRNA).

12. While not topics discussed in detail in the earlier editions of Cancer Biology, advances in diagnostic imaging such as magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography (PET) have significantly im proved cancer diagnosis. Improved radiation therapy, combined modality therapy, bone marrow transplant, and supportive care have also improved significantly.

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