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, andwithmoderncloningtechniques,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 bioinformatics
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. We knew that DNArepairwas 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.
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, 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. 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.
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 transduction mechanisms was primitive indeed.
Tumor growth factor a was known as sarcoma growth factor (SGF), and the
existence of its partner, TGF-b, 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 chromatin,
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 resonanceimaging (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
