Page 64 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 2 Tumor Biology and Metastasis 43

or the transcriptional machinery that controls its expression form the mode of inheritance is autosomal dominant, and about
may disrupt homeostasis and result in sustained prolifera- half the children are affected by the condition. Knudson’s model
tion signals or failure to respond to negative feedback signals.
required the retinoblastoma tumor cells (in either sporadic or
VetBooks.ir A classic example is the Ras proto-oncogene, in which point inherited forms) to acquire two separate genetic changes in the
DNA before tumor development. The first or predisposing event
mutations are a consistent finding in a number of human
tumors. Point mutations have also been identified in a number could be inherited through the germ line (familial retinoblastoma)
of canine tumors, suggesting a model for human disease. 45–47 or it could arise de novo in somatic cells (sporadic form). The sec-
• Viral insertions. The discovery of oncogenes was a direct result ond event occurred in somatic cells. Thus in sporadic retinoblas-
of studies on tumor-causing viruses. In some circumstances toma both events arose in the retinal cells. However, in familial
proto-oncogene function can be damaged by the insertion of retinoblastoma, the individual had already inherited one mutant
viral elements. 48–50 Occasionally, novel retroviruses are isolated gene and required only a second hit in the remaining normal gene
from leukemias or sarcomas in animals that have been vire- in somatic cells.
mic with a leukemia virus for some time. These viruses induce The mode of inheritance of retinoblastoma is dominant with
tumors very rapidly when inoculated into members of the spe- incomplete penetrance. However, at the cellular level loss or inac-
cies of origin and are referred to as acutely transforming onco- tivation of both alleles is required to change the cells’ phenotype.
viruses. The prototype of the acutely transforming virus is the The retinoblastoma gene codes for Rb, which was previously
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Rous sarcoma virus (RSV) isolated from a chicken in 1911. described as a normal cellular gene involved in control of the cell
Subsequently, many more have been isolated from animals cycle (see earlier discussion). Rb is described as a TS and, in a cell
infected with avian, feline, murine, or simian oncoviruses. These with only one normal allele, that allele usually produces enough
viruses are generated by a rare recombinant event between the TS product to remain normal. Generically mutations in TS genes
leukemia virus, with which the animal was originally infected, behave very differently from oncogene mutations. Whereas acti-
and a cellular proto-oncogene. In this, part of the viral genome vating oncogene mutations are dominant to wild type (they emit
is deleted and replaced with the cellular oncogene. The virus their proliferating signals regardless of the wild-type gene prod-
then becomes acutely transforming because this oncogene is uct), suppressor mutations are recessive. Mutation in one gene
now under the transcriptional control of a very efficient viral copy usually has no effect, as long as a reasonable amount of wild-
promoter. This then allows infection of a cell and insertion of type protein remains. Consequently, some texts refer to TS genes
this continuously expressed oncogene into the cellular genome, as “recessive oncogenes.”
leading to rapid progression and malignancy. Evidence suggests More recently Knudson’s hypothesis was confirmed when the
that these acutely transforming viruses are not transmitted nat- Rb gene was cloned and characterized. The TS Rb is the princi-
urally, but all events occur in the individual animal. Because pal member of a family of proteins that also encompass pRb2/
the virus has itself lost some of its own genetic material, it is p130 and p107. Rb plays a central role in regulating cell cycle
defective for replication; however, it is spread throughout an progression in G1 to S phase (see Fig. 2.2). Indeed, disruption
animal by the provision of help from the normal leukemia of Rb function has been found to be a common feature of many
virus, which provides the missing proteins in co-infected cells. human cancers other than retinoblastoma. Rb function can be
In addition to acutely transforming mechanisms, retroviruses abrogated by point mutations, deletions, or complex formation
can activate cellular oncogenes by integrating adjacent to them. with viral oncoproteins, such as SV40 large T antigen and adeno-
A good example of this is the myc gene, which is frequently viral E1a protein. The function of additional proteins associated
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activated in feline T-cell lymphomas. In one mode, the virus with the Rb pathway is also subjected to deregulation in human
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integrates adjacent to the oncogene, and transcription initia- cancers, including overexpression of D type cyclins, overexpres-
tion in the viral long terminal repeat (LTR) proceeds into the sion of CDK4, and downregulation of the CDKI cell cycle inhibi-
adjacent oncogene, producing a hybrid mRNA. In a second tor p16. Although loss of cell cycle control via the Rb pathway
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form, the enhancer of the virus overrides the regulation of the occurs commonly in many human tumors, little is known about
c-myc transcription from its normal promoter. the role of Rb, cyclin D, CDK4, and p16 in domesticated animal
tumors.
Tumor Suppressor Genes The p53 Tumor Suppressor Gene

Changes in genes can lead either to stimulatory or inhibitory As described previously, p53 is a gene whose product is intimately
effects on cell growth and proliferation. The stimulatory effects are involved as a negative regulator of the cell cycle control. Its dis-
provided by the proto-oncogenes, as described earlier. Mutations covery by Sir David Lane in 1979 marked a major milestone in
or translocations of these genes produce positive signals leading cancer research and has allowed greater understanding of molecu-
to uncontrolled growth. In contrast, tumor formation can result lar mechanisms of cancer and identified potential targets for thera-
from a loss of inhibitory functions associated with another class peutic intervention. 57
of cellular genes called the TS genes. The discovery of these genes The p53 protein has been described as the “guardian of
began by observations of inherited cancer syndromes in children, the genome” by virtue of its ability to push cells into arrest or
in particular studies of retinoblastoma. In the early 1970s epide- apoptosis, depending on the degree of DNA damage. Thus the
miologic studies of both retinoblastoma and Wilms tumor led p53 TS gene plays an important role in cell cycle progression,
Knudson to propose his “two hit” theory of tumorigenesis. 53 regulation of gene expression, and the cellular response mecha-
nisms to DNA damage. Under normal physiologic conditions,
Retinoblastoma Provides the First Clues to the Existence of wild-type p53 can bind specific DNA sequences and regulate
Tumor Suppressor Genes transcription of a number of genes involved in cell cycle pro-
Retinoblastoma occurs in two forms: a sporadic form and an gression and apoptotic pathways, including p21 waf1/cip1 and Bax
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inherited form (accounting for 40% of cases). In the inherited (see Fig. 2.5). The p53-mediated mechanisms are responsible