Page 63 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

42 PART I The Biology and Pathogenesis of Cancer

TABLE 2.2 Functional Classification of Tumor the second messengers such as guanosine triphosphate (GTP) and
Oncogenes proteins that bind GTP (G-proteins). During signal transduction
GTP is converted to guanosine diphosphate (GDP) by the gua-
VetBooks.ir Oncogene Name Abbreviation nosine triphosphatase (GTPase) activity of G-proteins. A group
of proto-oncogenes called Ras encode proteins with GTPase and
Platelet-derived growth factor
Growth factors
PDGF
Epidermal growth factor EGF GTP-binding activity and, in the normal cell, help modulate cel-
lular proliferation. Mutations in the Ras proto-oncogene can con-
Insulin-like growth factor-1 IGF-1 tribute to uncontrolled cellular proliferation.
Vascular endothelial growth VEGF
factor Nuclear Proteins and Transcription Factors
Transforming growth factor-β TGF-β Nuclear proteins and transcription factors encode proteins that
control gene expression. These proto-oncogenes may have roles
Interleukin-2 IL-2
in cellular proliferation. Not surprisingly, changes in transcription
Growth factor PDGF receptor PDGFR factor activity may contribute to the development of the malig-
receptors nant genotype.
EGF receptor EGFR, erbB-1
IGF-1 receptor IGF-1R Mechanisms by which Oncogenes Become Activated
VEGF receptor VEGFR The advent of recombinant DNA technology has allowed scientists
to unravel a number of mechanisms by which the normal prod-
IL-2 receptor IL-2R ucts of proto-oncogenes can be disrupted to produce uncontrolled
Hepatocyte growth factor C-met cell division. The conversion of a proto-oncogene to an oncogene
receptor is a result of somatic events in the genetic material of the target tis-
sue. The activated allele of the oncogene dominates the wild-type
Heregulin receptor neu/erbB-2
allele and results in a dominant gain of function. This means that
Stem cell factor receptor C-Kit only one allele needs to be affected to obtain phenotypic change;
this is in contrast to TS genes, in which both alleles have to be lost
Protein kinases Tyrosine kinase bcr-abl
for phenotypic change. The mechanisms of oncogene activation
Tyrosine kinase src are outlined in this list and are shown in Fig. 2.4. 34–41
Serine-threonine kinase raf/mil • Chromosomal translocation. When proto-oncogenes are trans-
located within the genome (i.e., from one chromosome to
Serine-threonine kinase mos another), their function can be greatly altered. The classic
G-protein signal GTPase H-ras example in human medicine is the chromosomal breakpoint
transducers that produces the Philadelphia chromosome found in chronic
GTPase K-ras myelogenous leukemia (CML). This involves translocation of
GTPase N-ras the c-abl oncogene on chromosome 9 to a gene on chromosome
22 (bcr). The point where two genes come together is referred
Nuclear Transcription factor ets to as a chromosomal breakpoint (or translocation breakpoint).
42
proteins
Transcription factor fos The BCR/ABL hybrid gene produces a novel transcript whose
protein product has elevated tyrosine kinase activity and can
Transcription factor jun
contribute to uncontrolled cellular proliferation. Transgenic
Transcription factor myb mice for this chimeric gene develop lymphoblastic leukemia
and lymphoma. Because this gene product is linked directly to
Transcription factor myc
CML formation, it is a logical target for tyrosine kinase inhibi-
Transcription factor rel tors in the treatment of CML in humans.
• Gene amplification. Quantitation of gene copy number is
GTPase, Guanosine triphosphatase. possible by a number of molecular techniques, including

comparative genomic hybridization, genotyping arrays, and
Southern hybridization. Amplification of oncogenes can occur
Protein Kinases in a number of tumor types and has been demonstrated in
childhood neuroblastoma, in which the myc proto-oncogene
Protein kinases are associated with the inner surface of the plasma (nuclear transcription factor) is amplified up to 300 times.
43
membrane and are involved in signal transduction after ligand- Gene amplification is possibly the most common mechanism
receptor binding. Structural changes in these genes and proteins of proto-oncogene activation. A further example is the MDM2
lead to increased kinase activity that can have profound effects on proto-oncogene, which has been identified in dogs and horses,
signal transduction pathways. and recently was shown to be amplified in a proportion of
canine soft tissue sarcomas. 44
Signal Transduction • Point mutations. These are single base changes in the DNA
The binding of an extracellular GF to the membrane recep- sequence of proto-oncogenes, leading to the production of
tor leads to a series of events by which the mitogenic signal is abnormal proteins. Point mutations can arise through the
transduced to the nucleus of the cell. Essential to this signaling actions of ionizing radiation, chemical carcinogens, or errors in
is the successive phosphorylation of signaling intermediaries or DNA replication and repair. A mutation in a proto-oncogene