world cancer report - iarc
world cancer report - iarc
world cancer report - iarc
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Common human oncogenes<br />
Many common proto-oncogenes encode<br />
components of the molecular cascades<br />
that regulate the cellular response to<br />
mitogenic signals [6]. They include growth<br />
factors (e.g. TGFA), growth factor receptors<br />
(e.g. the receptors for epidermal<br />
growth factor, EGF and its close homologue,<br />
ERBB2), receptor-coupled signal<br />
transduction molecules (in particular, several<br />
small guanosine triphosphate (GTP)binding<br />
proteins located on the inner face<br />
of the cell membrane, such as the various<br />
members of the RAS family), kinases<br />
(SRC, ABL, RAF1), regulatory subunits of<br />
cell cycle kinases (CCND1 and CCNA),<br />
phosphatases (CDC25B), anti-apoptotic<br />
molecules (BCL2) and transcription factors<br />
(MYC, MYB, FOS, JUN). The cumbersome<br />
nomenclature of these genes (Box:<br />
Naming genes and proteins, p101) owes<br />
much to the way they were discovered and<br />
identified. The SRC gene, for example, was<br />
the first oncogene identified, in 1976, as a<br />
modified version of a cellular gene incorporated<br />
in the genome of a highly transformant<br />
chicken retrovirus, the Rous sarcoma<br />
virus. The MYC gene was also originally<br />
identified in the genome of an avian<br />
retrovirus inducing promyelocytic<br />
leukaemia. The RAS genes were first identified<br />
as activated genes capable of inducing<br />
the formation of rat sarcomas, and<br />
various members of the family were found<br />
in different murine retroviruses, such as<br />
the Harvey sarcoma virus (HRAS) and the<br />
Kirsten sarcoma virus (KRAS).<br />
The most commonly activated oncogenes<br />
in human <strong>cancer</strong>s are ERBB2 (in breast<br />
and ovarian <strong>cancer</strong>s), members of the RAS<br />
family (in particular KRAS in lung, colorectal<br />
and pancreatic <strong>cancer</strong>s, and MYC (in a<br />
large variety of tumours such as <strong>cancer</strong>s of<br />
the breast and oesophagus and in some<br />
forms of acute and chronic leukaemia).<br />
These three examples give an excellent<br />
illustration of the diversity of the mechanisms<br />
of oncogene activation and of their<br />
consequences for cell growth and division.<br />
ERBB2<br />
In the case of ERBB2, oncogenic activation<br />
is almost always the result of amplification<br />
of the normal gene [7] (Fig. 3.16). This<br />
A<br />
Fig. 3.16 Analysis of the status of the ERBB2 oncogene by fluorescent in situ hybridization (FISH) with a<br />
rhodamine-labelled ERBB2 probe (pink). In breast tumour cells without amplification of the gene, each<br />
nucleus possesses two copies of ERBB2 (A). In tumour cells with high-level amplification of the gene,<br />
numerous signals are evident in each nucleus (B).<br />
gene is located within a region of the<br />
genome which is amplified in about 27% of<br />
advanced breast <strong>cancer</strong>s, leading to a<br />
spectacular increase in the density of the<br />
molecule at the cell surface. ERBB2<br />
encodes a transmembrane protein with<br />
the structure of a cell-surface receptor, the<br />
intracellular portion of which carries a<br />
tyrosine kinase activity. Overexpression of<br />
ERBB2 leads to constitutive activation of<br />
the growth-promoting tyrosine phosphorylation<br />
signal. The elucidation of this mechanism<br />
has led to the development of neutralizing<br />
antibodies and specific chemical<br />
inhibitors of tyrosine kinase activity as<br />
therapeutic approaches to the blocking of<br />
ERBB2 action.<br />
RAS<br />
The RAS genes are located one step downstream<br />
of ERBB2 in growth signalling cascades.<br />
The protein products of the RAS<br />
genes are small proteins anchored at the<br />
cytoplasmic side of the plasma membrane<br />
by a lipidic moiety. They indirectly interact<br />
A<br />
with activated tyrosine kinases and act as<br />
“amplifiers” to increase the strength of the<br />
signal generated by the activation of cellsurface<br />
receptors [8]. In their active form,<br />
ras proteins bind guanosine triphosphate<br />
(GTP) and catalyse its hydrolysis into<br />
guanosine diphosphate (GDP) returning to<br />
their inactive form. Oncogenic forms of<br />
activated RAS genes often carry missense<br />
mutations at a limited number of codons<br />
within the GTP-binding site of the enzyme,<br />
making it unable to hydrolyse GTP and thus<br />
trapping it in the active form. Activation of<br />
RAS genes thus induces the cell to behave<br />
as if the upstream, Ras-coupled receptors<br />
were being constantly stimulated.<br />
MYC<br />
The MYC oncogene may be seen as a prototype<br />
of the family of molecules which lies<br />
at the receiving end of the signal transduction<br />
cascades. MYC encodes a transcription<br />
factor which is rapidly activated after<br />
growth stimulation and which is required<br />
for the cell to enter into cycle [9].<br />
Fig. 3.17 In cell cultures, activation of a single oncogene may result in a changed morphology from<br />
“normal” (A) to “transformed” (B) and this often corresponds to a change in growth properties. Malignant<br />
transformation appears to require the co-operation of at least three genes.<br />
B<br />
B<br />
Oncogenes and tumour suppressor genes 97