Oncogenes, tumor suppressor
genes and the hallmarks of
cancer
Klas Wiman
Dept. of Oncology-Pathology
Cancer Center Karolinska (CCK)
Klas.Wiman@ki.se
What is a cancer cell?
How do cancer cells differ from
normal cells?
How do normal cells become cancer
cells?
Tumor development
A multistep process with similarities to Darwinian
evolution
Stepwise accumulation of genetic alterations, each
conferring some type of growth advantage
Tumors acquire a similar set of functional capabilities
but the molecular mechanisms can differ
Six Hallmarks of Cancer
Hanahan & Weinberg, Cell 2000
Genes involved in tumor development
• Oncogenes -- drive tumor growth
• Tumor suppressor genes -- prevent tumor growth
• DNA repair genes -- maintain intact DNA
What is an oncogene?
A gene that drives tumor growth when
illegitimately activated, for example due to
overexpression or mutation
Figure 3.4a The Biology of Cancer (© Garland Science 2007)
Acute or rapidly transforming RNA tumor viruses
Rous Sarcoma Virus (RSV)
Avian Myeloblastosis Virus (AMV)
Simian Sarcoma Virus (SSV)
Induce tumors with short latency
Carry an oncogene (v-onc)
RSV
LTR
LTR
gag
pol
env
src
src is the v-onc gene, required for transformation
Retroviral oncogenes are derived
from cellular genes
 Retroviral oncogenes have counterparts in
normal DNA, so called cellular oncogenes
or proto-oncogenes
 Cellular oncogenes genes can sometimes be
”captured” by a virus and become a viral
oncogene
Viral oncogenes (v-onc) are different from
cellular proto-oncogenes in two ways
1. They carry mutations and/or deletions, resulting
in a mutant and/or truncated protein
2. Expressed at high levels from the proviral LTR;
expression no longer tightly controlled
Figure 4.14 The Biology of Cancer (© Garland Science 2007)
Oncogenes promote tumor growth
their protein products mediate signal transduction from the outside
of the cell to the nucleus
sis (PDGF-B)
erbB
Ras
Raf
cytoplasm
Myc
pRb
p53
nucleus
Classification of oncogenes
1.
2.
3.
4.
5.
Growth factors
Growth factor receptors
Signal transducers
Nuclear oncoproteins
Anti-apoptotic regulators
Myc
 First identified as a retroviral oncogene (MC29)
 Gene family: c-myc, N-myc, L-myc
 c-myc activated by chromosomal translocation in
Burkitt lymphoma (BL)
 Transcription factor that binds DNA
 Regulates genes involved in cell cycle
progression, protein synthesis, metabolism
Burkitt lymphoma (BL)
• Childhood lymphoma
• All BL carry characteristic reciprocal chromosomal
translocations involving chromosome 8 and one of the
three immunoglobulin loci on chromosomes 14 (IgH),
2 (kappa) and 22 (lambda)
• c-myc localized near the chromosomal breakpoint on
chromosome 8
• Constitutive expression of c-myc driven by Ig
enhancer sequences
Figure 4.13a The Biology of Cancer (© Garland Science 2007)
Figure 4.13b The Biology of Cancer (© Garland Science 2007)
N-myc gene amplification in
neuroblastoma
40% of advanced neuroblastomas
Up to 150 copies of N-myc
Associated with bad prognosis
Also in astrocytoma, retinoblastoma, small
cell lung carcinoma
Figure 4.11a The Biology of Cancer (© Garland Science 2007)
Figure 4.11b The Biology of Cancer (© Garland Science 2007)
Myc-Max regulates transcription of genes
that stimulate cell growth
Max
Myc
Sin3 Mad
Max
Repression
Transactivation
+
CACGTG
Growth-promoting genes:
cell cycle, protein synthesis
metabolism
Activation of c-myc in human tumors
Burkitt lymphoma
reciprocal chromosomal
translocations (t8;14, t2;22),
mutations at Thr-58, Ser-62
Breast cancer
Gastrointestinal cancer
Myeloid leukemia
gene amplification (17-32%)
gene amplification (30%)
gene amplification (double minutes)
Prostate cancer, melanoma,
multiple myeloma
overexpresson, correlates with
advanced disease
The Philadelphia chromosome:
activation of c-abl by a t(9;22)
translocation
• t(9;22) is found in 90% of CML, also in ALL
• The chromosomal fusion gives rise to a bcr-abl
fusion protein, p210, with constitutive tyrosine
kinase activity
Figure 2.23a The Biology of Cancer (© Garland Science 2007)
Figure 2.23b The Biology of Cancer (© Garland Science 2007)
Figure 4.15a The Biology of Cancer (© Garland Science 2007)
Two different mechanisms for
oncogene activation by chromosomal
translocation
1. Overexpression of an intact gene
(c-myc, BL)
2. Creation of a fusion protein with altered
properties (bcr-abl, CML)