Adapted from The Biology ofCancer

First Edition

Chapter 3, 4 & 7

Copyright © Garland Science 2007

Robert A. Weinberg

Karobi Moitra (Ph.D)Karobi Moitra (Ph.D)NCI Frederick , NIHNCI Frederick , NIHCancer Inflammation ProgramCancer Inflammation ProgramHuman Genetics SectionHuman Genetics SectionFrederick MDFrederick MD..

Tumor VirusesOncogenes &Tumor Supressor genes

Figure 3.1 The Biology of Cancer (© Garland Science 2007)

Peyton Rous and Rous Sarcoma Virus (RSV)

1910 1966

Figure 3.2 The Biology of Cancer (© Garland Science 2007)

1909 Rous’s Protocol for inducing breast sarcomas in chicken

Viruses can cause cancer in chickens !

Figure 3.4a The Biology of Cancer (© Garland Science 2007)

The Virion (virus particle) of RSV and other related viruses:RNA viruses (retroviruses) can cause cancer

Figure 3.19 The Biology of Cancer (© Garland Science 2007)

Structure of the RSV genome

ALV = Avian leukosis virus Oncogene

The Double Helix

RNA vs DNA

Figure 3.4a The Biology of Cancer (© Garland Science 2007)

The Virion (virus particle) of RSV and other related viruses:RNA viruses (retroviruses) can cause cancer

RNA to DNA

Reverse transcriptionwith the enzyme

reverse transcriptase

The flow of genetic information- the central dogma

Figure 3.4b The Biology of Cancer (© Garland Science 2007)

Murine (mouse) Leukemia Virus particles budding from an infected cell

Figure 3.7a The Biology of Cancer (© Garland Science 2007)

Normal cells can be converted into tumor cells (transformation)

Figure 3.5 The Biology of Cancer (© Garland Science 2007)

An RSV induced Foci

Normal cells can be converted into tumor cells (transformation) :RSV can transform infected cultured cells (in a petri dish)

CALTECH:Dulbecco,Rubin & Temin

Some viruses can transform normal cells

1966Nobel prize in

Physiology and medicine

1910

Figure 3.9a The Biology of Cancer (© Garland Science 2007)

DNA Viruses can also induce cancer

Shopes virus Richard Shope

Figure 3.9b The Biology of Cancer (© Garland Science 2007)

HPV = Human papilloma virus - A DNA tumor virus

Table 3.1 The Biology of Cancer (© Garland Science 2007)

Oncogenes were first discovered in virusesand called v-oncs , viral oncogenes

Oncogenes &Proto-oncogenes

Genes and Cancer

Chromosomesare DNAmolecules

Heredity

RadiationChemicals

Viruses

Chemicals (e.g., from smoking), radiation, viruses, andheredity all contribute to the development of cancer by

triggering changes in a cell’s genes

Normal cellular genes with the potential to become oncogenesare called proto-oncogenes

Oncogenes or tumor genes are genes with potential properties for theinduction of neoplastic transformation

(either in natural or experimental conditions)

(Duesberg 1980)

Proto-oncogene Oncogene

Receptor

Normal Growth-Control Pathway

DNA

Cell proliferation

Cell nucleus

Transcriptionfactors

Signaling enzymes

Growth factor

Proto-Oncogenes and Normal Cell Growth

Oncogenes are related to normal genes called proto-oncogenes that encode components of the cell’s normalgrowth-control pathway. Some of these components are growth factors, receptors, signaling enzymes, andtranscription factors. Growth factors bind to receptors on the cell surface, which activate signaling enzymesinside the cell that, in turn, activate special proteins called transcription factors inside the cell’s nucleus. Theactivated transcription factors “turn on” the genes required for cell growth and proliferation.

Mutated/damaged oncogene

Oncogenes accelerate cell growth and division

Cancer cell

Normal cell Normal genes regulate cell growth

Oncogenes are genes whose PRESENCE incertain forms and/or overactivity canstimulate the development of cancer.

Oncogenes or tumor genes are genes with potential properties for theinduction of neoplastic transformation

(either in natural or experimental conditions)

(Duesberg 1980)

The word oncogene comes from the word ‘onkos ‘ meaning tumor

When a proto-oncogene becomes activated it iscalled an oncogene

Proto-oncogene Oncogene

When an oncogene becomes activated it mightcause cancer

Proto-oncogene -> oncogene -> other steps -> cancer

Activation of Oncogenes

1. Mutation

a. Insertional mutagenesis

b. Point mutagenesis

2. Amplification

3. Translocation

Mutation : A mutation is a permanent change inthe DNA sequence of a gene. Mutations in agene's DNA sequence can alter the amino acidsequence of the protein encoded by the gene.

Figure 3.23b The Biology of Cancer (© Garland Science 2007)

ALV provirus may become integrated with the c-myc oncogene

ALV switches on c-myc

1a. Insertional Mutagenesis

1b. Mutagenesis of oncogenes

Altered polypeptides produced by mutant oncogenes could berelated to the origin of some human tumors

Activation of oncogenes

Figure 4.10 The Biology of Cancer (© Garland Science 2007)

Mutation responsible for H-ras oncogene activtion

Human bladder cancer oncogene - 12th codon of H-ras ,mutation converts glycine codon to valine codon

Activation of oncogenes

2. Amplification of oncogenes

Activation of oncogenes

More than one copy of a gene:Amplification

Figure 4.11a The Biology of Cancer (© Garland Science 2007)

The N-myc gene is often amplified in human childhoodneuroblastomas

FISH - showing amplification of N-myc to produces HSR’shomogeneous staining regions(chromosome 2)

Activation of oncogenes

How are oncogenes amplified?

Double minute chromosomes

Activation of oncogenes

3. Translocation

A karyotype is the number and appearanceof chromosomes in the nucleus of a

eukaryote cell

A chromosome translocation is a chromosomeabnormality caused by rearrangement of partsbetween nonhomologous chromosomes. A genefusion may be created when the translocationjoins two otherwise separated genes, theoccurrence of which is common in cancer.

Figure 4.13a The Biology of Cancer (© Garland Science 2007)

Burkitts lymphoma t(8;14) the c-myc gene is placed under the control of the enhancer sequence of an immunoglubulin gene

Figure 4.15a The Biology of Cancer (© Garland Science 2007)

Reciprocal translocations between human Chr 9 (abl) and 22 (bcr)

Fusion protein

Bcr-abl oncogene formation gives rise to acute lymphocytic leukemia (ALL),chronic myelogenous leukemia (CML) or chronic

neutrophillic leukemia (CNL)

Activation of Oncogenes

1. a. Insertional mutagenesis

b. Point mutagenesis

2. Amplification

3. Translocation

Tumor Suppressor Genes

Tumor Suppressor Genes

Tumor suppressor genes are normal genes whose ABSENCE can lead to cancer

i.e. Tumor suppressor genes protect the cell

Tumor Suppressor Genes - Tumor suppressor genes are normal genes whose ABSENCE can lead to cancer

i.e. Tumor suppressor genes protect the cell

Normal genes prevent cancer

Remove or inactivatetumor suppressor genes

Mutated/inactivatedtumor suppressor genes

Damage to both genes leads to cancer

Cancer cell

Normal cell

If a pair of tumor suppressor genes are eitherlost from a cell or inactivated by mutation,their functional absence might allow cancerto develop

Tumor Suppressor GenesAct Like a Brake Pedal

Tumor SuppressorGene Proteins

DNACell nucleus

Signalingenzymes

Growth factor

Receptor

Transcriptionfactors

Cell proliferation

Tumor suppressor genes are a family of normal genes that instruct cells to produce proteins that restrain cell growth and division. Since tumorsuppressor genes code for proteins that slow down cell growth and division, the loss of such proteins allows a cell to grow and divide in anuncontrolled fashion. Tumor suppressor genes are like the brake pedal of an automobile. The loss of a tumor suppressor gene function is likehaving a brake pedal that does not function properly, thereby allowing the cell to grow and divide continually.

Tumor suppressors act similar to the ‘brakes’ of a car (analogy)

p53 Tumor Suppressor ProteinTriggers Cell Suicide

Normal cell Cell suicide(Apoptosis)

p53 protein

Excessive DNA damage

One particular tumor suppressor gene codes for a protein called “p53” that can trigger cell suicide (apoptosis). In cellsthat have undergone DNA damage, the p53 protein acts like a brake pedal to halt cell growth and division. If the damagecannot be repaired, the p53 protein eventually initiates cell suicide, thereby preventing the genetically damaged cellfrom growing out of control.

pRB - Tumor suppressor gene

From R Bernards

Petite arm(small)

NLM

Figure 7.4b The Biology of Cancer (© Garland Science 2007)

Retinoblastoma occurs when pRB is mutated (inactivated)or sometimes deleted

Figure 7.7 The Biology of Cancer (© Garland Science 2007)

Inherit mutant allele

Figure 7.10 The Biology of Cancer (© Garland Science 2007)

Deletion of a part of Chromosome 13 in a retinoblastoma patient

Tumor suppressor genes are normal genes whose ABSENCE can lead to cancer

Oncogenes or tumor genes are genes with potential properties for theinduction of neoplastic transformation either in natural

or experimental conditions (Duesberg 1980)

“Never, never, never give up” Winston Churchill

1966Nobel prize in

Physiology and medicine