Download - Bm 8-9 Oncogenesis
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Cancer is a Genetic Disease
Genome alterations
One nucleotide to large-scale chromosome
rearrangements, amplifications and
deletions
Mostly in somatic cells (unless associated
with inherited riskabout 1% of total)
Alter cellular functions DNA repair, cell division , apoptosis, cellular
differentiation and cell-cell
contact/communication
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Cancer is common
Lifetime risk of cancer in human populations is
around 1 out of 3
Each year 10 million cases are diagnosed
We have no global cure for cancer because ourcollective knowledge is complex and confused
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Cancer Stem Cells
Hot issue: to what extent is cancer (tumor growth)due to proliferation of all cells or a few special cells
(cancer stem cells)?
Hypothesis 1: all tumor cells are immortal- everycell in a tumor is the same
Hypothesis 2: only some cells immortal- special
lineage of cells (cancer stem cells) in a tumor isreally responsible for tumor growth and metastasis
To what extent should treatment focus on
targeting cancerstem cells?
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Ageing and Cancer
Cancer Cells Cancer is considered a disease of ageing because the
mutations that accumulate during ageing can
sometimes disrupt normal genetic control of cell
proliferation and cell death (apoptosis)
Ironically, these mutations make cancer cells immortal,
such that they fail to age and die
Due to weakness of selection with advanced age,
deleterious mutations accumulate. Some mutations
cause cancer, then the cancer cells cannot age and die
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The Irony of Cancer
Cancer(immortal) cells that fail to age and die
(tend to be expressed in older individuals)
Weak Selectionfails to remove mutations expressed in
older individuals in populations (higher extrinsic mortality
+ lower selection with decline in reproduction)
Mutationsin stem cells, by chance at genes
that affect cell growth, proliferation, DNA repair
Environmental assaults (oxidative stress; smoking,
pesticides, radiation) cause DNA damage, or mutationsarise from cell division in the germ line
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Once cells have become immortal, there is a
tradeoff between killing the cancer cells andaccelerating ageing in normal cells
Radiation and chemotherapy kills cancer cells but
will age normal cells (and induce mutations)
Cancer is a byproduct of ageing; yet, cancer
protection/treatment could accelerate ageing
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Clonal Origin of Tumors
Tumor arises from a single cell Burkitts lymphoma
Translocation involving chromosome 8 (myc)
and either chromosomes 2, 14, or 22 (near animmunoglobulin gene
All cells from a patient have breakpoints atexactly the same points as shown by DNA
sequence analysis Cancer cells in tumors of females all use same
X chromosome (same one in Barr body)
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Inherited Predisposition for
Cancer
About 1-2% of cancer has an inherited orfamilial component
50 different forms known at present
Inherited in Mendelian fashion but most allgenes/alleles are recessive
Second copy must be mutated in a somatic cell Called loss of heterozygosity (and loss of function)
Loss of second copy in germ line lethal RB1 and APC (lost in FAP, familial
adenomatous polyposis) are examples ofsuch genes
N l d C
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Normal and Cancer
Karyotypes
Chromosome painting
(a) is a normal cell, (b) is a very messed up
cancer cell
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Tumors arise from cells with
DNA damage or mutant DNA
that divide uncontrollably.
Cancer cells lose normal
restraints for replication ofdamaged DNA and G1/S
progression of cells with
damaged DNA.
Increased probability of tumor
progression by further genetic
change.
Role of cell division in tumor progression
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The Hallmarks of Cancer(Hanahan and Weinberg)
Tissuenvasionand
Metastasis
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Inactivated tumour
suppressor gene
Characteristics of Cancer
Activated proto-
oncogene
Oncogenes
Are a gas pedal for cell proliferation
A mutation results in permanent activation since
mutations are DOMINANT.
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Growth factors (I)
Growth factor receptors (II)
Signal-transduction proteins (III)
Transcription factors (IV)
Pro- or anti-apoptotic proteins (V)
Cell cycle control proteins (VI)
DNA repair proteins (VII).
Mutations in I-IV generally give rise to
oncogenes.
Class VI proteins act as tumour
suppressors; mutations in these act
recessively to release cells from control
and surveillance, increasing the probabilityof cancer developing.
7 proteins controlling cell growth
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For cancer: two classes of cellular
genes are targets for mutations
PROTO-ONCOGENES
TUMOUR SUPRESSOR GENES
The vast majority of these mutations are somatic
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Types of Mutations that lead to Cancer
Mutations to proto-oncogenes --> leading tooncogenes, or insertions of oncogenes(genesinvolved in cell growth and development; growth factors,growth factor receptors etc)
Mutations to tumor suppressor genes (e.g. Trp53;Genes whose products block abnormal growth)
Mutations to DNA repair genes (mismatch repairetc)
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Oncogenes are identified through their
dominant transforming effects
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Human Cancer-Associated
Viruses
To date no acute transforming retroviruses
have been discovered in humans
Viruses can contribute to but not be the solecause of human cancer
However, up to 15% of all cancers have a viral
association Papillomaviruses HPV 16 and 18, hepatitis B virus,Epstein-Barr virus, Human T-cell leukemia virus are
examples of cancer-associated viruses
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Human Viruses Associated
With Cancer
Non-retroviral varieties
Many of these v-oncgenes act to stimulate the cell
cycle (viruses needs host replication apparatus to
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Generalization
RNA viruses activate oncogenes
DNA viruses negate tumor suppressors
E i t l A t d
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Environmental Agents and
Cancer
Natural and man-made carcinogens Chemicals, radiation, chronic infections
30% of cancer deaths associated with cigarettes
Seems to preferentially mutate proto-oncogene and
tumor suppressor genes
Red meat consumption
How cooked?
Alcohol-based inflammation of the liverAflatoxin (mold on peanuts)
UV light or ionizing radiation
Radon gas (up to 50% of radiation exposure???)
E l f O
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Examples of Oncogenes
RAS- activated in many cancers (colon)
c-MYCover-expressed in colon cancer
(amplified in lung, rearranged in lymphoma)
RET- MEN 2a
MET- hereditary papillary renal cancer
CDK4- familial melanoma
BCR/ABL- chronic myelogenic leukaemia
BCL2 - follicular lymphoma