Bm 8-9 Oncogenesis

8/12/2019 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

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Bm 8-9 Oncogenesis