Cancer Genetics Regulated and unregulated cell proliferation L2 Flashcards
CDK- complexes help?
- CDK-cyclin complexes help regulate cell
cycle progression (checkpoints)
Malignant tumours of cancers are:
AGGREGATEs of cells,
DESCENDED from an INITIAL ABERRANT FOUNDER.
Virtually ALL CANCERS of SOMATIC CELLS arise
- due to a
SERIES OF MUTATIONS that ACCUMULATE
How?
2. Some mutations ALTER ACTIVITY OF A GENE
3., while
others ELIMINATE THE GENE’S ACTIVITY.
Cancer promoting mutations: 3
- INCREASE ability of cell to PROLIFERATE
2.DECREASE susceptibility of CELL TO APOPTOSIS
- INCREASE general MUTATION RATE in cell OR it LONGEVITY
Metastatic breast cancer …
- Metastatic breast
cancer masses (white protrusions) growing on a human liver (crowding out
normal cells) - Light Micrograph -
light pale-stained
cells are cancer cells
invading regions of
the darker normal
liver cells
MANY DIFFERENT CELL TYPES CAN BE CONVERTED TO MALIGNANT STATE …
Is there a common theme or does each arise in
different way?
- General way - due to accumulation of mutations -
single cell proliferates out of control - Cancer cell isolated state where they operate
without external constraint - “deaf” to signals from neighbouring cells to stop dividing or undergo apoptosis
Alfred Knudson (1971) proposed Rb results from two separate
genetic defects, both necessary for cancer to develop… STEPS = 5
- Rarely, a single cell undergoes 2 somatic mutations,…
- …resulting in a single tumour for example, in one eye.
- A predisposed person inherits one mutation.
- some cells undergo a single somatic mutation that produces cancer.
- because only a single mutation is required to produce cancer, the likelihoof of its occuring twise (in both eyes for example), INCREASES.
RETINOBLASTOMA in Children…
- Rare for a single
cell in one eye to
undergo two successive
mutations,
- Retinoblastoma is
rare and typically
develops in only
one eye. - Children with bilateral
retinoblastoma inherit
one of the two
mutations, and so
every cell contains this
initial mutation.
- All that
is required for cancer
to develop is for one
eye cell to undergo
the second mutation.
Clonal evolution of Tumors STEPS: 4
- A cell is predisposed to proliferate at an abnormally high rate.
- a 2nd mutation causes the cell to divide even more RAPIDLY
- After 3rd mutation, the cell undergoes STRUCTURAL CHANGES.
- A 4th mutation causes the cell to divide UNCONTROLLABLY and invade other tissues.
Cancer is the result
of a multistep process that = 5
- requires several mutations.
- Cells of the CLONE
divide more
RAPIDLY ; - they soon OUTGROW other cells.
- More AGRESSIVE PROLIFERATION
- ADVANCED CANCER CELLS tend to have
DEFECTIVE DNA REPAIR MECHANISMS
Colorectal cancer… STEPS = 9
- NORMAL CELL - loss of normal TUMOUR SUPPRESSOR gene ‘APC’
- A ‘polyp’ (small growth) forms on the COLON WALL
- A BENIGN, precancerous tumour grows.
- ACTIVATION OF ONCOGENE ras
- and ADENOMA (benign tumour) GROWS
- Loss of tumour - SUPPRESSOR GENE ‘p53’
- a CARCINOMA (malignant tumour) DEVELOPS
- Other changes: loss of ANTIMETASTASIS GENE
- The CANCER METASTASIZES (spreads to other tissue through BLOODSTREAM)
Mutations in multiple
genes contribute to the
progression of
COLORECTAL CANCER
Several distinct changes
seen in progression of
tissues from normal to
malignant state (10-35
years).
Common
mutational events in
progression
EXPLAIN Cancer cells exhibit aneuploidy -
EXAMPLE?
- Cancer cells exhibit aneuploidy
- possess chromosome
abnormalities, extra, missing and chromosome
rearrangements. - Colon cancer cell, mar = major chromosome rearrangements
Mutations in cancer cells
Two general kinds of mutations associated with tumours
list them:
- Proto-oncogene mutations
2.Tumour Suppressor gene mutations
EXPLAIN PROTO-ONCOGENE MUTATIONS
- Mutation only required in one allele for tumour
formation
(Dominant-acting mutation) - The gene in its normal mutated form = ONCOGENE
EXPLAIN Tumour Suppressor gene mutations:
For cancer to occur, both alleles of gene must be
mutated and have no activity
(Recessive-acting
mutation)
Oncogenes: Increase growth and division EXPLAIN - 2
- Proto-oncogenes normally produce factors that stimulate cell division
- MUTANT ALLELES (ONCOGENES) tend to be DOMINANT; one copy of the mutant is sufficient to INDUCE EXCESSIVE CELL PROLIFERATION.
Tumour-suppressor genes: Decrease growth and division EXPLAIN - 2
- Tumour-suppressor genes normally produce factors that INHIBIT CELL DIVISION
- Mutant alleles are RECESSIVE (both alleles must be mutated to produce Excessive cell proliferation)
EXPLAIN
Loss of heterozygosity – Inactivation of remaining WT allele
People heterozygous for tumour-suppressor gene are predisposed to CANCER.
(Aa) - this genotype is heterozygous for a tumour suppressor gene.
CHROMOSOME DELETION
leads to
(_a) loss of wild-type allele, in this case through chromosome deletion …CAUSES LOSS OF TUMOUR SUPPRESSOR ACTIVITY.
ONCOGENES
define PROTO-ONCOGENES:
- encode proteins that regulate normal cell proliferation
(eg. Signaling, control of
cell cycle, or apoptosis)
- Either positive or negative regulators
EXPLAIN proto-oncogenes
…Accumulate mutations to become oncogenes….4 WAYS
Accumulate mutations to become oncogenes:
1.– POINT MUTATIONS alter structure/function (eg. ras)
2 – LOSS OF PROTEIN domains resulting from DELETION
3.– GENE FUSIONS, often from TRANSLOCATION (eg. Bcr-ABL)
- – MUTATION may result in MIS-EXPRESSION (eg.
Bcl2-enhancer)
ras signal transduction pathway = 4
- Binding of growth factor to the receptor causes a conformational change and the addition of phosphate groups.
- Adaptor molecules bind to the receptor and link to Ras.
Ras binds GTP and is activated. - Activated Ras activated Raf, which activates MEK, which activates MAP kinase.
- Activated MAP KInase moves into the nucleus and activates transcription factors.
ras signal transduction pathway MUTATED
95% of pancreas tumours and 45% of colorectal tumors
- Point mutation of an intracellular signal transducer.
- Single base pair mutation of ‘ras’ gene creates oncoprotein - bladder cancer.
- Ras: G-protein in signal transduction, normally functions between active and inactive states
- Mutation causes onco-protein to always bind
GTP….always active - Continuously propagates cell proliferation signal
INACTIVE RAS TP ACTIVE RAS
- Inactive Ras
- GDP
- GTP — Sos interaction stimulates GDP-GTP exchange. —GDP. - Activate Ras —GTP
- Ras oncoprotein is blocked here. SIGNAL REMAINS ON.
- does not go back to INACTIVE Ras. - Continuously activates downstream serine/threonine kinase.
EXPLAIN Structurally altered oncoprotein caused by gene fusion
- eg Philadelphia chromosome (chronic myelogenous leukemia)
Translocation between chromosomes 9 and 22 - Cause fusion of 2 genes - BCR1 and c-ABL. The c-ABL proto-oncogene
encodes a protein kinase that participates in the signal transduction
pathway (a growth factor - cell proliferation). - bcr1-c-abl fusion onco-protein permanent protein kinase activity
SLIDE 17
Some oncoproteins are identical in structure to normal proteins, but the
mutation causes the protein to be mis-expressed,
eg B cell tumour
No protein fusion rather chromosomal rearrangement causes
gene near one
breakpoint to be turned on in wrong tissue
Explain Follicular Lymphoma…4
1 - translocation between chromosomes 14 and 18.
2.Near chr 14 is a transcriptional enhancer for a B cell-specific gene.
- Enhancer element fused with bcl-2 gene, negative regulator of apoptosis.
- Large amounts bcl-2 expressed in B cells, blocks apoptosis, these B cells have an unusually long life in which to accumulate mutations that promote
cell proliferation and Follicular lymphoma
Explain: Some tumour-suppressor genes encode
= 3
- negative
regulators of cell cycle, eg the Rb protein. - positive regulators of apoptosis, eg.
P53 - Others are indirect players, normal role in the
repair of damaged DNA or in controlling cellular
longevity
Tumour-suppressor genes
Knockout of protein : p53
= 7
- Knockout of protein: that inhibits cell proliferation and
promotes apoptosis - p53 (refers to protein with mass of 53 kDa)
eg of tumour suppressor gene, mutations associated with many types of tumours - ~50% of all tumours have mutated form
- normal p53 is a transcription factor that is activated in response to DNA damage
- Prevents cell cycle progression to allow repair
- Causes severely damaged cells to undergo
apoptosis - mutated form eliminates apoptotic response, allowing
damaged cells to survive, elevating mutation level
Viruses are associated with some cancers:
RETROVIRUS INSERTION to RNA into CELL…4
- A retrovirus inserts its RNA into the cell, the viral RNA undergoes reverse transcription and inserts into the host Chromosome next to a proto-oncogene.
- when the VIRUS REPRODUCES, the PROTO-ONCOGENE is INCORPORATED into the VIRUS.
- In repeated rounds of VIRAL infection and, REPRODUCTION, the proto-oncogene becomes rearranged or Mutated or Both, …
4…. producing an oncogene that is INSERTED back into the HOST CHROMOSOME.
Viruses are associated with some cancers:
RETROVIRUS INFECTS CELL…3
- A retrovirus infects a cell..
- …and the provirus inserts near a proto-oncogene.
- the strong VIRAL PROMOTER stimulates over-expression of the PROTO-ONCOGENE.
Retroviruses cause cancer by: 2
1 -mutating and rearranging proto-oncogenes
2 - inserting strong promoters near protooncogenes
Viruses are associated with some cancers: EXPLAIN
Eg. Human papillomavirus (DNA virus) & cervical cancer
- 70% cervical cancer
- inactivates Rb and p53
- Epstein-Barr virus & Burkitts lymphoma
- Human T-Lymphotropic Virus (HTLV-1) & T cell leukemia (retrovirus)
Cancer complexities:
- Numerous mutations promote tumour growth.
- Mutations alter normal processes that govern
proliferation and apoptosis - Different cancers have different phenotypes
with respect to rate of proliferation, ability to
metastasize, etc
Different cancers have different phenotypes ……Differences caused by: 2
- differences in somatic cell progenitor
- differences in types and severity of mutations
Main events contributing to tumour formation:
Increased cell proliferation and cell survival (decreased apoptosis)
Main events contributing to tumour formation: pathway
Gain-of-function dominant oncogene mutations
1 - Mitogen pathway
- CELL PROLIFERATION
- LOSS OF FUNCTION MUTATIONS IN TUMOUR-SUPPRESSOR GENES
- GROWTH INHIBITOR PATHWAYS
- p53 pathways
(irreparable DNA damage)
LOSS OF FUNCTION MUTATIONS IN TUMOUR-SUPPRESSOR GENES
- Irreparable DNA damage
- p53 pathways + Apoptosis
- APOPTOSIS
- survical factor pathways
Hanahan and Weinberg (2000) Cell. Jan
7;100(1):57-70.
hallmarks of cancer
> 15000 citations!!
~30 years in the making
6 major hallmarks of cancer:
- Evading apoptosis
- Self-sufficiency growth signals
- insensitivity to anti-growth signals
- Tissue invasion and metastasis
- Limitless replicative potential
- sustained angiogenesis
6 major hallmarks of cancer: EXPLAIN WHY
Most, if not all, cancers have acquired the same set of functional capabilities, albeit through various mechanistic strategies
Understanding Self Sufficiency in growth signals = 5
- Normal cells take up mitogenic signals from
neighbours, but tumor cells generate their own
growth signals. - Eg. Platelet derived growth factor made by glioblastoma or tumor growth factor alpha
by sarcoma - Tumor cells overexpress receptors in permanently active forms
- Tumor cells have mutations in the downstream signalling molecules.
- Eg. Ras-MAPK pathway
mutated in 25% of all cancers
explain Insensitivity to anti-growth signals
- Normal cells can be pushed into a quiescent/differentiated state.
- In G1, cells constantly monitor the environment to make decisions about division
Insensitivity to anti-growth signals:
For cells to maintain anti-differentiation: 3
1 – In embryonic development Myc-Max
transcription factor keeps cells pluripotent
2 – With maturity, cells make Mad-Max and this
triggers differentiation
3 – Cancers reactivate Myc, making more Myc-Max again
UNDERSTANDINGEvading apoptosis = 3
- Cell cannot undergo apoptosis, much longer
lifetime, accumulate proliferation-promoting
mutations - Sorts of damage taking place in tumour cell would otherwise induce the self-destruct pathway
- Tumour cells would not be able to survive unless
apoptosis is prevented by mutations
What are The first 3 hallmarks:
- self-sufficiency in growth signals,
- ignoring
anti-growth signals - and evading apoptosis
What are the second 3 hallmarks:
- Sustained angiogenesis
- limitless replicative potential
- tissue invasion and metastasis
explain Tissue invasion and metastasis: 3
- Changing physical coupling of tumor cells to the stroma:
activation of extracellular
proteases - Epithelial to mesenchymal transition is key
- Mesenchymal cells
lose E-cadherin –the molecule that bridges cell-cell contacts
explain Limitless replicative potential:
- 80-90% of cancers
upregulate telomerase
– the enzyme that lengthens telomeres
Explain SUSTAINED ANGIOGENESIS:
- All cells in a
tissue need to be ~100µm from a blood vessel - Without blood:
hypoxia and nutrient starvation
UPDATED Hallmarks of Cancer
10 hallmarks in total
THE + 4 Hallmarks ..
EMERGING HALLMARKS
- Deregulating cellular energetics
- Avoiding immune destruction
ENABLING CHARACTERISTICS
3. Tumour promoting inflammation
- Genome instability and mutation
explain Avoiding immune destruction:
emerging hallmarks
- Evade detection and attack by the immune system
explain Deregulating cellular energetics…
emerging hallmarks
- Alter metabolism to
support rapid growth
explain genome instability and mutation
enabling characteristics
- Accumulate genetic
mutations that drives further cancer development
explain tumour promoting inflammation:
enabling characteristics
1.Chronic inflammation supports cancer growth
