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Cell Cycle Regulation and
Cancer
Cancer
• Second leading cause of disease in Western
Countries
• 1 million new cases per year in U.S.
– 500,000 per year die
• War “declared” on cancer approximately 30
years ago
• Slowly treatments are changing/improving
based upon better genetic understanding of the
varieties
Cancer Rates in US
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 risk—about 1% of total)
– Alter cellular functions
• DNA repair, cell division , apoptosis, cellular
differentiation and cell-cell contact/communication
Normal and Cancer Karyotypes
• Chromosome painting
• (a) is a normal cell, (b) is a “very messed up” cancer
cell
What is Cancer?
• Large number of complex diseases
• Behave differently depending upon cell type
from which originate
– Age on onset, invasiveness, response to treatment
• Common general properties
– Abnormal cell growth/division (cell proliferation)
• If only this is a benign tumor
• When grow in culture without contact inhibition are
referred to as transformed
– Spread to other regions of body (metastasis)
• Malignant tumors
Clonal Origin of Tumors
• Tumor arises from a single cell
• Burkitt’s lymphoma
– Translocation involving chromosome 8 (myc) and
either chromosomes 2, 14, or 22 (near an
immunoglobulin gene
– All cells from a patient have breakpoints at exactly
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)
Multistep Process
• Cancer requires mutation of multiple genes
• Age relationship with cancer consistent with this
– If one mutation caused cancer then rate would be
constant independent of age
• It increases dramatically with age…
• Delay between carcinogen exposure and onset
– 5-8 year delay between carcinogen exposure
(Hiroshima and Nagasaki) and onset of leukemia
– 15 year delay between tuberculosis X-ray treatment
and onset of breast cancer
Age and Cancer
• Note log scale for
incidence rate
Multistep Process…Continued
• Cancers often develop in progressive steps
– From mildly aberrant cells to malignant
– See figure 18-3
– Process called tumorigenesis
Tumorigenesis
of Cervical
Cancer
Properties of Cancer Cells
• Genetic instability
– Mutator phenotype
– Duplicating, losing and translocating chromosomes
or portions of them common
• Chronic myelogenous leukemia (CML)
– Chromosome 9/chromosome 22 translocation
– BCR gene fused to ABL (protein kinase)
– Mutant signal transduction protein stimulates cells
constantly to proliferate
Genome Instability
• Double minutes
(DMs)
– Miniature
chromosomes giving
many copies of rgion
• Homogeneous staining
regions (HSRs)
– Tandem gene
duplications
Chromosomal Translocation in
CML
Xeroderma Pigmentosum
• Failure to remove pyrimidine dimers from
DNA
– Excision repair defect
• Patients often develop skin cancer and must
stay out of sunlight
HFNPCC
• Hereditary nonpolyposis colorectal cancer
• Higher than normal rates of colon (first
noted) but also elevated rates of ovary,
uterine and kidney cancers
• 1/200 persons, autosomal dominant
• Eight genes associated and four involve
mismatch repair systems
HNPCC Pedigree
• Colon, Stomach endometiral, pancreatic, bladder
• Orange also other cancers, multiple slashes unknown cause
of death
Defects in Cell Cycle Regulation
• Cell cycle
• G1, S, G2, M phases
• Progression through cycle is regulated and
specific blocks or checkpoints exist
• Nondividing cell (quiescent) is in an
extended G1 phase called G0
– Cancer cells never enter G0
Cell Cycle
Cell Cycle Checkpoints
• G1/S
– Monitors cell size and for DNA damage
• G2/M
– Replication complete, DNA damage?
• M
– Spindle fibers connected, etc.?
• G0
– Does body require more of my type of cell?
Regulators of Cell Cycle
• Cyclins and cyclin-dependent kinases (CDKs)
• Cyclins synthesized and destroyed in a precise
pattern
– A cyclin bind to a specific CDKs, activating it
• Other proteins phosphorylated/activated
• CDK4/cyclinD activate transcription factors for genes
such as DNA polymerase delta and DNA ligase
• CDK1/cyclinB trigger events of early mitosis
(chromosome condensation, nuclear membrane
breakdown, etc.)
Cyclin Levels
Activation
of CDKs
Apoptosis
• Programmed cell death, cell suicide
• Pathway should be activated if “something goes
wrong”
– Especially involving DNA/chromosome damage
• Involves proteases called caspases
• Regulated by Bcl2 and BAX
– BAX homodimer promotes apoptosis, Bcl2 homodimer
blocks apoptosis
– Some cancer cells overproduce Bcl2 and are resistant to
some chemotherapies and radiation treatment
• Proteins involved in cell cycle checkpoints regulate
pathway
Control of Apoptosis
Functions of Cancer Causing
Genes/Alleles
• Many disrupt control of cell cycle
• Oncogenes
– Proto-oncogenes
• Normal genes that if mutated may act to make a cell cancerous
• Recessive, cancer causing forms active and stimulates cell division
• C-oncogenes and v-oncogenes
• Tumor suppressors
– Genes whose products act to regulate cell cycle
– Loss of gene product function contributes to cancer process
– Recessive, commonly involved with inherited risk
• About 200 proto-oncogenes and tumor suppressor genes
Oncogenes/Proto-oncogenes
• Cyclin D1 and Cyclin E are proto-oncogenes
– Often amplified or over expressed due to other
mutations (e.g. translocation) in many cancers
• cyclinD1 allows for DNA replication (S
phase)
• Over expression seems to contribute to cell’s
progression from G0 phase and begin division
ras Proto-oncogenes
• Involved in signal transduction pathway
– As are many proto-oncogene products
• ras family genes mutated in 40% of all cancers
• Involved in signal transduction pathway from
growth factor receptor to nucleus
– G protein
– Mutant form lacks GTPase activity and remains active
• See figure 18-11
Ras Pathway
• Growth factor binds receptor
• Receptor exchanges GTP for
GDP on Ras
– Ras activated
• RasRafMekMap
Kinasetranscription
factors genes turned on
Mutant Ras Protein
• Single amino
acid changes
create N-ras
and K-ras
variants
p53 Tumor Suppressor Gene
• Mutated (inactivated) in more than 50% of all
cancers
• p53 regulates (activates or represses)
transcription of more than 50 different genes
• p53 regulated by Mdm2 (prevents the
phosphorylations and acetylations that activate
inactive p53)
• Activated p53 levels rise rapidly if DNA is
damaged or repair intermediates accumulate
P53 Function
• Activated p53 acts as transcription factor to turn
on genes that
– arrest the cell cycle so DNA can be repaired
• Initiates synthesis of p21, which inhibits
CDK4/cyuclinD1 complex, blocking entry into S phase
• Genes expressed which retard rate of DNA replication
• Other products block G2/M progression
– Initiate apoptosis if DNA cannot be readily repaired
• Turns on Bax gene, represses Bcl2 gene
• Bax homodimers activate process of cell destruction
• Cancer cells lacking p53 do not initiate pathway even if
DNA/cellular damage is great
RB1 Tumor Suppressor Gene
• Retinoblastoma 1 gene
• Involved in breast, bone, lung, bladder and
retinal cancers (among others)
• Inheriting one mutated (inactivated) copy of
gene increases chances of retinoblastoma
formation from 1/14,000-20,000 to 85% (plus
increases other cancer rates)
– Loss of second copy in a cell eliminates function
– Normal cells unlikely to lose both good copies
pRB Function
• Tumor suppressor protein that controls the G1/S
checkpoint
• Found in nucleus and activity regulated by level of
phosphorylation (by CDK4/cyclinD1 complex)
– Nonphosphorylated version binds to TFs such as E2F,
inactivating them
– Free E2F and the other regulators turn on >30 genes
required for transition to S phase
Familial Retinoblastoma
Inherited Predisposition for Cancer
• About 1-2% of cancer has an inherited or
familial component
– 50 different forms known at present
• Inherited in Mendelian fashion but most all
genes/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 of such
genes
Multistep Development of Colon
Cancer
• APC loss causes cells to partially escape cell cycle
regulation, DCC seems to be involved in cell adhesion
and differentiation
Transforming Viruses
• Viruses discovered to cause cancer in animals
– Acute transforming viruses
• Commonly but not always retroviruses
– Rous sarcoma virus (RSV) discovered by Francis
Peyton Rous discovered in 1910 as a causative agent
of chicken sarcomas (solid tumors of muscle, bone or
fat)
• Many years later shown to be retrovirus
• Nobel Prize in 1966 (link of viruses to cancer)
Retroviruses
• ssRNA chromosome
• Chromosome copied to DNA by reverse transcriptase
upon entry into cell
• DNA integrated into host cell chromosome
– Provirus
• Provirus has strong promoter elements in U5 and U3
terminal sequences
– U5 expresses gag, pol and env
• Oncogenic when
– Integrate near proto-oncogene and cause inappropriate or over
expression
– Bring v-onc as part of viral chromosome
Retroviruses
• Many transforming retroviruses are defective in the
sense that one or more of gal/pol/env have been
deleted to make room for the v-onc
Viral Oncogenes
• Most v-onc genes have normal cellular counterparts
– If simply mutated to the oncogenic form and not in a
virus are called c-onc
Human Cancer-Associated
Viruses
• To date no acute transforming retroviruses have
been discovered in humans
– Viruses can contribute to but not be the sole cause 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
Human Viruses Associated With
Cancer
• Non-retroviral varieties
• Many of these v-onc genes act to stimulate the cell cycle
(viruses needs host replication apparatus to multiply
V-onc Gene Product Action
• Some v-onc gene products have their
transforming effect by binding and thereby
“taking out” certain tumor suppressor gene
products
– Cell division required to provide replication
apparatus for virus
– Bad, but does open some interesting treatment
possibilities…
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 liver
• Aflatoxin (mold on peanuts)
• UV light or ionizing radiation
– Radon gas (up to 50% of radiation exposure???)