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Cancer and the Cell Cycle
Chapter 11
Central Points (1)
 Cancer involves uncontrolled cell division
 Mutations in certain types of genes may lead to
cancer
 Cancer is a disease of the cell cycle
 Breast cancer is a common type of cancer
Central Points (2)
 Chromosomal changes often a cause of
cancer
 Environmental causes of cancer are being
studied
 Lawsuits have addressed smoking as a
cause of cancer
11.1 What Is Cancer?
 Complex disease, affects many different cells
and tissues
 Characterized by uncontrolled cell division
 Malignant cells spread, or metastasize, to other
sites within the body
 Unchecked growth may result in death
Cancer Cells
Animation: How Cells Reproduce (cancer
cells)
Cancer Deaths
 Reduced deaths from infectious disease,
increases in life span in U.S.
 Cancer a major cause of illness and death
 Risk age-related, living longer, increased risk of
cancer
 Pedigrees suggest some cancer has genetic
component
Breast Cancer Pedigree
Cancer Is a Genetic Disorder
 Mutation: change in genetic makeup and cause
cells to become cancerous
 Carcinogens and certain behaviors increase
rate of mutations and cancer risk
 Not all tumors are cancerous, benign tumors,
increase in size, but do not metastasize
Characteristics of Cancer
 Tumors begin with a single cell that reproduces
by mitosis
 Cells in tumors divide continuously
 Metastasis: Process in which cells are invasive
and move to other sites in the body
11.2 How Is Genetics Involved?
 Two classes of genes: Oncogenes and tumor
suppressor genes
 Proto-oncogenes: control cell division
 Tumor suppressor genes turn off cell division
 Mutated alleles, oncogenes, and tumor suppressor
genes cause cells to divide uncontrollably
Cancer-Causing Mutations
 Exposure to environmental agents, virus, or
lifestyle changes may cause a mutation
 Certain virus infections can transform the cell
 Human papillomavirus (HPV): Viral proteins
interact with cell proteins, cause cervical cancer
 Mistakes in DNA replication also cause mutations
11.3 Cell Cycle
 Interphase: time between divisions
• G1, S, and G2
 Mitosis: division of the chromosomes
 Cytokinesis: division of the cytoplasm
 Checkpoints in the cell cycle regulate cell division
G2/M checkpoint
4
Cell
division
3
DNA
repair
1
Mitosis
G2
G1
Cell
grows,
doubles
in size
S
2
Chromosome
duplication
G1/S
checkpoint
Stepped Art
p. 181
Interphase
 G1
• Begins immediately after division
• New organelles formed
• End of G1, cell has doubled in size
 S phase
• Duplicate copy of each chromosome
 G2 phase
• Cell prepares to begin mitosis
Stages of Mitosis
Stages of Mitosis: Prophase
 Replicated chromosomes condense and
become visible
 46 chromosomes composed of two sister
chromatids
 Nuclear membrane breaks down
 Spindle fibers form
Prophase
Stages of Mitosis: Metaphase
 Chromosomes, with spindle fibers attached,
move to middle of cell
Stages of Mitosis: Anaphase
 Centromeres divide
 Converts each sister chromatid to a chromosome
 Chromosomes migrate to opposite ends of cell
 Complete set of 46 chromosomes at each end of
cell
Anaphase
Stages of Mitosis: Telophase
 Final stage of mitosis
 Chromosomes unwind
 Spindle fibers break down
 Nuclear membrane re-forms
Cytokinesis: Last Stage of Cell Cycle
 Cell membrane constricts and divides cell into
two daughter cells with 46 chromosomes
Identical Daughter Cells
Regulation of Cell Cycle
 G1/S checkpoint
 G2/M checkpoint
 Tumor suppressor genes and proto-oncogenes
control these checkpoints
• Tumor suppressor genes turn off or decrease rate
of cell division
• Proto-oncogenes turn on or increase rate
Signal Transduction
 In normal cells, signals from outside cell can
• Activate tumor suppressor genes (turning off cell
division) or
• Activate proto-oncogenes (turning on cell
division)
 Signals can be proteins, hormones, or nerve
signals
 May include steroids, pollutants, and other
molecules
Process of Signal Transduction
 Signal binds to a receptor in plasma membrane
 Binding sets off series of interactions inside cell
 Signal molecule may remain outside cell
 Binding of signal changes shape of receptor and
allows it to transmit signal to other proteins
 May alter gene expression
Outside cell
Signal molecule
Signal–receptor
binding
Receptor
Plasma
membrane
Cytoplasm
Protein
molecules
Cellular
response
Nucleus
Changes in gene
expression
Stepped Art
p. 183
Signal Transduction and Cancer
 Cancer related to loss of cell cycle control
 Often involves change in signal transduction
pathway
 Or change in cell cycle control machinery
Proto-Oncogene RAS (1)
 Produces RAS protein that:
•
•
•
•
•
•
Attaches to inside of plasma membrane
Is part of a pathway that turns on cell division
Is signaled by growth factors from outside the cell
Changes shape and switches on when activated
Transfers signal to another protein in pathway
Changes shape again after signal transmitted,
switches off (inactive)
Proto-Oncogene RAS (2)
 RAS mutations in many types of cancer, including
colon, lung, pancreatic, and stomach cancer
 Mutant RAS stuck “on” and produces
uncontrolled cell division
Animation: How Cells Reproduce (cell
cycle)
11.4 Breast Cancer
 Most common form of cancer in U.S. woman
 > 40,000 die, 178,000 new cases per year
 Environmental factors involved
 Mutations in BRCA1 and BRCA2 predispose
women to breast cancer and ovarian cancer
BRCA1 (1)
 In 1970s, Mary-Claire King and colleagues
analyzed the pedigrees of 1,500 families
 ~15% families, multiple cases of breast cancer
 Tested the blood of 100s of families to locate a
genetic marker for breast cancer
 Testing difficult, most breast cancers occur at
random
BRCA1 (2)
 In 1980s, used DNA markers and polymerase
chain reaction (PCR) for screening
 In 1990, after testing 100s of markers, found link
• D17S74 marker, chromosome 17
 Dominantly inherited, carry one mutant copy gene,
develop breast cancer if other copy mutates
• 82%: Second mutation = breast cancer
• 44%: Second mutation = ovarian cancer
BRCA1
BRCA2
 Discovered in 1995, chromosome 13
 When mutated, causes breast cancer susceptibility
 Rare in general population, < 1%
• Some populations much higher
• Ashkenazi Jews’ combined frequency of BRCA1
and BRCA2 is 2.5%
BRCA2
Breast Cancer in Men (1)
 Frequently diagnosed in later stages, often more
difficult to treat
 In U.S., ~1% of breast cancers in males
 Parts of Africa, rates significantly higher
 Egypt: 6% of all cases
 Zambia: 15% of all cases
Breast Cancer in Men (2)
 Ashkenazi Jews and black males have higher
rates of breast cancer
 Risk factors
• Age
• Family history of breast cancer
• Occupational exposure to heat, gasoline, or
estrogen-containing creams in soap and perfume
industry
11.5 Other Genetic Causes of Cancer
 Changes in number and structure of
chromosomes are common feature of cancer cells
 Down syndrome individuals: 18–20X more likely to
develop leukemia
 Connection not yet been discovered
Translocations and Cancer
 Philadelphia chromosome, between
chromosomes 9 and 22, common in:
• Chronic myelogenous leukemia (CML)
• Others, including acute myeloblastic leukemia
 Burkitt’s lymphoma and multiple myeloma,
associated with other translocations
 Suggests chromosomal changes related to the
development of the cancer
Cancer Genes on other Chromosomes
11.6 Environment and Cancer
 Solid relationship exists between environmental
factors and cancer
 Cancer cluster: Large number of cases in
restricted area
 Epidemiologists examine environment for link
 Cancer cluster in Woburn, Massachusetts,
environmental trigger, industrial solvents
Environmental Factors and Populations
 Determine types of cancer populations may
develop
 Many forms of cancer related to:
• Physical surroundings
• Personal behavior
• Or both
 At least 50% of all cancer can be attributed to
some type of environmental factor
Smoking
 Number one factor in cancer, either direct
(smoker) or indirect (secondhand smoke)
 Related to cancers of oral cavity, larynx,
esophagus, and lungs
• Accounts for 30% of all cancer deaths
• Most have very low survival rate (e.g. 13% lung
cancer sufferers survive beyond 5 yrs
 Snuff or chewing tobacco users 50X more likely
to develop cancer of the mouth
Lungs of Non-Smoker and Smoker
Skin Cancer (1)
 ~1 million new cases in U.S. per year
 Almost all cases related to UV light exposure
from sun or tanning lamps
 Increasing, may be due to outdoor recreation or
moving to regions with more sun exposure
 Lightly pigmented people higher risk, genetic
characteristics can affect the susceptibility
Skin Cancer (2)
 Ozone depletion also contributes to increased
UV exposure and risk
 > 80% of lifetime skin damage occurs by age 18
 In spite of risk, some choose suntans and only
25% of Americans consistently use sunscreen
Melanoma
11.7 Legal and Ethical Issues
 Lawsuits against tobacco companies
 Tobacco companies knew tobacco is harmful,
possibly fatal, and addictive
 Memos showed they did know, did not warn
smokers
 Warnings on packages, smoking and age
restrictions
Spotlight on Ethics: HeLa Cell Line (1)
 In 1951, cervical cells removed from Henrietta
Lacks during biopsy
 She died from cervical cancer
 Cells maintained in vitro (in the lab) and used for
worldwide scientific study
 HeLa cells immortal because they can divide an
unlimited number of times in a laboratory
Spotlight on Ethics: HeLa Cell Line (2)
 Originally grown without Lacks’ knowledge or
permission and later sold to medical schools
 Have been used for commercial products: HPV
vaccine
 See the textbook for questions on this case