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

Chromosomal changes often a cause of cancer

Environmental causes of cancer are being studied

Lawsuits have addressed smoking as a cause of cancer

Central Points (2)

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

p. 181

4Cell

division

Mitosis

3DNA

repair

G21

Cell grows,

doubles in size

G1

S

2Chromosome

duplication

G2/M checkpoint

G1/S checkpoint

Stepped Art

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

p. 183

Outside cell

Receptor

Plasma membrane

Cytoplasm

Nucleus

Changes in gene expression

Signal molecule

Signal–receptor binding

Cellular response

Protein molecules

Stepped Art

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