Cancer

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• Cancer
• Lecture 20

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• Cancer
• A group of diseases caused by loss of cell cycle
  control
• Associated with abnormal uncontrolled cell growth
• Carcinogens are substances that cause cancer by
  mutating DNA
• Many genes that can mutate to cause cancer
  control the cell cycle or DNA maintenance
  (repair)

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• Origin of Cancer
• Begins from the growth of a single abnormal cell
• A mutation occurs, allowing a cell to undergo
  inappropriate cell division
• Division produces more abnormal cells
• Mutations can occur
• In somatic cells - sporadic cancer only
  affecting the individual
• In germline cells - mutations that are inherited
  (usually require second somatic mutation)

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• Loss of Cell Cycle Control
• Timing, rate, and number of cell divisions depend
  on
• Protein growth factors
• Signaling molecules from outside the cell
• Transcription factors within
• Checkpoints control the cell cycle
• Loss of control of telomere length may contribute

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• Genetic disease
• Usually not inherited somatic mutation impact
  of carcinogen
• Predisposition may be inherited
• Uncontrolled cell growth
• loss of normal cell division controls
• Many genes that can mutate to cause cancer
  control the cell cycle or DNA maintenance
  (repair)
• Unusual and characteristic cell types
• Spread beyond restricted tumor or cell mass
• Involves 200 diseases
• Oncology Study of cancer - detection and
  treatment

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Origin of Cancer

• Begins from the growth of a single abnormal cell
• Mutation of factors involved in normal cell
  division controls
• Division produces more abnormal cells
• Mutations can occur
• In somatic cells - sporadic cancer only
  affecting the individual
• In germline cells - mutations passed on to
  offspring (expression usually requires second
  somatic mutation for expression)

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• Cell cycle controls
• 1. G1 favorable conditions?
• 2. G2 trigger for beginning of mitosis
• 3. M exit mitosis/cytokinesis enter G1

• Should cell divide?
• Has DNA been copied correctly?
• Has this cell line expired?

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• Two Classes of Genes Controlling Cell Division
• Tumor-suppressor gene Proto-oncogenes
• Slows
  stimulates
• Cell division

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• Mutations and Cancer
• Proto-oncogene mutation ? Oncogene
• Over stimulation of cell division
• Tumor suppressor gene mutation ? no check on
  DNA damage
• Loss of check on cell division
• Example p53
• Two mutations required for cancer to develop
• One mutation may be congenital predisposition
• May run in families

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• Examples of effects of mutated tumor suppressor
  and oncogenes
• See table 18.7

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A Proto-oncogene p53

• p53 acts as a cell cycle protein
• Determines if a cell has repaired DNA damage
• If damage cannot be repaired, p53 can induce
  apoptosis
• More that 50 of human cancers involve an
  abnormal p53 gene
• Rare inherited mutations in the p53 gene cause a
  disease called Li-Fraumeni syndrome
• Family members have many different types of
  cancer at early ages.

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• Proto-oncogenes to oncogenes
• Viral transformation rare
• First associated with Rous Sarcoma Virus
• First discovery of oncogenes
• Usually somatic mutation
• May involve single nucleotide change
• Translocation ? fusion protein
• Modified expression controls

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• Ras gene oncogene
• 189 amino acid protein
• Inactive/inactive forms
• Product in cell membrane functions to transfer
  growth promoting signal
• Altered form is permanently active constant
  signal for cell growth
• Due to single amino acid substitution
• Modified forms associated wit various cancers

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• Treatment strategies involving oncogenes
• Monitor of copies of mutant gene ? modify
  aggressiveness of treatment
• Turn off oncogene expression

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A tumor suppressor gene BRCA1 Gene

• A breast cancer susceptibility gene
• Tumor suppressor gene
• Increases risk of developing breast and ovarian
  cancer
• Within families a mutation in BRCA1 inherited as
  a dominant trait
• One mutation in the BRCA1 gene is inherited
• Tumors in people acquire a second mutation in the
  normal allele of BRCA1
• Lack of any functional BRCA1 leads to cancer
  cells
• At the level of the cell, BRCA1 acts in a
  recessive manner

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• Involvement of Multiple Mutations/genes
• Colon cancer an example
• 2 types
• Familial adenomatous polyposis (FAP)
• Autosomal dominant but sequential process
• Hereditary nonpolyposis colon cancer (HNPCC)
• Genomic instability microsatellite sequences
• Modified caretaker gene involved in DNA
  repair
• May also involve mutations of gatekeeper gene

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• Differences in Cancerous Tissues
• Cell division
• Normal checks on cell division
• Contact inhibition
• Activity of telomerase
• Appearance of cells lack in normal
  differentiated appearance
• Genetic damage
• Chromosomal abnormalities
• Extra copies
• Missing parts
• Extra parts

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Cancer cells abnormalappearanceChromosome
numbers
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• Characteristics of Cancer Cells
• Loss in contact inhibition
• DNA damage does not result in self destruction
• Divide indefinitely
• Attract a blood supply
• Do not adhere to neighboring cells (lact cellular
  adhesion molecules)

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• Tumor development to Cancer
• Tumor (neoplasm new growth) abnormal growth
  of cells resulting in a cell mass
• Benign
• Remain localized
• Surrounded by connective tissue
• Growth increases to critical size
• Increases blood supply
• Cells may escape via these vessels
• Malignant
• Spread to other tissues (metastasis) ? cancer

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• Telomeres Has this cell line expired?
• Specialized cells develop from stem cells
• Limited number of divisions occur from stem or
  undifferentiated cell
• Telomeres act as count-down device
• At end of chromosome

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• Telomere repeating sequence of double-stranded
  DNA at the ends of chromosomes
• Greater telomere length is associated with
  immortalized cell lines such as embryonic stem
  cells and cancer cells
• progressively shortened during lifespan of normal
  cell line

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Telomeres Affect the Cell Cycle

• Telomerase is the protein and enzyme complex that
  adds telomere sequences to the ends of
  chromosomes
• Presence of telomerase and telomeres allows cells
  to pass a cell cycle checkpoint and divide

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Figure 18.4
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• Aptosis programmed cell death
• Cells divide only so many times
• Genetic controls tell cells when to die
• Also a normal part of development you dont
  have webbed fingers but you did once!

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• Causes of Cancer
• Viruses
• 5 in US
• Certain Herpes, Hepatitis, papilloma
• Chemicals esp. organic compounds
• Many
• Tobacco smoke
• Benzene, formaldehyde, pesticides, etc.
• Radiations
• UV, radon, uranium

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• Potential Control Measures Experimental and
  Clinical Trials
• Immunotherapy aimed at T-cells
• Stimulate immune system
• Vaccines
• Drugs
• Inhibit blood vessel formation in tumors
• Gene Therapy
• No current FDA approval
• Insert normal control genes p53
• Antisense DNA blocks transcription
• Modification of cancer cell susceptibility to
  drugs

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Cruciferous Vegetables Can Lower Cancer Risk
Figure 18.17
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The End.