Cancer Cells

1
Chapter 24

• Cancer Cells

2
Cancer

• 2nd leading cause of death in the US behind
  cardiovascular disease

3
Cancer Categories

• Based on the cell type involved
• carcinoma epithelial cells lining internal and
  external body surfaces
• 90 of all cancers
• lung, breast and colon
• sarcoma cells of supporting tissue
• cartilage, fat, connective tissue, bone and
  muscle
• lymphomas/leukemias cells of blood and
  lymphatics
• solid tumor vs cells in the blood stream

4
Properties of Cancer

• Ability of cells to proliferate in uncontrolled
  manner
• Ability to spread throughout body

5
Uncontrolled Cell Proliferation

• Balance between cell division and differentiation
  is disrupted in a rather autonomous fashion
• results in tumor or neoplasm
• Rate may not be altered but raher the balance is
  off between cell division and differentiation
• differentiation is acquiring specialized
  properties
• once differentiated less likely to divide

6
Skin Development

• Cells replaced from basal layer
• cell divides and one becomes the new basal cell
  and the 2nd becomes differentiated to become a
  skin cell
• cell flattens, makes keratin fibrous protein to
  impart mechanical strength
• no increase in the of cells
• similar in BM and GI tract
• Tumor cell division and differentiation are
  uncoupled
• 2 cells made and both keep dividing
• Rate of division determines how fast tumor grows
• if large, usually disrupts organization and
  function

7
Types of Tumors

• Benign tumors confined to a local area and is
  rarely dangerous
• Malignant tumors capable of invading
  surrounding tissue, enter the bloodstream and
  spread
• serious condition
• cancer

8
Anchorage Independent Growth

• Normal cells will grow in culture only is
  provided with a support system
• require anchoring to a surface, in vivo use the
  extracellular matrix
• integrins hold cells to the matrix and if
  interfered with, cell no longer replicates and
  usually undergoes apoptosis
• Cancer cells can anchor to the surface but also
  can grow in suspension or on a soft agar medium
• cancer cells by-pass the attachment control and
  are anchorage independent
• in vitro they can form clumps rather than stop
  growing when they contact one another

9
Cancer Cells are Immortal

• Normal cells usually only replicate in culture a
  limited number of times before undergo serious
  changes
• Cancer cells are immortal seem to grow forever
• HeLa cells from Henrietta Lacks uterine cancer
  whose cells were cultured from tumor in 1953 and
  still today

10
Cancer Cells have Telomerase

• Long term division is because of the telomeres
  that are at the end of the chromosomes
• Normal cells telomeres shorten over time and
  replication shuts down
• Cancer cells overcome by making telomerase
  continues to add the telomere at the end and
  therefore allows replication to continue

11
Abnormalities

• Uncontrolled proliferation caused by signaling,
  cell-cycle control and apoptosis
• Telomeres allow unlimited division but dont
  actually stimulate cell division
• Mechanistic defects in signaling and cell cycle
• mechanism that restrains cells from entering cell
  cycle are overcome at the restriction point and
  the cell doesnt look to see if enough nutrients,
  DNA repair finished, etc. dont respond to
  control
• cancer cells can also block apoptosis so damaged
  cells proliferate

12
Causes of Cancer

• Epidemiology frequencies and distribution of
  diseases
• Found link between smoking and lung cancer
• Japan has decrease in colon cancer but high
  stomach cancer, when move to US see a flip in the
  incidence
• environmental and lifestyle factors more
  important than heredity

13
Chemicals Cause Cancer

• 1761 snuff users increase in nasal cancer
• Increase in scrotum cancer in chimney sweeps
• Since then the list of carcinogens has grown
  can cause in humans and animals when exposed
  not always thru direct interaction

14
Activation by Liver

• 2-naphthylamine can cause bladder cancer when
  exposed to but direct placement in bladder
  rarely cancer forms
• Movement thru the liver activates the compound to
  a cancer causing agent
• Many carcinogens need metabolic activation
  precarcinogens
• Activated by cytochrome P450 which usually less
  toxic and easier to excrete but occasionally made
  into carcinogens

15
Ames Test

• Proposed in 1950
• Bacteria that cant make His are used to see if
  chemical is mutagenic
• if mutagenic, may make a mutation to allow
  bacteria to make His
• count number of colonies, more colonies, more
  mutagenic
• treat chemicals with liver extract to see if
  modification can make them mutagenic

16
Multi-Step Process

• Give DMBA and see no tumor
• Add croton oil (phorbol ester) and see increase
  in tumors
• Croton oil cant cause tumor by itself
• No tumor if DMBA is added after croton oil

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1st 2 Steps

• DMBA initiation converts cells to
  precancerous
• Croton oil promotion causes division and
  tumors
• DMBA causes a permanent change in cells cause
  DNA damage mutations
• Phorbol esters stimulate cell proliferation
• Proliferation favors cells with cells with
  enhanced growth rate and invasive propeties

18
3rd Stage

• Tumor progression
• cells gradually change over time
• more aberrant traits and increasingly aggressive
• selective advantage
• usually a 2nd DNA mutation after initiating
  mutation
• May also be an epigenetic change change in
  expression of gene rather than structure of gene

19
Ionizing and UV Radiation

• Usually cause DNA mutations
• Ionizing radiation X-rays, nuclear explosions
  and radio-chemicals see increase in cancer with
  increase in dosage
• ionizing radiation and remove electrons from
  molecules DAN damage
• UV excessive exposure trigger pyrimadine dimers
  if not repaired causes improper base pairings
• specific CC to TT is a unique product of UV
  exposure

20
p53 Mutations

• See gene with CC to TT mutation is frequently
  observed in skin cancer
• Other p53 cancers do not have the signature
  mutation as seen in skin cancer
• p53 mutations are not randomly distributed,
  usually alter that change amino acid sequence

21
Viruses and Infectious Agents Can Cause Cancer

• 1st link was to Rous sacroma virus that caused
  tumors in chickens
• oncogenic virus
• dozens of viruses and few bacteria have been
  found to cause cancer
• Hepatitis B and C liver
• Human Papilloma Virus cervical
• Helicobacter pylori stomach

22
Burkitts Lymphoma EBV

• 1950s Burkitt saw an increase in cancers of
  neck and jaw during certain seasons Burkitts
  lymphoma
• Found to be caused by Epstein-Barr Virus
• proof
• DNA sequences and proteins of EBV in tumor cells
  but not normal cells
• Add EBV to normal lymph cultures cause cells to
  acquire properties of cancer cells
• inject EBV into monkeys to induce lymphomas