Download Cancer - Biochemistry

Cancer
Why Haven’t We Cured Cancer?
Definition
• Abnormal and uncontrolled cell growth
• Most abnormal cells are repaired, stop
growing, or undergo the process of apoptosis
or programmed cell death, but cancer cells do
not
• Cancer Cell Behavior
Normal Cell Cycle
G1 checkpoint
Control
system
G1
M
G2
M checkpoint
Figure 12.14
G2 checkpoint
S
Cell Cycle Phases
Interphase:
G1: Growth just after division – synthesis of
proteins
S: Synthesis (replication) of new DNA
to prep for division
G2: Growth and synthesis of proteins in
preparation for division
M Phase:
- Mitotic or Meiotic phase
- Mitotic: makes new body cells
- Meiotic: makes gametes (sperm or egg)
Cell Cycle Gates
• Moving from different stages G1  S, G2  M,
and the Metaphase Checkpoint are regulated by
“Gates”.
• “Gates” are internal signals that tell the cell when
to proceed. These signals are a specific level of
intracellular proteins that build up until they
reach the correct concentration.
• Once the set concentration is reached, the cell
proceeds to the next step.
• Allows time for specific processes, such as
checking DNA for damage, to occur.
• Normal and Abnormal Cell Division Behavior
• The levels of the control signals are regulated by
external chemical (hormones) or physical
signals that bind to surface proteins.
• These external signals tell the cell to promote
or inhibit the production of the internal
signals.
- Called the Signal Transduction Pathway
Signal Transduction Pathway (STP)
EXTRACELLULAR
FLUID
Reception
CYTOPLASM
Plasma membrane
Transduction
Response
Receptor
Activation
of cellular
response
Relay molecules in a signal transduction pathway
Signal
molecule
Figure 11.5
Changes in STP  Cancer
- Changes in the STP can lead to the promotion
of cell division without proper adherence
to checkpoints
1. Increase number of receptors or receptor
sensitivity to cell division signals
2. Increase responsiveness of transduction
pathway
3. Block suppression signals
Promotion of Cell Division
- Cell Cycle check points are regulated by two
major proteins: Cyclin and Cyclin
Dependent Kinases
- Cyclin levels fluctuate with each checkpoint,
rising until the correct level is reached, followed
by a quick decline in concentration
• Cyclin Dependent Kinases (CDK) generally have
stable concentrations and responsible for
reacting with Cyclin, ATP, and other
proteins to activate them for the process of cell
division
Cyclin and Cyclin Dependent Kinases
• Cyclin Dependent Kinases
(CDK) bind to cyclins and then
activate proteins with a
phosphate from ATP.
• As cyclin increases, CDKs
activate more proteins which
allows cell division to progress.
Cell Division Inhibition
• Proteins p53 and p21
• Regulate cell cycle – p53 binds to DNA and
causes the expression of another protein called
p21.
• p21 protein binds to Cyclin Dependent Kinase
(CDK) and inactivates it.
Role of p53 in response to Cell Damage
• p53 becomes over produced when cells are
damaged
• p53 forms a tetromer – unit of four p53
proteins
▫ Tetromeric p53 either stops the cell cycle,
initiates DNA repair, or induces apoptosis
• Mutation in the p53 gene causes a faulty
protein which cannot regulate the cell cycle or
prevent a damaged cell from growing = cancer
Normal Growth Regulation
External:
Chemical: hormone signals bind to cell
membranes and trigger cell division
Ex: platelete derived growth factor stimulates healing of wounds - made by platelets
which release the factor at a wound
erythropoietin: released with the loss
of blood – stimulates the bone marrow to
make more blood cells
Physical: Density Dependent Inhibition:
Growth is inhibited when cells become crowded
Anchorage Dependency: cells must be
attached to something
- can’t just grow in a solution
(a)
Normal mammalian cells. The
availability of nutrients, growth
factors, and a substratum for
attachment limits cell
density to a single layer.
Cells anchor to dish surface and
divide (anchorage dependence).
When cells have formed a complete single layer, they stop
dividing
(density-dependent inhibition).
If some cells are scraped away, the remaining cells divide to fill
the gap and then stop (density-dependent inhibition).
Figure 12.18 A
25 µm
Cancer cells do not exhibit
anchorage dependence or
density-dependent inhibition.
(b)
Cancer cells. Cancer cells usually
continue to divide well beyond a
single layer, forming a clump of
overlapping cells.
Figure 12.18 B
25 µm
• Abnormal Cell Signaling
Common Characteristics of Cancer
1. Immortality: most cells have a limited capacity
to divide. Cancer cells can divide continuously.
2. Do not rely on external signals to stimulate
division.
3. Ignore external signals that tell the cells to stop
dividing.
4. Do not undergo apoptosis (programmed cell
death)
5. Angiogenesis: stimulate the growth of blood
vessels to deliver nutrients
6. Metastasis: spreading
Role of DNA
DNA directs the manufacture of proteins
Protein functions:
- enzymes – control cell reactions
- structure – shape of cell
- hormones – stimulate cell growth
- inhibitors – suppress cell activities
Changes in DNA (mutations) alter can change the
shape and function of the protein or change
how often a protein is expressed.
General Mutations
1) Locking the cell in “On” mode.
Cell division is stimulated by outside signals that
bind to receptor proteins. Changes in these
receptor proteins (due to DNA mutation) can trick the
cell into responding as if they have been signaled to
divide.
Genes that respond to normal signals are called
proto-oncogenes and regulate cell growth. If these
are mutated, they can become oncogenes, which act
as though they are constantly stimulated.
CHANGES IN A PROTO-ONCOGENE
A. New promoter: translocation or transposition
puts a new promoter in front of the gene and
overstimulates the production of the protein - cell
grows too much - change is passed down from
generation to generation because the new promoter
sequence is copied in DNA replication
B. Gene Amplification: genes can be copied and
duplicated (transposons or errors in replication or
crossover) results in double the amount of genetic
materials so double the amount of enzyme is made =
abnormal growth
C. Point Mutation – may make the gene highly
durable or hyperactive = longer activity = abnormal
growth
Proto-oncogene
DNA
Translocation or transposition:
gene moved to new locus,
under new controls
Gene amplification:
multiple copies of the gene
New
promoter
Normal growth-stimulating
protein in excess
Point mutation
within a control
element
Oncogene
Normal growth-stimulating
protein in excess
Point mutation
within the gene
Oncogene
Normal growth-stimulating Hyperactive or
degradationprotein in excess
resistant protein
2) Turning off the “don’t divide” signals.
Blocking the control of a tumor suppressor
gene. Genes that regulate cell division.
Inform a cell when it should stop dividing.
BRCA 1
3) Altering the signal transduction pathway.
CAUSES OF MUTATIONS IN THE DNA
1. Environmental Factors:
- chemical carcinogens
- radiation
2. Viruses – integration of viral nucleic acids into
host DNA
3. Transposons – jumping genes
4. Errors during mitosis or meiosis
5. Old age - cells lose ability to correct mutations
- increase in replication errors
6. Epigenetic Factors : chemicals that bind to
the DNA and alter its expression
▫ - can turn genes off or on
– methylation of tumor suppressor genes
▫ Video
How Does Cancer Spread?
• Metastasis: Spread of cancer
Stages:
1. Growth of Tumor
2. Intravasation: tumor cells break through
basement membrane of a blood vessel or
lymphatic vessel and enter the circulatory
system
3. Migration: cancer cells move through the
body in the blood and interact with
platelets making them “sticky”
4. “Sticky” cancer cell gets stuck in a small
blood vessel (capillary) and begins to grow
5. Extravasation: cells break through the wall
(diapedesis)of blood vessel and enter the tissue
of the new area
6. Growth of new tumor and angiogenesis
(initiation and growth of new blood vessels to feed
the growing tumor)
Metastasis