1. Cancer

2. From the syllabus Define cancer. List some types of cancer.
List characteristics of cancer cells including:
lack of contact inhibition,
vascularity,
plasma membrane
cytoskeleton and cytoplasm changes
abnormal disorganized growth.
List some mechanisms and causes of cancer.
Identify and define the genes involved
proto-oncogenes, oncogenes.
tumor suppresser genes
DNA repair genes. Define apoptosis.
Briefly discuss the multistep theory and genetic predisposition.
Identify treatment and side effects
historical perspectives such as drug discovery
screening and early detection
surgery
concept of how chemotherapy works using fluorouracil, taxol
radiation

3. Don’t forget to include stuff from chapter 6 next semester.

4. From the syllabus Define cancer. List some types of cancer.
List characteristics of cancer cells including:
lack of contact inhibition,
vascularity,
plasma membrane
cytoskeleton and cytoplasm changes
abnormal disorganized growth.
List some mechanisms and causes of cancer.
Identify and define the genes involved
proto-oncogenes, oncogenes.
tumor suppresser genes
DNA repair genes. Define apoptosis.
Briefly discuss the multistep theory and genetic predisposition.
Identify treatment and side effects
historical perspectives such as drug discovery
screening and early detection
surgery
concept of how chemotherapy works using fluorouracil, taxol
radiation

5. Cancer Evolution in action A disease of the genome
Survival of the fittest and natural selection are directly observable.
A disease of the genome
Genomic instability
A disease of the cell cycle
Checkpoint failures
A disease of the aged
Mutations occur throughout life.
Benign vs. Malign
Benign isn’t necessarily “good” – a benign brain tumor can still pinch nerves and arteries. Benign cancers are simply not spreading.
Malignant cancers are those in which cells are shedding off the primary tumor, and going throughout the body.

6. Overview
The pathway to carcinogenesis consists of 4-7 rate-limiting events. It can also be as little as only 2!
1. Activation of a pro-growth factor
2. Activation of a survival factor or suppression of a “death” factor
Tumor development proceeds by a process analogous to Darwinian evolution.
The multiple lines of cellular defense may explain why cancer is not more frequent during an average human lifetime.
If you live long enough, you will develop cancer.
Reference:Cell, Vol. 100, 57–70, January, 2000

7. General Charactistics of Cancer
Cell, Vol. 100, 57–70, January, 2000
General Charactistics of Cancer
All cancers must acquire several of the same six hallmark capabilities
Means and order of acquisition vary significantly.
The catalyst of acquiring these is
Genomic Instability.

8. Cancer: A disease of the Genome
Genomic Stability
Given the standard mutation rate in dividing cells, coincident with the fidelity of DNA replication, the time it would take to achieve a sufficiently mutated state for cancer would far surpass the human lifespan.
A normal error frequency of 1 base-pair change in roughly 109 base pairs for each cell generation (1 in a billion).
A single gene that encodes an average-sized protein (~103 base pairs) suffers a mutation once in about 106 cell generations.
This number is roughly consistent with the evolutionary estimate - one mutation appears in an average gene in the germ line every 200,000 years.

9. How is Fidelity Normally Maintained?
Protein level: Wobble Effect.
Genetic level: Distinct DNA repair mechanisms.
DNA polymerase exonuclease activity
post-replicative recognition, excision, and repair of mismatches
Other strategy Affecting stability:
5% exons
Extensive introns

10. Genomic Instability DNA Damage Normal Cell No! Yes! Cancer Cell
Apoptosis
No!
Growth Arrest
Can Damage
Be Repaired?
Mitosis
Yes!
Cancer Cell
DNA Damage
Damaged
Repair
Mechanism
Inability
To Sense
Damage
Inability to Arrest
Damage to
Apoptotic
Pathway
Mitosis
Rapid accumulation
of genetic damage
Perpetuation of
Errors to
Daughter Cells

11. Aneuploidy
Euploidy: Having a chromosome number that is an exact multiple of the monoploid number.
Aneuploidy: Having a chromosome number that is not an exact multiple of the usually haploid number.
Develops from defects in the process of chromosome segregation.
Most benign tumors are diploid.
All malignant tumors are aneuploid; this is one of the identifying characteristics of malignant tumor cells.
Is required for cell immortalization; it is a critical rate-limiting step of tumorigenesis – therefore, it develops early in the progression.
Caused by the same factors which cause genomic instability.

12. Environmental Causes of Genomic Instability and Aneuploidy
Oncogenic Viruses
Chemical carcinogens
Ionizing radiation
Loss of checkpoints +
circumvention of apoptosis =
genomic instability

13. Once genomic instability is in effect, cancer cells then follow a quicker path towards the accumulation of necessary mutations required to reach full-blown carcinogenesis.

14. Acquired Characteristics of Tumor Cells
Self-Sufficiency in Growth Signals
Insensitivity to Antigrowth Signals
Evading Apoptosis
Limitless Replicative Potential (Immortalization)
Sustained Angiogenesis
Tissue Invasion and Metastasis

15. Acquired Characteristics of Tumor Cells
Self-Sufficiency in Growth Signals Normally, cells need to be TOLD to grow. If they aren’t given the signal to start the cell cycle (recall the cell cycle…), they will rest (remember G0 / quiescence?) Cancer cells don’t listen to the environment – they do what they want. And they want to grow! They will bear a mutation in a gene normally involved in cell growth – the mutation causes the gene to be turned on ALL THE TIME.

16. Acquired Characteristics of Tumor Cells
Insensitivity to Antigrowth Signals
Normal cells can be told to die. (recall apoptosis).
Cancer Cells ignore the environment again – this time not killing themselves when being told to.
Keep in mind, the cancer cell might still have all the machinery in place to kill itself – it just doesn’t use it.

17. Acquired Characteristics of Tumor Cells
Evading Apoptosis
Normal Cells, once they start killing themselves, have to follow complex “genetic programs” to carry out this self-destruction.
Cancer cells that can “listen” to the order to self-destruct might have a mutation in a gene that carries out the order. You can’t kill yourself if your gun is broken.

18. Acquired Characteristics of Tumor Cells
Limitless Replicative Potential (Immortalization)
Normal cells stop growing after a certain number of divisions. Why? The linear chromosomes shrink a little after each generation. Finally, they stop growing (this is senescence).
Cancer cells all (yes, ALL) have a way to maintain the ends of their chromosomes. In this way, cancer cells can divide “forever”. Most of them use the enzyme telomerase to keep their telomeres healthy.

19. Acquired Characteristics of Tumor Cells
Sustained Angiogenesis
Normal cells need to be in contact with the body’s blood supply – this is how cells get the oxygen to carry out cellular respiration.
As tumors get larger, they need more oxygen – so they send out signals to the body to grow new blood vessels!

20. Acquired Characteristics of Tumor Cells
Tissue Invasion and Metastasis
Normal cells can’t grow beyond their immediate environment. Why? The environment tells them to kill themselves if they “get out of line”.
Cancer cells, which ignore these signals, can grow in places they normally can’t.
Draw “metastasis” on the board. Show the major capillary beds, and show this is why these areas are the most common places for metastatic tumors.

21. CAMs Integrins Growth Inhibitory Signal via binding
Extracellular Matrix
CAMs
Integrins
Epithelial Cancers
antigrowth signals
antigrowth signals

22. Apoptotic Signals via detachment

23. Can still bind ligand, but unable to transduce signal
Decoy Receptor
TRAIL
TRAIL
Can still bind ligand, but unable to transduce signal DD
DR-4/5
DcR

24. 5. Sustained Angiogenesis
All cells, normal and cancer alike, must reside within 100 mm of a capillary blood vessel.
A tumor which fails to activate angiogenesis can only grow to ~2mm in diameter

25. Cell 2000 Jan 7;100(1):57-70

26. Molecular Defects in Cancer: Two Paradigms
Tumor Suppressors
Loss of function
p53
p16 Rb
pTEN
p27
etc. etc.
Oncogenes
Gain of function
c-myc
Ras
Cyclin D
CDK4
Bcl-2
Survivin
Oncogenic Viral Proteins
Each protein is resopnsible in evading one or more
of the core six characteristics necessary for tumorigenesis

27. Fighting Cancer

28. Chemotherapy
The idea behind chemotherapy is simple: kill cells that are proliferating.
Chemotherpeutic agents induce apoptosis (specific to the cycling cells) and necrosis (nonspecific and therefore less effective)
The Failure of Chemotherapy
unfortunately, many cancers have damaged apoptotic response pathways, leading to ineffective treatment
50% of cancers have a mutation in p53, which is crucial for apoptotic response.
Many normal cells proliferate at the same rate (if not faster) than tumor cells
Many tumor cells don’t necessarily grow faster as they simply just don’t die.

29. current chemotherapeutic
Strategy: Exploit cancer’s inactivated apoptotic pathways
current chemotherapeutic
approaches
Novel
approaches
Lesion 1
Lesion 2
Myc
Growth
Apoptosis