Lecture 34, 12/1; Chapter 18, Cell Cycle Regulation and Cancer

Chap 18
Cell Cycle Regulation and cancer.

-Cancer is the 2nd leading cause of death in western world.  1 in 3 people will be diagnosed with cancer at one point in their life.
-1,000,000 new cases of cancer in the U.S. each year.
-500,000 deaths attributed to cancer

Cancer is a genetic disease. 
-The genomic alteration associated with cancer range from single nucleotide changes to large deletions.

• Vast majority of these mutations arise in somatic cells.
• only 1 % of cancers are linked to germline mutations which predispose an individual to cancer.

Most cancers are a result of multiple mutations (6-10 avg) as opposed to a single mutation.

(9:20) Common traits of cancer.

• cell proliferation - abnormal unchecked growth
• Metastisis - cells have the ability to spread to other parts of the body

typically two broad categories of tumors

• benign - tumors that are localized to one region and are not metastisis.
• malignent - tumor which has the ability to spread to other areas of the body

all tumors arise from a single cell.

• begins to accumulate mutations and eventually starts to grow uncontrolably.

(15:25) The idea that "all tumors arise from a single cell" is supported by x inactivation data. 

• cells in a single tumor all share a common inactivated X chromosome.
• Because X inactivation is random the likelihood that all cells in a tumor share an inactivated X chromosome by chance is extremely low.

(18:05) Broadly: Cancer is a multi-step process.

• This idea that "cancer is a multi-step process" is supported by the following data.
• 1.) There is a definite increase in the incidence of cancer as age increases.
• 2.) Also when looking at victims of the atomic bombing in WWII we see that 5-8 years after the bombing there was an increase in the rate of cancer for survivors of the initial blast.

(21:30) Example of the multi-step process: Cervical Cancer.

• In the normal cervix a number of cells, after time, become quiescent cells (a cell that has entered Go phase and stopped dividing). 
  
• However, a number of basal cells exist in the cervix (not quiescent) which are actively dividing or have that ability.
• Occasionally basal cells form mutations.  When these mutations happen they can form a dysplasia (tumor area).  This is early cervical cancer and easily treatable.  Untreated the cells in the dysplasia will develop additional mutations over time.  With time the dysplasia becomes carcinoma which is much more difficult to treat.

(32:15) Genetic causes of cancer
Some cancer cells contain genetic defects affecting DNA repair and genomic stability. 
-On average, cancer cells have higher rates of mutations than normal cells. This suggests problems with DNA repair.
-Mutator phenotype - a cell more prone to mutation.

(34:45) Two types of cancer caused by mutations in the DNA repair system (inheritable forms of cancer)
-Xerodermo pigmentosum - very susceptable to the effects of UV light.  These indivuduals have a mutation in one of the 7 genes involved in nucleotide excision repair. 
-Hereditary nonpolyposis Colon cancer - this is an autosomal dominant allele (will run through families very strongly).  Mutation is involved in genes involved in mismatch repair system.

(39:05) Cancer is often caused by mutations that affect the cell cycle.
One of the hallmarks of cancer is that cells grow and divide at a greatly increased rate.
The cell cycle control system helps to prevent the uncontrolled growth of cells.

• During G1 the cell makes a decision about whether or not to continue to divide. A cell that stops actively dividing enters the Go phase.  In the Go phase cells are metobolically active . . . but not dividing.  A cell in the Go phase is referred to as a quiescent cell.
• Another one of the hallmarks of a cancer cell is that it skips Go phase.  If the cell does enter Go phase it passes through very quickly.
• (45:30) Normal cells will exit the Go phase in response to environmental signals --> A signal transduction pathway accomplishes this. 
  In a cancer cell, the genes in that signal transduction pathway are mutated so that the signal pathway is always on (tells it to grow more). 
  
• The cell cycle has checkpoints to help prevent this from happening: G1s checkpoint, G2 M checkpoint and the M checkpoint.
• BUT mutations in the genes for these checkpoints have an association with cancer.
  

(50:25)Apoptosis - programmed cell death.  A pathway  a cell can activate when its too damaged to continue.  When it is activated the cell self-destructs.

• BUT mutations in the genes for apoptosis are also associated with cancer.