Wednesday

Lecture 35, 12/3; Cancer


We have been talking about genes effect on cell cycle regulation.  We are now going to talk about how they directly impact the cell cycle.  

Two types of genes that fall into each category

1.) Proto-oncogenes.  Normally function to promote the growth of the cell and cell division.  These genes are not always on.  When a proto-oncogene is mutated it typically is a constituitive mutation.  The gene is constantly telling the cell to grow and divide.
A mutated proto-oncogene becomes an oncogene.
  • EX. ras family genes.
  • Normally proteins from these genes are GTP binding proteins.  GTP binding protein bound to GTP is on.  Over time, GTP is converted to GDP and the protein becomes inactive.  Eventually GDP is released and GTP is rebound (It's a cycle).  When the gene is mutated it loses the ability to convert GTP to GDP.  Because of this, the GTP protein becomes permenantly bound to GTP and is always on. 
  • SO . . . the ras family genes normal role is promoting cell division.  When the mutation is made and the gene is on all the time (cell division occurs at high rate).  Often, what causes this is a point mutation.  Mutations in ras family genes found in 40% of cancers. 
(10:00) 2.) Tumor supressor genes.  Normal function of a tumor supressor gene is to slow/stop cell growth.  Often, tumor supressor's help trigger apoptosis. Mutated tumor suppressor genes = loss of the ability to stop cell growth. 
  • EX. P53 gene.  A mutation in the p53 gene is found in 50% of cancers.  
  • P53 is constantly transcribed, but the protein is rapidly degraded which results in low levels of the protein.  Normal roll of p53 is that it is a transcription factor and it regulates the expression of 50 genes.  It is both a positive and negative regulator. 
  • The expression of p53 is turned up in certain situations such as repairing DNA damage caused by UV light.  The normal roll is to arrest the cell cycle to allow time for DNA repair.  If we can't fix the damage we trigger apoptosis.
  • SO . . . when p53 is mutated the cell cycle con't arrest and the cell begins to rapidly accumulate mutations.  In addition you can't trigger apoptosis as easily. 

(20:35) Predisposition to cancer can be inherited.  1 to 2 % of cancers are hereditary.  Overall there are 50 forms of hereditary cancer.
  • Typically the genes responsible for these cancers are autosomal dominant.  By themselves they are not sufficient to cause cancer, however. 
  • One mutated allele = no cancer.  When you mutate the second allele in a heterozygote head down the pathway to cancer (loss of heterozygosity. 
  • After loss of heterozygosity the cell will form a number of additional mutations then you see tumor formation. 
  • (25:40) EX.  Familial adenomalus polyposis.
    • individuals with this mutant syndrome have an extra copy of the APC gene which is a tumor supressor. 
    • THis mutation will cause a number of cells in the colon to lose cell cycle control.  The result of this is the formation of 100 to 1000 rectal polyps.
    • Polyp can transition to a malignant tumor.  This happens as you accumulate a second mutation in a ras family gene.  Finally you have a mutation in the DCC gene.  The end result is a late stage adenoma.

(31:25) Viruses can contribute to cancer.  This started with the understanding that viruses can cause cancer in animals.
  • in animals it is caused by a retrovirus which is broadly labeled as an acute transforming virus. 
  • Discovered in 1910 by Francis Rous as he was looking at sarcoma's in chickens (tumores in muscle bone or fat).  
  • What he did: Injected chickens that did not have a tumor with "ground up tumor" and found that they developed this tumor.  Referred to as the Rous virus.

(36:45) How does this work?
  • a virus enters a cell and their RNA is converted to DNA by reverse transcriptase.  the DNA integrates itself into the genome of the host cell. 
  • Two ways this can cause cancer.
  • 1.) if the DNA is inserted near a proto-oncogene it can cause the proto-oncogene to become an oncogene.
  • 2.) The viral DNA can ring with it a proto-oncogene which becomes an oncogene over time. 

15% of all human cancers are caused by viruses.  2nd leading cause of cancer. 

(40:00) Common human viruses associated with cancer: Human papilloma virus (HPV), epstein Bar virus, human t-cell leukemia virus.  The disease itself is not sufficient to cause the cancer, you need additional mutations to happen over time.

A closer look at HPV - leading cause of anogenital cancer in the world. 
  • Can lead to Cervical cancer.  90% of all cervical tumors have HPV DNA
  • The virus carries two proto-oncogenes (genes that help it cause cancer)
    • E6 - binds p 53 and inactivates it
    • E7 - functions to stimulate cell growth and division.

(46:15) Environmental Agents that cause cancer.
Any substance that damages DNA can be a carcinogen.
Chemicals and radiation are the primary environmental contributers to cancer.  The most common environmental carcinogen is tobacco smoke.  Compounds within tobacco smoke interact with both the p53 gene and the ras genes.
-->30% of all cancers are caused by tabacco smoke. 

Diet can also impact cancer.  Colon, prostate and breast cancer is higher in individuals that eat high fat and high red meat diets.  It is suggested that hormones in the meat or byproducts in them are a contributing factor. 

UV light is another major contributor to environmental causes of cancer.  It causes DNA lesion which leads to cancer.

Monday

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.