(From Dr. Savant’s Lecture, 3 July 2000, by Brian Buschman)
Return to Semester One Goodies
Return to The Unofficial Ross Page
Cancer has many factors/causes associated with it which include:
1) Abnormally high mitotic rates.
2) De-differentiation.
3) Disordered growth patterns.
4) Metastasis
5) Major genetic abnormalities.
6) Immortality – the cells are unable to go through apoptosis.
7) Altered cellular characteristics.
8) Phenotype can be heritable.
Two general themes tend to appear in all cancerous growths:
1) Abnormal activation of a growth promoting protein. It may be related to GFs, MAP kinases or just whatever it feels like.
2) Abnormal inactivation of a growth inhibiting protein such as p53, pRB, CDK inhibitors or whatever.
It is known that many retroviruses are able to contain oncogenes that are inserted into the host genome with reverse transcriptase. There are also some such oncogenes which already occur naturally as proto-oncogenes which can be activated to oncogenes by a virus. Many of the viral encoding oncogenes are analogues of GFs and hormonal system components.
There are a number of different changes that may occur in a gene that will cause it to become an active oncogene. They include:
1) Altered proteins where the structure of the new protein is similar but has a significantly altered function.
2) Altered regulatory sequences where transformations causes exceptionally high levels of expression of genes.
3) Loss of degradation signals. Some cancers are a result of the loss of intracellular signals that tell the cell when the protein’s job is done and it can be degraded. In this case the protein sticks around longer then needed and may cause increased cell division.
4) Chromosomal rearrangements can cause a gene to become associated with another gene’s regulatory mechanism. This is the case in the Philadelphia chromosome when the bcr and abl genes which are usually on separate chromosomes. This can cause excessive expression of the wrong chromosome.
5) Gene amplification can result in MANY copies of the same gene. It has been found with some tumor suppressor drugs that function by preventing expression of a certain gene that after some time the gene may come to exist with many duplications of the gene to try to overcome the suppression by drugs. In this example the tumor may be held in check for some time and then grow or metastasize once again without changes in the therapy.
6) Viral insertion of oncogenes. As previously mentioned an oncogene could be inserted by reverse transcriptase or the viral altering of an existing proto-oncogene.
7) Loss of inactivation of the tumor suppressor gene.
Cervical cancer is caused by the papova virus and has two oncogenes E6 and E7. E6 binds to and removes p53 and E7 binds to and removes PRB. With this change you now have the loss of two regulatory mechanisms. That of the molecular policeman, p53, and uncontrolled action of E2F/DP growth factors without the regulation of pRB.
Retinoblastoma is a tumor of the eyes which results from inactivation of the pRB gene. It has been found to transmit heritably when a parent has a mutated pRB gene. Some patients inherit one mutated pRB gene and some two. Most cases of retinoblastoma are associated with two bad copies of the pRB gene. If you are born with one bad copy (one hit) then nature tends to give you the other.
Cancer which is a result of mutation in the p53 gene. This is obviously a family of cancers since the p53 gene is mutated in about half of all known cancers.
The NF1 gene is inactivated which usually activated the GTPase activity of the ras oncogene. If NF1 is missing ras operates too much and causes neural tumors.
Colon cancer has many primary etiologies of which at this level we need to know two:
1) An autosomal dominant cancer which involves a defect in hMSH2. If first appears as a benign tumor and then becomes malignant.
2) Familial adenomatous polyposis is a cancer with a legion in the MCC locus on chromosome #5.
Return to Semester One Goodies
Return to The Unofficial Ross Page