Introduction :

Image : Rapid and unrestrained proliferation of Human breast cancer cells in vitro. The black arrow points to a plastic bead to which the cells adhere.
A larger image is not available.

Although we don’t know what exactly is responsible for causing cancer, we do know a bit about how cancer cells continue to divide almost indefinitely. Halting this uncontrolled division of cells (which is made possible by an enzyme called telomerase) is the basis of  the new anti-cancer vaccines under development.

What exactly are telomeres??

As you know chromosomes consist of a large number of nucleic acids (Adenine, Guanine , Cytosine and Thymine) arranged in a particular sequence. This sequence, which differs from individual to individual, is responsible for manufacturing proteins in the body.

However, all the nucleic acid sequences do not code for proteins. A large proportion of the chromosome consists of sequences which do not code for any proteins. These parts of DNA, previously called as "Introns" were believed to be useless, and the exact reason for having such redundant pieces of genetic code were not known.

Turning to the subject proper, although the function of introns is still not completely understood, they are no longer regarded as unimportant. The ends of all chromosomes contain specialized repeated sequences of DNA (TTAGGG in humans) called "Telomeres", that serve to maintain the integrity of the chromosome. (It is easy to visualize these sequences as "caps" at the end of the chromosomes)

Chromosome structure : Please click on the image to view a bigger picture.

As a cell divides these "caps" gradually shorten in length. When the "caps" or telomere sequences disappear completely, the inner genetic material is exposed to damage and when that occurs, the cell can divide no more and it dies. In short, the telomeres act like "Biological clocks" that limit the number of times that a cell can divide.

What is the reason then, that cancer cells can divide repeatedly?

The reason WHY the cancer cells do so is still not known. But the mystery of how the cancer cells manage to do so, inspite of the problem of telomere shortening is now beginning to be unraveled.Almost 90% of all cancer cells in humans contain an enzyme called "Telomerase" which helps to replace the lost parts of the telomere, in other words restoring its length. Thus, the protetive "caps" remain intact, the inner genetic material is protected from damage and the cancer cell can divide more times as compared to normal cells.

Cancer cell division (simplified :) ) : Please click on the diagram to view a larger image.

Most of the newer vaccines being tested now induce a immunological response against telomerase, so that the cancer cells , too , die a "Natural death" due to telomere shortening.

Some of the older vaccines under research , however, work in the same way as vaccines we are familiar with do. These vaccines target specific antigens which seem to be found on the surface of all ( or almost all) cancer cells, thereby inducing an immune response against the cells themselves.

Specific Vaccines under development:

1) Theratope™ ( Vaccine for Breast cancer ) :

Image : Mammogram showing a lobular Ca in the upper region of the breast

 
The carbohydrate antigen , STn , is present on the cell membrane of a large proportion of rapidly growing Breast Ca cells.The vaccine synthesizes these carbohydrate molecules and injects them back into the patient, which triggers an immune response that targets the cancerous tumors
Because the Ag is more common in rapidly dividing cells that slowly dividing ones, the vaccine is less effective against slow growing tumours. The phase III clinical trials currently approved by the FDA are limited to patients with metastatic breast tumours.

Status :  Phase III (last phase) of Human trials. This vaccine has been placed on the FDA's (food and drug administration's) "fast track list" for approval.

2) TERT vaccine ( "Universal Cancer Vaccine " based on telomerase research):

Research currently on at :
Duke University Medical Center and Geron Corp
UCSD School of Medicine and Cancer Center
Dana-Farber Cancer Institute

The vaccine causes expression of a specific part of telmorase , called TERT (or Telomerase Reverse Transcriptase), on the surface of the "dendritic cells" of the immune system. These dendritic cells then present this antigen to other cells of the immune system, producing an immune response which is cell mediated (either Killer-Nk / Cytotoxic T cells.). This immune response is directed against telomerase and thus halts the rapid division of the cancer cells.

In tests, the vaccine stimulated an immune response that slowed tumor growth of melanoma, breast and bladder cancers implanted into genetically unrelated mice, and an effective response against two different mouse cancer cell lines in lab studies

Status : Animal studies

Interesting fact : Both the above studies use a genetically engineered retrovirus to get the genes coding for TERT inside the dendritic cells. This is how it works : The RNA of a retrovirus is modified so that it becomes harmless to humans. The gene coding for TERT is now integrated into the viral RNA. When this virus is injected into animals/humans , it infects the body’s cells (in particular the dendritic cells). The normal retroviral process now occurs and the proteins coded by the RNA (namely TERT) are produced. These proteins are recognized by the dendritic cells, setting off an immune cascade and subsequently, cell-mediated immunity against telomerase.

This technique is also being touted as the route of delivery of "normal" genes to the cells of persons affected by genetically determined diseases e.g. Homocystinuria .

3) TF / TN Carbohydrate complex vaccines ( older kind of vaccines)

Research currently on at:
Sloan-Kettering Institute for Cancer Research

Don’t be intimidated by the short forms. TF and TN are simply two carbohydrate antigens which are present on the cell surface of many cancer cells. Obviously therefore, these vaccines have nothing to do with telomerase and depend upon inducing an immune response against the cancer cells themselves (Specifically, against the cell memb. proteins)

TN , in particular, has been found in abundance in prostrate cancer cells. The TN cabohydrate complex was also very efficient in inducing an antibody response in mice.

Currently both these vaccines are under clinical trials in humans. Antibody production against the TN antigen has been noted, but the actual clinical effects remain uncertain.

Status : Human trials

Links :
Click on the headings to go to the sites

1) Transformation of normal cells into Ca-cells by expression of telomerase :
If you are not entirely convinced that telomerase plays an important part in cancer cell division, please read this article about how normal HUMAN cells can be made cancerous.

2) Non- Profit distributed computing program for Ca- research :
This program is supported by Intel and United devices, and is similar to the SETI program that you might have heard of.

If you have not, here is a brief description : Many of the research projects in Ca-research require enormous amounts of computing power which may not always be available, because not every researcher has access to a supercomputer. Instead of having a single very powerful computer, the same processing can be done by several less powerful computers which are connected to one another, a process which is called "Parallel Processing"
In this case, the less powerful computers are your own PCs at your home and the connection between your PC and the mother PC is the internet.
Note that you will not have to be connected to the internet all the time and the program will only work when your computer is idle (It works as a "screensaver" and shows you exactly what is being computed.)

3) Description of the normal structure of a chromosome :
Very good and in-depth description. Also includes descriptions of mutations. However, it lacks adequate visuals. Recommended if you are interested or have difficulty understanding genetics.

4) American Cancer society :
Excellent site! Although the site is geared towards cancer patients, see the "Clinical decisions" section which tries to identify the therapy that is most suitable for a particular cancer at a particular stage.
Free online registration required.

- Oncogen
 Comments? Additions? Corrections? Please contact :( oncogen@kemates.com )

.