Cancer Basics

ResearchBlogging.orgOne aspect we’ve discussed before about cancer development is the requirement that the cells (more specifically cancer stem cells) become immortal, able to replicate into daughter cells indefinitely. This is seen most prominently in HeLa cells, cervical cancer cells taken from Henrietta Lacks, who died in 1951. These cells have an overactive telomerase enzyme and have continued to replicate in research labs around the world since they were collected.

Telomerase is an enzyme that adds short pieces of DNA onto the end of chromosomes (telomeres) after replication, necessary because the mechanism for replication shortens the telomeres with every round. If enough of the telomere is lost a signal is sent to the cell to quit replication. In stem cells and progenitor cells this signals the end of self renewal.

Another pathway able to produce renewal and proliferation is the Wnt/β-catenin pathway. This pathway has been shown to be important in maintaining cells in a stem cell-like state and are thought to be able to initiate tumorigenesis.

The blue dye shows where Axin2 is being expressed from TERT induction

The blue dye shows where Axin2 is being expressed from TERT induction

A paper published July 2 in Nature has shown how these two pathways are linked, finding a molecular bridge between the immortality and stem cell/proliferative pathways in the cell. The researchers were looking at a portion of telomerase called TERT (telomerase reverse transcriptase). Early looks at the molecule found that overexpression in mice could lead to anagen in the epidermis, the same result that happens when β-catenin is overexpressed.

Using the gastrointestinal tract of mice, where Wnt signaling through β-catenin is required for stem cell maintenance, the researchers showed that inducing TERT expression in the crypts significantly upregulated Axin2 expression, a gene target of the Wnt/β-catenin signaling pathway (figure b). This in vivo display of pathway convergence is great evidence for the link between the two. Furthermore, the research team used catalytically inactive TERT to show that its function in Wnt signaling is not based on its telomerase activtiy.

The link between these two pathways I guess shouldn’t be too surprising. In cells which are programmed to be stem cells and divide many times throughout an organism’s life it should be expected that a pathway to maintain chromosomal integrity would communicate with the pathway that is pushing the cell to divide. What may be surprising is just how intimately these two are linked with the actual telomerase enzyme associated directly with the chromatin and Wnt signaling targets.

Tert knockout homeotic mutationsAnother reason I love this paper is the amazing images of Xenopus homeotic transformations. Since the Wnt pathway is also involved in axis formation and early patterning when you knock out TERT you do some weird things to the frog’s body plan. These images show how the vertebra and ribs are shifted from their location or display axis abnormalities, further putting the nail in the coffin for the link between TERT and Wnt signaling.

The significance of this finding may lead to another chemical therapeutic target in the future. Now two pathways may be able to be controlled in one swoop. Ideally a drug would be able to knockout TERT activity which would have the dual effect of ending immortality in that cell and forcing it out of a stem cell state. Since most cancers have the higher morbidity and mortality with more stem cell like cells in primary tumors this could be a means at a genetic double shot. Once you can get cells to commit to a differentiation status it is very hard for them to reclaim the ability to proliferate and produce daughter cells.

As the authors say:

“Our findings provide a mechanism to understand previous observations showing that TERT overexpression activates epidermal stem cells, as well as previous findings linking TERT to proliferation, survival and stem-cell biology in diverse contexts. Our data reveal unanticipated level of convergence between the telomerase and Wnt/β-catenin signalling pathways with important implications for understanding development, stem-cell regulation and cancer.”

Park, J., Venteicher, A., Hong, J., Choi, J., Jun, S., Shkreli, M., Chang, W., Meng, Z., Cheung, P., Ji, H., McLaughlin, M., Veenstra, T., Nusse, R., McCrea, P., & Artandi, S. (2009). Telomerase modulates Wnt signalling by association with target gene chromatin Nature, 460 (7251), 66-72 DOI: 10.1038/nature08137

Killer T-cells attack a cancer cell

Killer T-cells attack a cancer cell

In Part 1 of my Cancer Basics series I briefly covered the general theory on how cancer develops.  To recap, basically cells become independent of replication and migration pathways through instability in their genome.  This instability is brought on through different mechanisms of introducing mutations into certain genes which regulate essential functions of cooperative cell regulation.  The most well known of these genes is p53, the Guardian of the Genome.

p53 is a protein that acts as a barrier to the cell cycle.  In order for the cell to replicate its DNA, dissolve the nuclear envelope and initiate mitosis, and exit the mitotic cycle there are checkpoints that must be passed.  From the previous article we can use the analogy of a hallway with three locked doors which must be unlocked to proceed through the cell cycle.  p53 is one of the keys to these locks.  When p53 is present it prevents the cell from opening the lock and proceeding into the next step of the cell cycle.  So what exactly is p53 doing?  Why is it the guardian of the genome?  And what makes scientists and physicians so sure that this one gene out of the thousands involved in cell regulation is so important in protecting us against cancer?

This simple diagram gives a good overview of p53’s action.  When the cell is proceeding through the cell cycle there is a checkpoint just before it begins to segregate its DNA into two separate compartments which will become daughter cells.  It is very important that there is exactly 2 versions of each chromosome (I’m ignoring sex chromosomes here, we’ll stick with the autosomes) and that these two copies are going to be segregated equally into each daughter cell.  p53 acts as a major checkpoint signal to make sure these two prerequisites are fulfilled before the cell actually tries to separate into two daughter cells.

If p53 is present at this check point it will stop the cell cycle in order to either fix the damage to the DNA, arrest the cell until the DNA can be repaired, or it can initiate apoptosis.  Apoptosis is the last ditch effort of p53 to save the individual from cell division.  Questions remain as to what causes p53 to initiate either a repair or apoptotic response but it depends on a multitude of different pathways.  This diagram should show you just how complicated this regulation process is:

I know its hard to see but that little dark blue circle with all the lines converging on it is p53, everything else represents different pathways of regulation of the level of p53 at different points in the cell cycle.  We’ve established that p53 is important in making sure that daughter cells receive their full and correct compliment of DNA and in activating pathways that will stop the cell cycle if this isn’t going to happen, but exactly why is this so important?

Recalling from Part 1, cancer is a cell lineage that breaks away from its cell cycle regulation and eventually gains the ability to break away from its neighbors and implant into other tissues, what we call metastasis.  A good way to look at the importance of p53 is to see what happens when the gene that makes the protein is mutated or completely missing.  Li-Fraumeni Syndrome is a disease in which people have a mutated p53 gene (either inherited from germline transmission or de novo during embryogenesis).  These individuals have a very high susceptibility to cancer, which usually begins early in childhood and is a recurring problem throughout life.

This chart is a pretty good graphic for showing the rates of cancer around the world as well as how many of those cancers have a mutation in the p53 gene (green percentages on the right side).  Given these two facts it can be assumed that p53 plays a huge role in the development of cancer.  Well, let’s look at where p53 fits into our overall theory of cancer to find out exactly how these mutations cause such a high susceptibility to cancer.

Genetic instability is the hallmark beginning of cancer.  Once the cell cannot fix DNA errors, segregate chromosomes equally to daughter cells, or fully carry out recombination events the genome becomes unstable.  Without these regulations the cell is free to pass on mutated and error-filled DNA which will become further mutated and passed on to further progeny.  If the environment around these uncontrolled growths is right and the right mutations take place the cell can then break away from the migration regulation and become a metastatic cell, seeding tumors in other tissues of the body.  We have seen that p53 makes sure the cell has a full complement of error-free DNA for each daughter cell and that it can even initiate a suicidal response in the cell if this isn’t fulfilled.  With a mutation in p53 the cell can no longer regulate whether the DNA is ready to be passed on, one of the doors that was blocking our hallway has been blown off of its hinges, it now doesn’t matter if we have the key (p53) or not.  Now that p53 isn’t guarding the genome from errors it is free to pass these errors onto daughter cells, the first step in cancer generation.  These daughter cells inherit the p53 mutation as well as any other chromosomal abnormalities that are passed onto it and are free to continue passing on these errors as well as generating new mutations which no longer are under apoptotic control.  In this way p53 mutations initiates a complicated cascade where cells who can no longer arrest their cell cycle or commit to a suicidal ending are allowed to pass their error-prone genetic complement into the next generation of cells.  The daughter cells are not able to regulate the integrity of their DNA either so as replication continues mutations will continue to build until a cell line becomes cancerous.

p53 is only one of many “tumor suppressor” genes that have been identified, but its presence in such a high number of cancer cases reflects the importance it plays in the development of cancer.  This gene has truly earned its name, “The Guardian of the Genome”.

Recently I’ve been talking with my students about cancer in my cell biology class.  I was amazed at how little the class understood about general mechanisms of cancer.  The majority of the students are sophmores and have just started to scratch the surface of biology but I was still rather taken back by their lack of knowledge.

Last week I began asking people around town what they knew of cancer and got a pretty mixed bag of responses.  Some people had no clue about cancer and some were very well versed, I assume that a lot of this variation is dependent on how proximal cancer has affected your life.  Despite some very good answers I feel that there needs to be more awareness about what cancer is because it affects such a large portion of the population.  So today I will start part 1 of my Cancer Basics series.  This is intended for the lay audience and won’t be ground breaking other than to clearly summarize some of the most important aspects of cancer.

What is Cancer?

A cancer is a group of cells which shows uncontrolled growth.  Throughout the body cells must be replaced as they age, break down, or are damaged.  The replacement of old cells by new ones is a highly regulated process throughout all systems depending on internal checks from the cell as well as external factors which are communicated by surrounding cells.  Before a cell is able to divide all of the internal and external signals must correspond to pass certain checkpoints of division.  Imagine a long hallway with three locked doors along the way, you must have the correct keys to pass through each door before you reach your destination.  A cell that has broken free from the regulation cycle (essentially obtaining a masterkey) can now divide at whatever pace it decides no matter the messages coming from those around it.  This is how tumors develop in the body.  There are benign tumors in the body that grow unchecked but that are not cancerous because they are not invasive and do not spread to other locations in the body (invasion and metastasis will be covered in another post).

How does a cell break from the growth cycle?

Almost all cancers are believed to be caused by an alteration in the genetic material of the cell.  Your DNA encodes for all proteins in the body, including those that participate in the maintenance of the growth cycle.  An alteration in these genes can allow the cell to ignore the normal cues and administer its own reproductive clock.  It is worth it to be noted that not all mutations in these proteins will cause cancer, there are mechanisms which the body uses to destroy those cells that are not dividing correctly (showing why cancer is so complex, it evades multiple cellular systems to survive).

The alterations which cause cancer can be induced by carcinogens such as tobacco smoke, radiation or chemicals.  Recently viruses have been in the news for causing cancer such as the HPV virus giving rise to cervical cancer.  It is not hard to imagine viruses (invade hosts DNA) giving rise to cancer (specific alterations in DNA). Cancer can also arise through errors in the replication of DNA or it can be inherited.

So that’s it for part 1 of my Cancer Basics series…part 2 will be up in the next few days.