Creation of Human Tumour Cells with Defined Genetic Elements

Hahn, W.C. et al. (1999). Nature 400: 464-468.

In this article, the authors report that they have successfully transformed a normal human cell (actually two different types of human cells--epithelial cells and fibroblasts--to show that it is not specific to one cell type) into a cancerous cell.  Now, this may not seem like a large achievement for you since scientists have been studying cancer for some time now.  Suprisingly however, this has been quite a difficult task. 

Many cancer-research related labs (including the one that I work in) use rodent cells.  Why?  Rodent cells are a bit easier to transform, i.e. make cancerous.  So, in a mouse or rat cell, you generally need to do two things to make it cancerous.  One, you have to inactivate certain tumor suppressor genes (whose protein products normally suppress tumor formation by inhibiting cell growth), including p53 and Rb.  Two, you have to activate certain oncogenes (whose protein products normally stimulate cell growth and proliferation), such as Ras.  However, this same technique does not work in human cells.  Why?  Well, the difference appears to be in telomere biology.

What's a telomere?  Great question!  Telomeres are at the ends of chromosomes, and although they are not involved in the "blueprint" of the cell (i.e. they do not encode genes), they are involved in DNA replication (and, of course, a cell needs to replicate its DNA if it's going to proliferate and divide).  Every time a cell divides, the telomeres become just a little bit shorter.  Once they become too short, the cell can no longer divide its DNA and thus can no longer replicate.  How does this explain the difference between rodent and human cells?  Well, rodent cells have much longer telomeres than human cells, suggesting that they can divide many more times before becoming senescent (this is the state that a cell goes into once it is unable to proliferate anymore).  Further, rodent cells have much higher telomerase activity as well.  Telomerases are proteins that maintain the length of the telomere.  So, even as the cell divides, telomerases help keep the telomeres from shortening.

Do you see where this is going?  Great!  The idea, then, is that you need three things to transform a normal cell into a cancerous cell.  One, you need to inactivate tumor suppressor genes.  Two, you need to activate oncogenes.  And three, you need to maintain telomere length.  Since rodent cells already have the last item covered, you only need to do the first two to transform it.  However, maybe you need to alter all three in human cells.

That's exactly what this article is all about.  First, the authors expressed a mutant telomerase in a normal human cell that is constitutively active (i.e. it is always on and maintaining telomere length).  Then, they went ahead and inactivated tumor suppressor genes and activated oncogenes...and voila! they had successfully transformed the normal human cell into a cancerous one.  Pretty interesting, eh?  I think so too!

Well, I don't think I need to explain why cancer research is important.  I'm sure that most of you know someone has or had this disease.  I think a better question here would be, why is this important to the treatment of cancer?  Before delving into this answer, let me briefly (and I mean briefly!) explain common treatments of cancer that have been used for a while now. 

Surgery: Basically, the surgeon literally removes the tumor mass from the body.  Now, this is fine if the tumor has not metastasized (traveled to another part of the body), but in either case, the chance that the surgeon will be able to remove every cancerous cell is very very slim.  And, since you only need one cancerous cell to start a tumor, the redevelopment of tumors can be frequent.

Radiation: Here, the tumor is irradiated which in turn kills the cells.  Again, if the tumor is localized and yet spread, many of the cancerous cells will be killed.  However, any left over cells (that survived the radiation treatment, or were localized in a different tissue) can lead to the redevelopment of tumors.  Further, radiation not only kills cancerous cells, it will also kill normal cells, so the procedure does have some risk and side effects.

Chemotherapy: This is the pharmacological approach.  Chemotherapeutic drugs are designed normally to kill actively growing cells.  So, since cancerous cells are actively growing, they will be killed by these drugs.  Further, since the drugs are administered into the bloodstream, they can kill cancerous cells in many tissues (unlike surgery or radiation).  The main problem is that these drugs will also kill actively growing normal cells as well.  As a result the therapeutic index is very low (i.e. the therapeutic dose is very close to the toxic dose) and leads to many side effects.  Often times, chemotherapy is used in conjunction with the other procedures...to clean up any cancerous cells that escaped the surgery or radiation.

As you can see, each of these treatments has its problems.  Therefore, pharmaceutical companies are working hard at trying to find better ways to treat cancer.  This is where cell biology has become helpful: if we understand the mechanisms by which the cell becomes cancerous (i.e. which proteins are mutated and how these mutated proteins differ from their normal counterparts), then we may be able develop more specific and less toxic drugs.  What about telomerases?  Should we inhibit these proteins to combat cancer?  I mean, normal human cells have low telomerase activity, so they shouldn't be effected too much, right?

Well, that's the topic of a really good review paper that just came out in a recent issue of Cell (de Lange, T. & Jacks, T. [1999]. For better or worse? Telomerase inhibition and cancer. Cell 98: 273-275.).  In this review, they focus more on mouse genetics, so there may be some differences when extrapolated to humans (see above).  Regardless, it appears that inhibiting telomerases can have two effects, depending on the context (which genes have been mutated in the cancer) as well as the stage of the cancer.  Inhibiting telomerase during the beginning stages (when there are not many mutations and the tumors are not very aggressive) may actually increase the number of mutations within the cell, possibly making the cancer even worse.  On the other hand, if the cancer is in later stages (so it is already "worse"), inhibiting telomerase may be able to inhibit the growth of these tumors and may even be able to cause the tumors to regress.  Of course, before solid statements can be made on this topic, further research needs to be carried out to see how this might work in humans (again, the statements from this article are extrapolated from mouse genetically manipulated to lack certain genes).

Anyway, I hope you enjoyed this summary (my first one by the way...and much longer than I expected!), and I hope that you will check back soon!  Thanks!