A recent German study has found an association between familial and non familial malignant melanoma and the telomerase gene. I think we should talk about this because it shows where the seemingly unending association with telomerase and cancer came/comes from.
First concept: Cancer cells are not normal. They are the result not only of loss of growth control but of multiple other aberrations and mutations that change them into monsters. This most likely happens long before they hijack telomerase.
The monster is not born immortal. The immortalization of any cell line appears to involve OVER EXPRESSION of telomerase. So when the monster that is cancer is born there are many places it can be stopped before it takes over the village. The problem is the village elders (in this case the immune system) are weak, old and disorganized. Too weak, too old and too disorganized to stop it.
So it grows more powerful with every step (cell division) and eventually obtains the ability to hijack several processes including the ability to invade surrounding tissue (matrix metallo-proteinases), carry away its own anaerobic excrement (angiogenesis), and finally its own immortalization (telomerase).
Second concept: Telomerase is not oncogenic by itself. The enzyme telomerase does not cause cancer and may actually help prevent it (JAMA 2010 article showed association of short telomeres and poor type and prognosis of cancer).
The monster has to be “made” before telomerase gets involved and then it hijacks telomerase for its own purposes. In the cell lines studied the hijacking of telomerase was the LAST step in the creation of an immortal cancer cell.
The amount of telomerase needed to sustain cancer growth in general is massive. While I cannot assign an absolute number to it (telomerase expression is measured in arbitrary units and no one has done this comparison study) it could easily be 20 to 100X the amount present in those cell lines that actually express telomerase. This is far beyond the amount provided by TA-65, which is usually the next question I get asked.
When you add TA-65 to pre existing cancers (xerographs) there is no change in the cancer growth rate and as we have seen in mouse studies, no increase in the rate of cancer formation.
The same holds true for some genetic manipulations and also for Maria Blasco’s AAV-9 virus with regards to cancer formation.
Third concept: Telomerase inhibition as a sole or adjunctive agent to fight cancer is likely to fail for the following reasons:
a) Most cancers are capable of using an alternate (ALT) method of preserving their telomere length. Destroying the telomerase dependent cells (the competition) allows the ALT cells to thrive and multiply. There are at least 2 studies where this has happened. ALT is often associated with cancers that are more deadly and more resistant to treatment.
b) Inhibiting telomerase may weaken the already weakened immune system in the cancer patient which of course may be further weakened by chemo and radiation. It may also inhibit the growth of healthy tissues.
Forth concept: Mutations in the telomerase gene have been shown to be associated with super longevity.
Fifth concept: Increased Telomerase expression at sub cancer levels has been shown to improve the parameters of health and longevity. So far the only proven ways to have enough telomerase to actually affect telomere health are: TA-65, virosome expression, genetic “boosting” of telomerase.
Sixth concept: So far in humans the only safe way to affect telomere length (critically short telomeres) is TA-65. No ethics committee is going to allow a healthy human to be injected with a virus (ask me how I know!) and genetic boosting of telomerase still carries with it a risk of cancer.
The pharmacologic or more correctly nutraceutical approach (again TA-65) has the he advantage of being on then off and non constitutive (not continuous) and well below the threshold for cancer.
OK back to the German melanoma study before we wrap this up. After the researchers found a familial mutation that is associated with melanoma they looked at non familial cases.
Guess what! They found it was a frequent mutation in melanoma, although not the same mutation.
Honestly, guys, is that really a surprise given that cancer as a process hijacks telomerase?
My only hope is that other cancers will be studied this way. I am sure they will find similar situations there as well where the creation of cancer leads to a mutated form of telomerase.
Sadly the lead researcher in this team went on to talk about how telomerase inhibitors were already in Phase III clinical trials.
Yeah, I know of one for sure: Imetelstat and it made things worse. If people do not examine the literature and the results as a whole, then the myth that “telomerase causes cancer” will only propagate.
One other thing that is not a surprise: The researchers identified solar radiation as a common cause for melanoma-telomerase mutation.
Given the highly repetitive and highly vulnerable nature of the telomere (perhaps the most vulnerable chunk of DNA we have!) in particular the Thymidine residue which forms adducts with carcinogens with relative ease, and the Guanine which is super vulnerable to free radical damage it makes complete sense.
I hope the German study will lead to more help or even a cure for melanoma patients, but it will not be a telomerase inhibitor this I know for sure!
For all of us, the best policy is to keep our fragile telomeres long enough and healthy enough that we do not age prematurely and get these nasty diseases! Telomerase activation is one sure fire way to do that!
PS as always I have over simplified some concepts here so they are easier to understand. It is not my intention to offend anyone involved in basic or clinical research but I do think Occam’s Razor applies here: the simplest explanation is usually the best!