Imagine finding a small lump on your body one day that
causes pain like nothing you’ve ever felt before. Imagine that upon discovering
this lump and visiting the doctor, the physician confirms that you have cancer.
What’s worse is that it is inoperable and doctors say there is nothing they can
do. The doctor then says you have a month (or even less) to live. Now imagine
this: one day, all the pain goes away and a resulting trip to the doctor
reveals no sign of cancer, and there are no signs of cancer in the years to
come. Sounds hard to believe, right?
Wrong. That’s what happened to Charles Burrows. In 2005, Burrows was diagnosed with an inoperable liver cancer and given
60 days at most to live. Against all odds, Burrows’ tumor disappeared in 2006
and he remained cancer-free for years until his most recent battle with cancer took his life in January 2013.
Burrows’ story of spontaneous tumor regression sounds like
something out of a fairy tale. But Burrows isn’t the only one to have a tumor
spontaneously regress. In fact, it happens more than you might
think—spontaneous tumor regression occurs approximately once out of every
140,000 cases of cancer (2), meaning a cancer patient is over 1,000 times more
likely to get a second chance at life than they are to win the lottery on a
single ticket (that’s about 1 in 175 million in case you’re wondering). While
this is still a small fraction, it’s big enough to suggest that something
interesting is going on here. The only question is, what exactly is going on in
people whose tumors spontaneously regress?
It turns out
that a lot of things could be responsible for spontaneous tumor regression, and
the things responsible for spontaneous tumor regression may differ in different
types of cancer. Moreover, these reasons can be more complicated and
intertwined than we might think they are. While spontaneous tumor regression
may be attributed to things like immune-mediated events, processes of terminal
differentiation or even vascular compromise (2), I will focus on Telomerase,
another possible explanation for why some tumors spontaneously regress.
Telomerase—what role
does it play in spontaneous cancer death?
Telomerase is the enzyme responsible for lengthening
telomeres after DNA replication by adding repeating sequences (TTAGGG) to
telomeres, which protect the ends of chromosomes and prevent chromosomes from
joining other ones and protects against the loss of important DNA near the ends
of chromosomes. Through doing this, telomerase is able to ensure that the
important DNA is protected. Many times in cancer, cell immortality is
associated with the up-regulation of telomerase. However, because telomeres
shorten over one’s lifespan due to the end replication problem, the important
DNA can potentially be damaged. This can potentially lead to cancer or an
increased chance of getting cancer as one gets older. But if lack of telomerase
can cause mutations that lead to cancer and up-regulation of telomerase in
cancer cells makes them immortal, how is telomerase involved in spontaneous
tumor regression?
It turns out that inhibiting telomerase seems to play a role
in spontaneous cancer death, especially in the presence of short telomere
length, which would undoubtedly result from the absence of telomerase. This is
because short telomere length helps limit tumor growth by bringing about a
genomic crisis in the absence of telomerase because of the end replication problem (2). Moreover, it appears that shorter telomeres even help block tumor
formation in the first place (3).
This figure shows a Kaplan-Meier plot measuring the survival
rate of mice in an established model of Burkitt’s lymphoma. The mice used in
this study over-express the Myc oncogene in B cells, which leads to B cell
lymphoma after 4-6 months (3). Myc;mTR+/+ mice are wild type
for telomerase, Myc;mTR-/- G1 mice lack telomerase but have long
telomeres, and Myc;mTR-/- G5/6 mice lack telomerase and have short
telomeres. After disabling apoptotic signaling in these mice by infecting whole
bone marrow with a murine stem cell retrovirus (MSCV) that expresses Bcl2 and
using adoptive transfer to place it in lethally irradiated mice (this causes
lymphoma to develop after about 6 weeks), mice with no telomerase and short
telomeres did not develop any palpable tumors for more than 100 days after
transplant while wild type mice and mice without telomerase and long telomeres
had all developed tumors by 42 days (3). This suggested that tumor suppression
was not entirely dependent on apoptosis. These researchers later determined
that a p53-mediated mechanism of senescence (continued cell viability without
any further cell division) that occurs due to shortened telomeres is
responsible the suppression of tumors in these mice (3).
Perhaps spontaneous tumor regression can be attributed to an
absence of telomerase in cancer cells if one’s telomeres are short enough in
their cancer cells—after all, shortened telomere length brought about by the
lack of telomerase has been shown to prevent cancer entirely (see the Kaplan-Meier plot above). If a person’s
cancer developed to a more aggressive state marked by large amounts of cellular
replication and no telomerase, the end replication problem would cause drastic
telomere shortening over many replications. This would ultimately lead to the
destruction of important DNA after the telomeres have been destroyed, which
could result in senescence or even apoptosis of cancer cells at a later point
in their development. Such an occurrence in the later stages of cancer cell
development would seem to be a reasonable explanation for how exactly Charles
Burrows and other lucky cancer patients were able to overcome what seemed to be
certain death.
Final Thoughts
Spontaneous tumor regression is
exceedingly rare and may happen for a number of different reasons in different
cancers and different patients. However, it does seem that the absence of
telomerase, which results in shorter telomeres due to the end replication
problem, could cause cancer to spontaneously regress at certain points in a
cancer’s development. Moreover, shorter telomeres and the absence of telomerase
have been shown to prevent the onset of certain cancers entirely (see the graph
above). So then should people just take drugs that shorten their telomeres by
inhibiting telomerase in order to prevent the onset of many cancers and call it
a day? Well, not exactly. Telomerase does enough good in humans through
strengthening the telomeres that protect the innermost DNA of our chromosomes
alone to justify having it around. Telomerase shortening is also seen by
scientists as a “molecular clock” that triggers aging since lower telomerase
activity is associated with increased cellular senescence (1), so unless you
want die a lot faster than the average human life expectancy for the sake of
avoiding cancer, this is not the way to go. What’s more is that doing so
wouldn’t even guarantee a person a cancer-free life—shortened telomeres have
been associated with poor disease progression in CML patients and in patients
with other cancers (2). Moreover, the increased amount of mutations that would
inevitably occur due to shortened telomeres and thereby more instances of
genomic crises might just end up causing cancer in an individual anyway. In any
case, you’d probably still die way before becoming a senior citizen. Thus, the key to
spontaneous tumor regression becoming a viable option in all cancer patients
might just depend on inhibiting telomerase so that telomeres disappear over
time and ensuring that telomerase is not inhibited in normal cells. The next
step is figuring out just how to do that.
Sources
1. Allison,
Lizabeth Ann. Fundamental
Molecular Biology, 2e. Hoboken, NJ: Wiley, 2012. Print.
2. Elston, D.
M. "Mechanisms of Regression." Clinical Medicine & Research 2.2 (2004): 85- 88. Clinmedres.org. Marshfield
Clinic. Web. 5 May 2014. <http://clinmedres.org/content/2/2/85.short>.
3. Feldser,
David M., and Carol W. Greider. "Short Telomeres Limit Tumor ProgressionIn
Vivo by Inducing Senescence." Cancer Cell 11.5 (2007):
461-69. Cell.com. Elsevier
Inc., 8 May 2007. Web. 10 May 2014. <http://www.cell.com/cancercell/abstract/S1535-6108(07)00087-6>.
