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.
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.
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>.