Everybody’s Free To Wear Sunscreen…And Prevent Skin Cancer

Our last article discussed using sunscreen to help protect skin against damaging UV radiation. When used properly, sunscreen prevents sunburn and sun-induced skin aging, and protects from skin cancer. Studies have shown that sunscreen use reduces the incidence rate of squamous cell carcinoma (SCC) and melanoma, but currently no evidence supports a protective role against basal cell carcinoma (BCC).

While some people, including supermodel Gisele Bundchen, believe sunscreen is dangerous (she declared “I cannot put that poison on my body”) experts such as The Skin Cancer Foundation and the American Academy of Dermatology—and even Cosmopolitan magazine—disagree with her and other skeptics.

A large, randomized controlled trial examined the effect of daily sunscreen use on the development of skin cancers. Researchers followed 1621 Australians from 1992-2006. From 1992-1996, participants were randomly placed in a group and instructed to either use the study-provided broad spectrum SPF 16 sunscreen daily on face, arms, neck and hands, or to continue personal discretionary use of sunscreen. At the 2004 follow up, researchers noted that the daily sunscreen use group had a 35% rate reduction in the incidence of SCC (considering all SCCs that appeared throughout the entire study). However, the incidence of BCC was not statistically different between the two groups. More recent studies corroborate these results.

US Senator and 2008 Republican Presidential Candidate John McCain has had multiple melanomas removed. Other political figures have battled skin cancer, including former Presidents Jimmy Carter (metastatic melanoma) and Bill Clinton (BCC), and former First Lady Laura Bush (SCC).

In 2006, researchers followed up again, this time looking for melanoma. The overall incidence rate of melanoma was 50% less in the sunscreen intervention group than the discretionary use group (out of approximately 800 people in each group, 11 people in sunscreen group and 22 in the control group developed melanoma). It should be noted that these results had borderline statistical significance, with a P value of 0.051 (P = 0.05 is the accepted cutoff for significance). This essentially translates to a 5.1% probability of these findings being due to chance, rather than to the actual sunscreen intervention. Also, there was a 73% lower rate of invasive melanoma in the sunscreen group. Although there was no significant difference in number of melanomas diagnosed at the prescribed intervention sites, it is possible that sunscreen use reduced the risk, as participants in the sunscreen intervention group reported more frequent use of sunscreen over the whole body after the intervention terminated.

Although these results are not the most compelling, they nonetheless point to a protective role of sunscreen. Many factors may contribute to a less than straightforward outcome. First, the sunscreen intervention was in adults and lasted 4.5 years. Melanoma and BCC are thought to result from both long term sun exposure and intense, intermittent episodes (sunburns), whereas SCC is mainly caused by cumulative UV exposure (both natural and indoor tanning bed). Furthermore, blistering childhood sunburns are a risk factor for melanoma. One study that examined sunscreen use in children found a significant protective benefit. Regular use (applied any time sun exposure would exceed 30 min) of a broad-spectrum SPF 30 sunscreen over a 3-year period resulted in significantly fewer newly developed moles, the number of which is a risk factor for melanoma.

Second, participants in the non-sunscreen intervention group continued their discretionary use of sunscreen. No trial in humans could ever prohibit sunscreen use or provide a placebo for ethical reasons. Therefore, perfectly delineating the protective effect of sunscreen is difficult.

Many questionnaire-based studies that rely on participants’ memory of sunscreen use suffer from recall bias. Some of these studies showed no benefit of sunscreen for melanoma prevention but memory limits the reliability of these results. The bottom line is that sunscreen protects from UV radiation, a known human carcinogen.

The skin consists of two layers, the dermis and epidermis. The epidermis contains a variety of cell types, including squamous cells, basal cells and melanocytes. These are the sources for squamous cell carcinoma, basal cell carcinoma and melanoma, respectively.

UV radiation is implicated in up to 90% of nonmelanoma skin cancers, squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). Mutations consistent with UV radiation were also found in the genomes of melanoma tumors; UV radiation is thought to be responsible for the majority of melanoma. Whereas SCC and BCC are more frequent, melanoma is more often fatal. While UV radiation is the single most important risk factor for skin cancer, it’s worth noting that it is not responsible for all skin cancers. Aside from environmental carcinogens, cancer can arise due to a person’s genetics (familial effect) or random mutations.

Acral melanoma is a type of skin cancer not caused by UV radiation and is genetically distinct from UV-induced cutaneous malignant melanoma. Bob Marley’s acral melanoma metastasized and ultimately claimed his life.

UVA radiation primarily damages the components of skin cells by generating reactive oxygen species, or ROS. These highly active molecules can cause single-strand breaks in the DNA or crosslink DNA to protein, resulting in mutations or improper functioning. Both UVA and UVB can cause a more significant type of DNA damage called pyrimidine dimers, where two adjacent pyrimidine nucleotides (the “C” and “T” of DNA; the “A” and “G” are purines) fuse together. Because the higher energy UVB is absorbed directly by DNA, UVB can cause other modifications that compromise the integrity of DNA, leading to instability of the genetic code.

Indeed, the cell has repair mechanisms to fix pyrimidine dimers and other errors, but sometimes the very genes encoding the repair mechanisms are mutated. UV-induced DNA damage can result in highly characteristic mutations in critical genes, for example in the tumor suppressor gene p53. As the “guardian of the genome”, the p53 protein is involved in directing the repair of mutations and guiding the cell through its controlled death pathway, called apoptosis. Mutations in p53 are thought to be among the first steps in development of non-melanoma skin cancer. Formation of malignant melanoma is more complicated and not fully understood.

Yes, p53 has its own superhero persona. That’s how cool (and significant) it is. Image by Susanne Harris.

Cells that carry mutations in p53 proliferate uncontrollably, a hallmark of cancer. In some cases, the immune system will recognize malignant cells as a threat and effectively eliminate them. However, UV radiation is also known to suppress the immune system by at least two mechanisms. One is by diminishing the production of antigen-presenting cells, which engulf foreign-looking cells and display an alert to activate the immune system). The other is by inducing the production of an immune suppressive cytokine, interleukin-10. Additionally, some skin cancer cells display proteins on their surface that prevent the immune cells from killing them. Thus, in addition to mutations in key genes, immune suppression and immune evasion contribute to the development of skin cancer.

Even the mutant Wolverine wears sunscreen! In this Instagram post, Hugh Jackman urged his fans to use sunscreen. He became a fervent sunscreen proponent after having a BCC removed from his nose.

Contributed by: Julia van Rensburg, Ph.D.
Follow Julia on Twitter.

van der Pols JC, Williams GM, Pandeya N, Logan V, & Green AC (2006). Prolonged prevention of squamous cell carcinoma of the skin by regular sunscreen use. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 15 (12), 2546-8 PMID: 17132769

Lee TK, Rivers JK, & Gallagher RP (2005). Site-specific protective effect of broad-spectrum sunscreen on nevus development among white schoolchildren in a randomized trial. Journal of the American Academy of Dermatology, 52 (5), 786-92 PMID: 15858467

Koh HK, Geller AC, Miller DR, Grossbart TA, & Lew RA (1996). Prevention and early detection strategies for melanoma and skin cancer. Current status. Archives of dermatology, 132 (4), 436-43 PMID: 8629848

Leiter U, & Garbe C (2008). Epidemiology of melanoma and nonmelanoma skin cancer--the role of sunlight. Advances in experimental medicine and biology, 624, 89-103 PMID: 18348450

Brenner M, & Hearing VJ (2008). The protective role of melanin against UV damage in human skin. Photochemistry and photobiology, 84 (3), 539-49 PMID: 18435612

Quicksilver: The Avenger With Mutations For Speed

Quicksilver can run really fast. People can’t really

see him, but he can see everything that is going on

and make sense of it even though his speed is

phenomenal. He’s fast enough to have been in an

X-Men movie last year and an Avengers movie

this year.

May 1^st brings yet another movie of comic book characters to life. I think we went about two weeks without one. The Avengers: Age of Ultron brings back our favorite superheroes – Iron Man, Black Widow, Hawkeye, Hulk, Thor, and Captain America – but adds some new characters as well.

Brother and sister duo of Pietro and Wanda Maximoff become reluctant Avengers in the new film. They have been characters in the comic books for years, and are two of the most promiscuous characters in terms of which stories they enter. Pietro has appeared in X-Men, Fantastic Four, and even the DC Comics Justice League of America.

Wanda (Scarlett Witch) and Pietro (Quicksilver) are different kinds of Avengers. They don’t have fancy toys like Iron Man; they don’t have as much martial training as Natasha Romanov or Hawkeye. They aren’t gods from another planet like Thor, but they do have some similarities to Hulk and Captain America.

Dr. Banner was a victim of gamma radiation–induced mutation during his research and Captain America had his body altered via science. The Maximoffs’ are mutants, but they were born with their individual mutations – heck, Magneto is their father.

Quicksilver’s mutations let him run amazingly fast, up to Mach 4 (4x the speed of sound, about 3044 mph) in some iterations of his character. He’s strong too, some websites say he can bench press about 1000 pounds. This is pretty amazing stuff, and I’m wondering how these feats might come about. 

How would Quicksilver’s physiology have to be altered in order for him to achieve faster than normal speeds? Believe it or not, science has identified mutations that could account for at least some of his abilities.

Mercury is the only metal that is liquid at room

temperature. The Greeks called it Hydragyrum (water

silver); that’s why it’s element symbol is Hg. The other

name, quicksilver, is from English, where "quick" means

living (ie. the quick and the dead). Therefore,

quicksilver means living silver.

First of all, Quicksilver would have to have some changes in his physiology other than just fast, strong muscles – muscles don’t mean anything if you can’t supply them with what they need. To go really fast, he would need cardiovascular and oxygen utilization systems that could get oxygenated blood to his muscles faster and in larger volume than anyone else.

But it is true that Quicksilver would need large muscles and muscles that would move quickly. Mammals have two basic types of skeletal muscle fibers, slow twitch (red, type I) and fast twitch (Type II, white). Slow twitch are good for endurance. They use oxygen well and have lots of myoglobin (an oxygen carrier like hemoglobin). Fast twitch are for speed and they come in two flavors. Type IIa are good for speed and endurance, and Type IIx are for pure, short-term speed.

People are born with a mixture of Type I and Type II fibers, usually around 50:50. Sprinters usually have more Type II fibers, maybe 60:40. Quicksilver must be 99:01 or more; Usain Bolt is 90:10 fast twitch and I don’t see him coming close to the speed of sound.

A ridiculously high fast twitch ratio is genetic, not a mutation per se, but it would be mighty unusual. My guess is that Quicksilver would be mostly Type IIa, since he can run fast for hours, Bolt maxes out at about 200 meters.

There is a certain mutation might help Pietro increase his fast twitch fibers. In a 2015 study, knocking out a gene called Fnip1 (codes for folliculin interacting protein-1) led to an increase in slow twitch fibers. Fnip works with follicullin (imagine that) in the area of energy and nutrient sensing. If having less Fnip1 leads to more slow twitch, then maybe more Fnip1 might call for making more energy in the cell, which would tend to support Type II fiber development.

Myostatin-induced muscular hypertrophy makes body

builders out toddlers. It isn’t just the increased muscle

mass, it’s the lower adipose levels (muscle requires

energy, so there is less fat). The muscle doesn’t create a

problem – it’s usually the parents that are the problem.

So being fast twitch makes him fast, but Quicksilver would need more – he would need a whole lot of Type IIa muscle fibers. We’ve got a mutation for that too. The protein myostatin is a regulator of muscle growth; it’s function is to limit the growth of muscle. With a mutation that prevents function of myostatin, you end up with myostatin-induced muscular hypertrophy - a huge amount of muscle and very little body fat. Maybe this isn’t such a bad mutation to have; it would certainly get Quicksilver closer to his onscreen abilities.

Other mutations can affect muscle performance as well. The gene for angiotensin converting enzyme (ACE) comes in several forms. One form, termed D, is associated with increased speed in athletes. The normal form is called I; but in a study of Japanese runners, people with I/D or D/D (you have two copies, one from mom and one from dad) were much faster. This is just one of many studies to conclude that the D allele is associated with speedy muscles.

There is another protein called alpha-actinin 3. If a person has a specific mutation in the gene for this protein, called the X allele, then the individual will have more muscular endurance, and perhaps more speed, according to a 2014 study.

More than 10 other genes have polymorphisms (small changes) that can be associated with promoting or inhibiting speed and endurance. There is no study showing an athlete with all the polymorphisms that make you faster or stronger – but Quicksilver would likely need them all if he wants to approach Mach 4.

Aside from muscle mass and speed, our Avenger of interest would need the oxygen and carbohydrates to power those muscles – certainly much more than you or I need. Oxygen is taken from the air by the lungs and the oxygen is carried to the muscles by the blood. When sugar and oxygen get to the muscle, they are used to produce ATP in the mitochondria. Quicksilver needs more oxygen, more blood flow, more carbohydrate and more mitochondria if he wants to be really fast. We’ve got mutations for that.

Heat shock protein 72 (HSP72) usually works in protecting proteins from damage, but it can have other functions. A 2014 study showed that activating HSP72 increases contraction of the heart, oxygen usage, and mitochondria number in cells. There are mutations that gives constitutively active HSPs (working all the time). It is these forms that could increase energy production in muscle.

Even superheroes need to be in shape. Running requires

you to put more oxygen into your blood and blow off

more CO2, so you breathe harder. Eventually, you get to

a point when you don’t have enough oxygen and you start

anaerobic metabolism. You’re going to panting for a

while to catch up.

Another way to increase blood flow and cellular activity would be to increase the basal metabolic rate. A 2014 paper described a mutation in a Japanese family that led to hyperthyroidism. Increased thyroid function leads to increased cardiac output, stroke volume (amount of blood moved with each heartbeat) and heart rate. We better give Quicksilver one of these mutations as well.

He needs more oxygen, so we also better provide Pietro with a mutation in growth hormone receptor. A 1998 study showed that increased growth hormone (GH) in adolescent males was associated with higher VO₂ (amount of oxygen moved to blood). A recent study indicates that if you knock out the growth hormone receptor (GHRP) protein in mice, it is also associated with higher VO₂. This suggests that GHRP mutations result in more circulating GH, and higher levels of GH lead to increased VO₂ via some receptor-independent mechanism.

Finally, Quicksilver has to get more carbohydrates to the cells, which means he has to take in more carbohydrate as well. A mutation in the primary cilia of the POMC neurons of the hypothalamus (in the brain) leads to dysregulation of appetite (see this post). If you have this mutation, you’re always hungry, a condition called hyperphagia. This would lead to more calories and more energy for those strong muscles.

This could also be accomplished by mutations in the appetite hormones ghrelin and/or leptin. Leptin tells you when you are full, so a mutation that reduces its function would make you hungry, as would a mutation that increases the levels or function of the hunger hormone, ghrelin.

Neo could slow time down. Is it because he could increase

his metabolism and processing speed? Quicksilver has to

be able to do the same thing, or else everything would be

a blur as he sped by. That’s not good for avoiding

obstacles and catching the bad guy.

There is a final mutation that Quicksilver will need. Not so much to be speedy, but to keep from running into things. Brain processing speed is fast, but perhaps not fast enough for you to know what’s in front of you when you’re moving 3000 miles an hour. A recent study shows that the brain can visualize and recognize an image in just 13 milliseconds, but Quicksilver will need a serious upgrade to his operating system to go as fast as he is reputed to run.

Or will he? Another study shows that small animals have high metabolic rates, and higher metabolic rates are associated with faster brain processing speeds. Like Neo in The Matrix, perhaps Quicksilver’s increased metabolic rate due to thyroid mutations (see above) will make time slow down for him. This is how houseflies keep from being swatted (see this post), so it could work for him too.

Personally, I’m wondering what kind of mutations Pietro would need to prevent the horrible chafing he would probably experience. Wouldn’t he cook himself, or at least burn his crotch to ash? I guess this is where the fiction part of the story comes in.

Contributed by Mark E. Lasbury, MS, MSEd, PhD

As Many Exceptions As Rules

Reyes, N., Banks, G., Tsang, M., Margineantu, D., Gu, H., Djukovic, D., Chan, J., Torres, M., Liggitt, H., Hirenallur-S, D., Hockenbery, D., Raftery, D., & Iritani, B. (2015). Fnip1 regulates skeletal muscle fiber type specification, fatigue resistance, and susceptibility to muscular dystrophy Proceedings of the National Academy of Sciences, 112 (2), 424-429 DOI: 10.1073/pnas.1413021112

Henstridge, D., Bruce, C., Drew, B., Tory, K., Kolonics, A., Estevez, E., Chung, J., Watson, N., Gardner, T., Lee-Young, R., Connor, T., Watt, M., Carpenter, K., Hargreaves, M., McGee, S., Hevener, A., & Febbraio, M. (2014). Activating HSP72 in Rodent Skeletal Muscle Increases Mitochondrial Number and Oxidative Capacity and Decreases Insulin Resistance Diabetes, 63 (6), 1881-1894 DOI: 10.2337/db13-0967

Nakamura, A., Morikawa, S., Aoyagi, H., Ishizu, K., & Tajima, T. (2014). A Japanese family with nonautoimmune hyperthyroidism caused by a novel heterozygous thyrotropin receptor gene mutation Pediatric Research, 75 (6), 749-753 DOI: 10.1038/pr.2014.34

Westbrook, R., Bonkowski, M., Arum, O., Strader, A., & Bartke, A. (2013). Metabolic Alterations Due to Caloric Restriction and Every Other Day Feeding in Normal and Growth Hormone Receptor Knockout Mice The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 69 (1), 25-33 DOI: 10.1093/gerona/glt080

Potter, M., Wyble, B., Hagmann, C., & McCourt, E. (2013). Detecting meaning in RSVP at 13 ms per picture Attention, Perception, & Psychophysics, 76 (2), 270-279 DOI: 10.3758/s13414-013-0605-z

Gunel, T., Gumusoglu, E., Hosseini, M., Yilmazyildirim, E., Dolekcap, I., & Aydinli, K. (2014). Effect of angiotensin I-converting enzyme and α-actinin-3 gene polymorphisms on sport performance Molecular Medicine Reports DOI: 10.3892/mmr.2014.1974