By Doris Loh
AN IN-DEPTH CONSIDERATIONS ABOUT MELANOMA AND HOW TO PREVENT IT (part 1)
Now that you understand how melanin contributes to the development of dangerous skin cancers like melanoma, I am sure you are also wondering why there has been evidence linking increased incidences of skin cancers despite reductions in sun exposure. If melanin causes skin cancer by generating free radicals when it absorbs UV radiation from the sun [1], then why would one develop skin cancer if one reduces or even eliminates sun exposure?
The Genetic Evolution of Pheomelanin
When the skin is exposed to UV radiation, melanogenesis begins to produce melanin. In the skin, melanogenesis actually produces a combination of two different types of melanin at different mixed ratios. One is the brownish black colored eumelanin, the other is the reddish, yellow pheomelanin. [2] The variation in skin pigmentation found in the various Fitzpatrick Skin Types is due to the type and quantity of melanins generated, melanosome size, and the manner in which keratinocytes sequester and degrade melanins [3] In people with fair skin categorized as Fitzpatrick Skin Type I, the ratio of pheomelanin to eumelanin is higher as a result of genetic mutations.
The evolution of most of the alleles associated with light and dark skin pigmentation actually began prior to the beginning of the modern human over 300,000 years ago. Darker pigmentation is believed to be a specialization in the genus Homo in the past 2 million years or so when the species lost its protective body hair. Evidence is clear that over hominid history, both light and dark pigmentation continued to evolve. [4]
In our modern world, human pigmentation is found to be correlated with geographic and environmental differences. People living at lower latitudes have darker pigmentation, meaning the ratio of eumelanin to pheomelanin is higher, whereas the opposite is true for those living at higher latitudes. The mixture of this ratio is determined by tyrosinase activity and the substrate concentrations of tyrosine and cysteine that form a multi-enzyme complex with melanocytes. The disruption of these enzyme complexes due to mutations significantly affects pigmentation. [5]
Studies have determined that the genetic loci associated with skin pigmentation that are responsive to UV radiation were targets in nature’s selection process during evolution. The genetic polymorphism associated with light skin pigmentation is fixed in European, East Asian, and Native American populations. [4]
When early humans began migration out of Africa approximately 2 million years ago, it is reasonable to assume that genetic adaptations were made to increase the efficiency for the capture of beneficial solar radiation, responsible for many vital biological functions, from the regulation of circadian rhythms that can affect the modulation of immune responses [6], to the generation of important hormones like vitamin D.
The question is, why did Nature increase the ratio of pheomelanin to eumelanin as latitudes increased? The answer is tied the variation in photosynthetically available radiation (PAR) at higher latitudes. Low solar elevations at high latitudes can cause a spectral shift resulting in proportionately more blue light being transmitted. [7] So why is pheomelanin preferred over eumelanin at high latitudes? Because pheomelanin is exquisitely sensitive to blue light. Nature cleverly uses this specific feature of pheomelanin to capture photon energy from the sun at high latitudes. Unfortunately, Nature certainly did not anticipate how our world can create an excess of visible light, at all hours of the day.
Pheomelanin Reacts with UVA and the Visible Spectrum
It has been observed that people with light skin pigmentation are at higher risk for developing skin cancer by 70-fold, when compared to those with dark skin pigmentation. [8] The unique physiological reactions between pheomelanin and electromagnetic radiation offer relevant insight as to why light skin pigmentation contributes to higher occurrence of skin cancer.
In contrast to UVB radiation, which is directly absorbed by DNA, UVA radiation acts essentially through photosensitization that results in the generation of singlet oxygen and other radical species leading to damage in DNA (nuclear and mitochondrial) as well as other epithelial biomolecules. Melanin as an effective photosensitizer, actively absorbs UVA, and is responsible for direct damage to skin cells upon exposure. [10, 11] Glass used in windows can block complete penetration of UVB radiation from the sun. But not all glass can block UVA. Laminated glass totally blocked UVA radiation, while smooth ordinary glass transmitted the highest dose (74.3%). [12] Why is the blockage of UVA important for people with high ratios of pheomelanin in their skin?
Pheomelanin Modifies Catalase Electrical Charge under UVA Irradiation
Pheomelanin has been shown to induce modification in the electrophoretic properties of native catalase when exposed to UVA radiation. By acting as a photosensitizer, pheomelanin causes charge modification in catalase through mechanisms that involve singlet oxygen or its downstream products. [13] So if you stay out of the sun, block UVA transmission from glass, are you safe from the potential damage from the photosensitizing effects of pheomelanin? For that answer, you have to remember why the ratio of pheomelanin was increased as adaptation to migration of humans to higher geographic latitudes.
Pheomelanin Is More Effective than Eumelanin in the Production of Free Radicals When Exposed to Visible Light
New evidence now show that melanin responds also to visible light between 380 to 740 nanometers (nm). It has been observed that at 532 nm, the photosensitization of melanin can generate singlet oxygen that increase membrane permeability to cause both DNA photo-oxidation and necro-apoptotic cell death. Surprisingly, pheomelanin generated 30% more singlet oxygen than eumelanin when exposed to visible light at 532 nm. [14] When exposed to UV radiation, pheomelanin produces almost five times as much superoxide as eumelanin after exposure in vivo. [15]
Pheomelanin Produces ROS via UV-Independent Pathways
Latest discoveries now link pheomelanin to UV-INDEPENDENT risks in the development of melanoma in humans. As Nature experimented with genetic polymorphism that selectively favored the creation of light skin color that facilitates vitamin D production at high latitudes, it is possible that she deemed it less important to address the consequences of those mutations that left the skin unprotected against damaging ultraviolet radiation, as well as the formation of reactive oxygen species from biosynthetic intermediates of pheomelanin production. [16]
The mechanism by which pheomelanin generates reactive oxygen species is not fully understood. It is possible that the lower ionization potential of pheomelanin than eumelanin results in a higher capacity for pheomelanin to be involved in radical-producing reactions than eumelanin. [17] Or it could be due to the depletion of glutathione as a result of pheomelanin synthesis. Pheomelanin, unlike eumelanin, incorporates cysteine into its structure. Glutathione, one of the most important cellular antioxidants, is the major cellular store of cysteine. [17] In animal models, the pheomelanotic coat color of wild boars is associated with increased levels of oxidative stress and lowered glutathione levels in their muscle cells [18]
Can the Sunshine Vitamin Save the Day?
One question that you may have, regarding how our skin responds to radiation from the sun, is the protective effects of Vitamin D that is synthesized in our skin upon UVB exposure. Is Vitamin D capable of protecting us from cancer, especially skin cancer?
Vitamin D Supplementation does NOT PREVENT Cancer
The association between cancer progression and vitamin D deficiency is well documented. [19] Due to inconsistencies reported by in vitro and in vivo studies, the largest-ever randomized clinical trial was conducted recently to test the effectiveness of vitamin D supplementation in the prevention of cancer. A nationwide, randomized, placebo-controlled trial known as the VITAL study involving a total of 25,871 participants in the USA (including 5106 black participants), were given a daily dose of 2,000 IU of vitamin D3 (cholecalciferol). The results obtained at the end of the median follow-up period of 5.3 years led to the conclusion that vitamin D did not reduce the occurrence of breast, prostate, or colorectal cancer in the total study population. There was a suggestive 17% reduction in cancer deaths, with African Americans assigned to vitamin D experiencing a suggestive 23% reduction in cancer risk. [20]
There are many who frown upon this largest-ever clinical trial as inadequate due to the fact that exogenous vitamin D was used as opposed to endogenously synthesized vitamin D from sun exposure. Is vitamin D produced endogenously different? A group of scientists tested this hypothesis, and their results would surprise you.
This excellent study conducted in 2017, gathered statistics from six cities in Chile, South America at different latitudes ranging from Arica at 18.18° S to Punta Arenas at 53.00° S. The study considered monthly solar UV Index measurements from each city; non-melanoma skin cancer (NMSC) and melanoma skin cancer (MSC) rates; mortality rates per 100,000 inhabitants and the association with the time required to synthesize adequate levels of vitamin D in different geographical locations of Chile. Total vitamin D was also calculated to explain the association between NMSC and MSC rates in 6 cities in Chile between latitude 18 and 53°S. [21] The conclusions drawn at the end of this study was indeed nothing less than shocking.
Endogenous Vitamin D does NOT PREVENT Skin Cancer
Contrary to what most would anticipate, the study found that non melanoma skin cancer (NMSC) rates actually decreased as latitude increased. This supports the correlation between low solar UVI measured in cities at high latitudes, and lower ROS damage incurred by UV radiation. NMSC is one of the most common malignant skin tumors in people with fair skins. In many sunny countries the prevalence of NMSC exceeds the total number of all other neoplasms. [21]
Melanoma skin cancer (MSC), on the other hand, actually decreased between latitude 18°S (Arica) and 23°S (Antofagasta) in MALES. But MSC rates was found to be INCREASED between latitude 23°S (Antofagasta) and 40°S (Valdivia) in males AND females. However, MSC rates DECREASED at higher latitudes in both genders, consistent with the observed annual doses of UVA radiation that decreased with increasing latitude. The decrease in MSC in males at extreme low latitudes could be explained by increased protection from higher eumelanin ratio in males who commonly have Type IV skin in Chile, whereas most females in Chile have Type III Skin. [21]
When the total vitamin D accumulated in 1 year was analyzed, the results showed that there was absolutely no correlation between NMSC and total Vitamin D accumulated, meaning that this type of cancer would not depend on vitamin D synthesis. However, similar to the VITAL study, there was a strong correlation between MSC mortality rates and total vitamin D accumulated over the same period. Consistent with this finding, at the highest latitude at Punta Arenas, the MSC mortality rate was higher despite a lower MSC incidence. [21]
The relationship between the sun, our skin, vitamin D and cancer development is a complex one, as both the VITAL study and this elegant study on MSC/NMSC progression in various Chilean cities managed to show. Raising vitamin D levels with sun exposure does not decrease your risk in skin cancer. But not having adequate vitamin D, whether endogenously produced or exogenously supplemented, does increase your mortality risk. How is that possible?
Vitamin D is a Regulator of Redox
Vitamin D is now being recognized as a major modulator of plasma thiol/disulphide redox systems [22]. Its effects include inducing expression of thioredoxin reductase in prostate and breast cancer cells. [23] If you remember, thioredoxin reductase is coupled with ascorbate in electron/proton transfers. [24] Do you think vitamin D will be able to achieve its intended effects in redox regulation if there is a deficiency in vitamin C, ascorbic acid?
Ascorbic Acid: The Ultimate REDOX Balancer
We know that while protecting our cells from electromagnetic radiation, both eumelanin and pheomelanin especially, can generate reactive oxygen species and singlet oxygen. However, Nature did supply us with ascorbic acid, or Vitamin C, the perfect anecdote to balance excess oxidative stress. Vitamin C is one of the most effective scavengers of superoxide [24] and singlet oxygen. [26] The unique attributes of ascorbate allow it to combine fast proton-electron transfers with high reactivity in enzymes that are designed to use it exclusively, yet ascorbic acid is able to remain relatively stable and unreactive until activated by those enzymes. This is the reason why ascorbate remains unchallenged as the most efficient and effective reductant found in living systems [27] [28]
Protect Your Skin from Dangerous Ambient Lighting
Now that you understand how light can affect your skin, it is important to remember that pheomelanin and eumelanin are both reactive to visible light. Artificial light is all around us both day and night. The intelligent control of ambient lighting while indoors, especially during night time is critical to ensure optimal functioning of the skin pigmentation system devised by Nature. She may not be perfect, but we also need to be responsible for the world we have created. Nature did not fail us, we only need to heed her messages and live by her mandates.
Thank you for reading, and I look forward to your comments.
REFERENCES:
[1] https://www.ncbi.nlm.nih.gov/pubmed/6087733
[2] https://www.ncbi.nlm.nih.gov/books/NBK459156/
[3] https://www.ncbi.nlm.nih.gov/pubmed/21326292
[4] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444068/
[5] https://www.jidonline.org/article/S0022-202X(15)61036-3/fulltext
[6] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5763605/
[7] https://aslopubs.onlinelibrary.wiley.com/doi/pdf/10.4319/lo.1989.34.8.1490
[8] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4299862/#R51
[9] https://www.ncbi.nlm.nih.gov/pubmed/21723388
[10] https://www.ncbi.nlm.nih.gov/pubmed/10336420
[11] https://www.ncbi.nlm.nih.gov/pubmed/21494240
[12] https://www.ncbi.nlm.nih.gov/pubmed/19614895
[13] https://www.sciencedirect.com/science/article/pii/S0022202X15325975#bb0020
[14] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4236153/
[15] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC524044/
[16] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241673/?fbclid=IwAR2Z5er9rorMLE7cAkutpiW-6o7gSyEtBxUX8snmwksnwaMEhTPXvckTrvM
[17] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4033715/#R8
[18] https://www.ncbi.nlm.nih.gov/pubmed/22705484/
[19] https://www.ncbi.nlm.nih.gov/pubmed/19817700
[20] https://www.ncbi.nlm.nih.gov/pubmed/30415629
[21] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5431270/#b20-ol-0-0-5898
[22] https://www.ncbi.nlm.nih.gov/pubmed/24628365
[23] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938036/
[24] https://www.ncbi.nlm.nih.gov/pubmed/9722529
[25] https://link.springer.com/article/10.1007/BF02704692
[26] https://www.frontiersin.org/articles/10.3389/fphys.2018.01109/full
[27] http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.922.1554&rep=rep1&type=pdf
[28] https://www.linkedin.com/pulse/vitamin-c-mitochondria-part-1-redox-5g-world-doris-loh/
