by. Yaron Lohr
for Dr. Logan
Over the last decade and a half, there has been much progress on revealing the complex sequence of events that result in the onset of skin cancer. Two main pathways have been proposed, one that gives rise to tumors itself, the other to a general suppression of the human immune system. Each takes place through different chemical reactions - the agent of initiation; however, is that of UV-B radiation - something that is causing great worry due to its gradual increase in intensity.
For many years now, there has been an ever-growing concern by scientists and oncologists alike that the incidence of skin cancer has shown not only a marked rise; however, that North American society is encouraging light-skinned persons to contribute to an epidemic. In the early 18th century it was fashionable for light-skinned persons to appear as "pale" - this look was enhanced by the application of creams and powders, which were later found to be toxic. Now, as we approach the 21st century, fashion seems to have taken a flip-flop of sorts. The ideal "bronze" complexion is made possible free of charge via yet another toxic agent - rays of light from our very own Sun. I work in a tanning parlor every day hundreds of people come in to tan exposing themselves to harmful rays,. maybe I'm a hypocrite because I sell packages everyday but society today is aware of the harmful consequences and advised constantly to stay out of the sun. When I lived in Canada, numerous families plan their vacations in "sun-soaked" regions of the world where they can escape from cold weather and lie down on a beach for hours on end, their exposed skin not just slowly darkening, but also mutating. "Is it really cool to look good even thou serious consequences can arise. Herein lies the problem: people are aware that there is something called Ultra-Violet radiation that is harmful to them, yet they refuse to abstain from activities that may potentially threaten their lives, for the sake of vanity. Little do they know how complicated the matter is and that skin cancer has recently become the most common form of the disease in Australia, pushing "cancer of the small bowel" into second place
Skin cancer takes one of three different forms corresponding to the three major types of skin cells. There are basal cells, which lie near the base of the epidermis; squamous cells, which are flattened and near the surface; and finally melanocytes that are interspersed in the basal layer and have numerous extensions that reach outward. Solar radiation, which contains ultra-violet radiation (light with a wavelength of 290-320 nm) is able to penetrate these cells and alter their DNA base pair sequencing - this gives rise to mutations and tumor promotion
There are many complex chemical reactions that take place between UV radiation and these skin cells, many hypotheses for what those reactions are, and much debate between scientists and doctors as to what is really going on. What they seem to agree upon is that UV radiation not only gives rise to cancerous cells, it also allows for their proliferation by causing a systemic immunosupression. The mechanisms for both of these effects will be thoroughly examined, although there is great uncertainty in them being absolute. First of all, however, we must realize that one of the variables that increase the incidence of skin cancer is the greater intensity of UV-radiation that is reaching the earth's surface - this increase is due to an unprecedented thinning of the Stratospheric Ozone Shield.
The Stratospheric Ozone layer is what allowed for the evolution of terrestrial life as we know it. Although the layer (when compressed) is only 3mm thick, it absorbs light of very energetic wavelengths (<325 nm) which the DNA in our cells react with irreversibly. It is not a coincidence that terrestrial life evolved following the establishment of the ozone layer as all life forms had to remain submerged in the sea until UV-radiation was finally filtered out by the ozone layer. Before human intervention, stratospheric ozone was kept at a steady-state concentration through a number of naturally occurring chemical reactions.
Sources:
Photolysis of Diatomic Oxygen
NO + O3 ---> NO2 + O2
a lot of CH3Cl is produced by marine biomass (100 tons/yr)
Exactly how does UV-radiation react with our DNA to give rise to cancerous cells? There is no absolute answer for this; however, many mechanisms have been proposed. The most popular theory currently is that UV-radiation has a "signature mutation", it strikes at a precise location on the DNA base pairs and then the photon of light reacts with it 5. After many years of research by independent and joint efforts, the trademark of UV has been deciphered. There are only four bases in DNA and these are categorized in two groups: Purines that are bicyclic structures (Adenine & Guanine) and Pyrimidines that are monocyclic structure (Cytosine & Thymine). The trouble with UV-radiation is that it is able to alter the specificity of DNA-Base-pairing and it specifically affects the Pyrimidines (C and T). This alteration is seen when the Pyrimidines lie adjacent to one another i.e. CC, TT. On a strand of DNA, whenever there are adjacent Pyrimidines, the photons of UV-light absorbed will cause a dimerization of the two Bases. Unfortunately, when it comes time for the cell to replicate, it will do so incorrectly as the RNA transcript will correspond with the new Dimer, not the original Pyrimidine. What actually happens is that the dimerization causes a substitution of Thymine to pair up with Cytosine on the replicated DNA, which is clearly an incorrect match, as Cytosine should only pair with Guanine. Although the cell normally has proofreading measures, these errors are far too numerous that go on to form many new faulty DNA strands. When these strands go on to encode for amino acids, they are read as a triplet code; however, the codes are drastically altered and give rise to "frame-shift mutations" resulting in faulty protein synthesis. Now we begin to see tumors. More specifically, the UV-radiation targets a specific gene for its attack, the p53 tumor suppressor gene. Therefore, a gene that encodes for a protein that normally suppresses the proliferation of tumors is being mutated itself. Normally when DNA damage occurs in skin and it is extensive, the p53 protein induces those cells to undergo "programmed cellular death"6 . Since p53 is now not functioning properly, those cells are unable to kill themselves. Furthermore, adjacent healthy cells, when damaged do undergo "programmed cellular death" and this gives space for the proliferation of p53 cells. Therefore, UV-radiation "throws two punches", it mutates the p53 gene to encode cancerous cells and it allows for healthy cells to die, which allows for p53-cell takeover. This type of mutation is seen in squamous cells and basal cells, but not in melanocytes. With this effect being exclusive to Squamous and Basal cells the mutation is less fatal; however, this leaves us in the dark about the mechanism for melanoma - the skin cancer that shows the highest mortality rate.
UV radiation also triggers another distinct immunological effect - systemic immunosupression. What this means is that although tumors appear on the surface of skin, there is also a large-scale effect being experienced by the body which compounds the severity of the disease. What many people of color many not know is that although they do posses the pigment melanin that prevents UV light from affecting the cells in their skin, they are not safe from this second effect of UV which operates via a completely different mechanism. It has been hypothesized that the initial event in immune suppression is UV-B absorption by urocanic acid (UA), the most abundant substance found in the outer layer of skin. Researchers found that urocanic acid switches from a trans to cis geometry at exactly the wavelength that triggers immune suppression. When it absorbs a photon the molecule bends, and when that happens it becomes immunologically active 7. UA exists as its trans isomer (t-UA) in the uppermost layer of the skin which is formed as cells of the second layer become metabolically inactive. During this process proteins and membranes degrade, histidine is released, and histidase catalyzes the deamination of histidine to form t-UA. Due to an absence of epidermal urocanase that could metabolize UA further, t-UA accumulates in the epidermis until removal by either the monthly skin renewal cycle or through sweat 8. It is still not completely clear how t-UA goes on to suppress immunity; however, many hypotheses have been put forward. Mary Norval of the University of Edinburgh has discovered that the active t-UA may hamper the ability of Langerhans cells. These are dendritic cells stationed in the epidermis which are believed to play a part in immune "surveillance" which scan skin tissue for invading organisms in order to recruit killer T-cells to the lymph nodes. Killer T-cells are the component of the immune system that is responsible for destroying foreign antigens by literally "blowing them up". Reeve and Sydney used urocanic acid that was tagged with a radioactive marker to find that UA is not restricted to the skin, but that it can migrate to the lymph nodes. If the killer T cells are not fully functional, this allows for any foreign microbe to enter the body and infest us with disease until they are destroyed by a delayed and weakened response by the killer T-cells. All these theories have compelled some to ask, "if UV really causes a general suppression of the immune system, why does Australia, the country with the highest incidence of skin cancer not also have an unusually high incidence of infectious disease?" 10. You cannot rule out a link between UV exposure and infectious disease, it's not just a question of incidence, the effects of UV exposure are likely to be more subtle and might include altering the duration or severity of an infection.
The question of whether or not UV light really does affect systemic immune suppression has sparked much debate which resulted in a report by the University of Miami in 1990 which presents a very strong case that UV light can suppress human immune responses. The research group exposed a group of 40 volunteers to low doses of UV and then applied to them an immunogenic chemical, 2,4-dinitrochlorobenzene. Under normal conditions, this chemical usually initiates what is called "contact hypersensitivity response", a standard measure of the responsiveness of someone's immune cells. An astounding 40% of the subjects failed to give such a response on patches of skin that had been exposed to UV-B light. Furthermore, those with skin cancer were actually able to develop a tolerance to 2,4-dinitrochlorobenzene. This report was of monumental importance in the progression of understanding the intricacies of the disease; however, there is still so much unknown as to what sequence of events takes place.
There is no doubt that so long as people cannot resist the urge of going to the beach for a tan, or remain outdoors in conditions of high sunlight, they will not be free from the hazardous effects of exposure to UV-B radiation. For instance, the "sunshine capital of the world", Australia has shown to have the highest incidence of skin cancer worldwide. More than two out of every 100 people surveyed had skin cancer 13. Most of them had non-melanoma type cancer; however, this can at anytime spread to other parts of the body at which time it becomes fatal. Regardless, the people still do not refrain from doing what they have been doing all their lives - enjoying the sunshine. What "sunbathers" do to protect themselves; however, is apply sunscreen to their skin which acts to prevent the absorption of UV-B by DNA. What researchers have found though is that the sunscreens do not prevent UV radiation from activating urocanic acid in the outer layer of the skin. Thus, the immunosuppressive effects of UV are still occurring - this gives the wearer a "false sense of security". In fact, the most recent work on mice, by the University of Sydney, shows that the two most popular UV-B absorbers - octyl dimethyl para-aminobenzoate (Padimate-O) as well as 2-ethylhexyl-p-methyoxycinnamate (2-EHMC) - prevent UV light from destroying Langerhans cells but fail to block immune suppression 14. Since there is still a long way to go in skin cancer research, there must be alternative solutions to decrease the numbers of a growing problem of this size.
Many of the solutions to a "large scale" problem are similar to the ones used for another epidemic of our time - AIDS. Since the cure is far from being discovered, the best way to avoid the situation is through prevention. Public Health awareness promotion in nations such as Australia and New Zealand that are most affected by increased UV levels have gone to great efforts to educate their people as to the severity of the situation. Reports such as the UV-index which rates the UV-level any given day on a simple scale of 1 to 10 serve as a warning to the people of the dangers of venturing outside for prolonged periods of time. The downfall with this is that they may not consider a UV-index reading of "8" to be "severe" after a period of desensitization to the reports. Mandatory rules such as children wearing hats while school is a step in the right direction. Furthermore, they are not allowed outside on days when the UV-level is too high. The Anti-Cancer Council of Victoria has actively promoted a campaign for Australians to unite and plant trees to increase the amount of shade available to them. The preventative measure that will most probably contribute to the greatest decrease in incidence of skin cancer will be the most difficult to impose - for people to change their lifestyle. So long as the pursuit of a golden complexion remains in fashion, tears of regret in later years will continue to pour.
R. H. Logan, Instructor of Chemistry, Dallas County Community College District, North Lake College.
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All textual content copyrighted (c) 1997 R.H. Logan, Instructor of Chemistry, DCCCD All Rights reserved
Revised: 5/1/99
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