Summary

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Ultraviolet radiation directly and indirectly induces DNA lesions, which cause mutations and trigger inflammation and immunosuppression, which mediate tumour growth. Both ultraviolet radiation itself and ultraviolet-induced inflammation lead to the generation of reactive oxygen species. These reactive oxygen species also cause DNA lesions and increase the frequency of mutations. Furthermore, lipid peroxidation caused by ultraviolet radiation and reactive oxygen species also contributes to immunosuppression.

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The incidence of skin cancers is increasing worldwide, and especially in older people.

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The most effective way to reduce skin cancer incidence is to avoid unnecessary sun exposure, use protective measures when in the sun, and avoid tanning devices.

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Photocarcinogenesis is a complicated, multistep pathway, which is initiated by the formation of dipyrimidine photoproducts, which lead to the formation of mutations (the initiation phase). Sunburn and inflammation caused by the presence of persistent DNA lesions, including dipyrimidine photoproducts and oxidative DNA lesions, function as the promotion phase in photocarcinogenesis. Dipyrimidine photoproducts trigger ultraviolet-induced immunosuppression, which leads to the failure of immunosurveillance and enables the cancer cells to grow and progress.

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People who are taking immunosuppressants or some other kinds of medication, including voriconazole and hydrochlorothiazide, should be careful to protect themselves from exposure to sunlight.

Box

Fundamentals.

Solar radiation encompasses a broad range of wavelengths of photon energy in the electromagnetic spectrum, including ionizing radiation, ultraviolet (UV) radiation, visible light, and infrared radiation (Fig. 2.4.1). UV radiation is conventionally classified into three types: UVA (wavelengths of 315–400 nm), UVB (280–315 nm), and UVC (100–280 nm). Solar UV radiation has beneficial biological effects, including enabling vitamin D synthesis, but its adverse effects include the induction of skin cancers (see Chapter 5.8).

Fig. 2.4.1

Schematic diagram of bands of solar radiation, classified by wavelength. UVR, ultraviolet radiation.

A simple perspective is that UVB-induced DNA photolesions cause mutations, which may be equated with initiation, a term originally used to describe the first phase of chemically induced carcinogenesis in rodents; on the same basis, UVB-induced inflammation, and specifically sunburn, equates to the promotion phase of carcinogenesis. However, recent findings have revealed that the photocarcinogenesis pathway is more complex; each of these processes is mediated by various cellular, biochemical, and molecular changes, which are closely interrelated (see Chapter 3.11).

The accumulation of DNA photolesions caused by UV radiation in several cancer-related genes, which may still be regarded as the initiation phase, plays a crucial role in carcinogenesis. These DNA photolesions contribute to the development of skin cancers through specific mutations that lead to the upregulation or downregulation of signal transduction pathways of cell growth and cell-cycle dysregulation [1,2]. In addition, pyrimidine dimers play a role in UV-induced immunosuppression, which also plays an important role in photocarcinogenesis [3], partly by upregulation of interleukin 10 (IL-10), an immunosuppressive cytokine [4]. In skin cells, UV radiation also produces oxidative stress and oxidative DNA damage, which cause alteration of the genes involved in apoptosis and modification of cell signalling by redox regulation, resulting in inflammation (Fig. 2.4.2).

Fig. 2.4.2

Schematic summary of photocarcinogenesis as detailed in the text. COX-2, cyclooxygenase 2; IL-1β, interleukin-1β; iNOS, inducible nitric oxide synthase; MAPK, mitogen-activated protein kinase; 8-OHdG, 8-hydroxydeoxyguanosine; ROS, reactive (more...)

In this chapter, knowledge about photocarcinogenesis is summarized.

Sources of ultraviolet radiation

The main source of human exposure to UV radiation is solar radiation. In addition, many people have been exposed through the use of tanning devices (sunlamps and sunbeds), which are artificial sources of UV radiation; this warrants concern for human health (as discussed later).

In some occupational circumstances, UV lamps are used for the purpose of polymerization, typically in the course of hardening resin and coating. Modern factories have production processes designed so that employees are well protected, and therefore such lamps are rarely associated with harmful impacts on human health. Germicidal UV lamps are commonly used to disinfect rooms, the floors of laboratories, and sometimes public spaces, including hospitals, gymnasiums, and swimming pools.

Special UV lamps are used therapeutically to treat certain skin diseases, including vitiligo vulgaris, psoriasis, and atopic dermatitis. Currently, for therapeutic purposes, narrow-band UVB sources that emit specifically radiation of wavelength 311 nm are widely used, to reduce exposure to wavelengths shorter than 305 nm, which are most harmful in relation to developing skin cancer.

During the welding process, UV radiation is emitted, and therefore welders should use personal protective equipment in the course of their work (see Chapter 2.10).

The ozone layer in the stratosphere absorbs solar UV radiation of wavelengths shorter than 300 nm. Therefore, only UVA radiation and UVB with wavelengths longer than 300 nm reach the Earth’s surface. The radiation reaching the Earth’s surface is largely composed of UVA (95%), with a small UVB component (5%).

The level of solar UV exposure at the Earth’s surface varies with latitude, altitude, time of day and time of year, cloud cover, other atmospheric factors (specifically including pollution), and reflection from nearby surfaces. UV radiation is stronger at high altitudes than at ground level, because the thinner atmosphere blocks less UV radiation. About 80% of solar UVB penetrates thin cloud. UVB scatters in the air and is reflected by buildings and land surfaces. The reflection of solar UV radiation varies depending on the condition of the land surface. Snow, sand, and other surfaces reflect UV radiation to varying degrees: new snow reflects 80%, a sandy beach reflects 10–25%, concrete or asphalt reflects 10%, the surface of water reflects 10–20%, and a lawn or grassy plain reflects 10%. The intensity of solar UV radiation depends on the height of the sun in the sky; it is strongest at solar noon and during the summer months.

Some weather services provide daily forecasts of the intensity of solar UV radiation. Such information may be helpful as a rough indication, but caution should be exercised, because the intensity of solar UV radiation differs greatly between locations where relevant measurements are conducted. Although several UV dosimetry instruments are commercially available, not all of the equipment is accurate and reliable. The best way to protect oneself from the sun is to adopt multiple personal measures, such as wearing protective clothing, wearing a hat, applying sunscreen, and using shade.

Epidemiology of skin cancers

The incidence of both melanoma and non-melanoma skin cancers is increasing worldwide, not only in White populations [5] but also in Asian populations. In addition, there is marked variation in incidence by geographical location between and within countries. Epidemiological studies have demonstrated a negative correlation between the latitude of residence and the incidence and mortality rates of melanoma and non-melanoma skin cancers in homogeneous populations.

According to statistics from the Ministry of Health, Labour and Welfare of Japan, the incidence of skin cancers in Japan has increased dramatically over the past decades, especially in people older than 65 years (Fig. 2.4.3). A longer life expectancy contributes to this increase in risk, because non-melanoma skin cancer is more common in older people. Furthermore, the incidence of non-melanoma skin cancer in men is strikingly higher than that in women in Japan as well as in Australasia, Europe, and North America, probably because the effects of lifestyle factors are similar in different countries.

Fig. 2.4.3

Incidence of skin cancers in Japan in 1975–2010 in different age groups.

The IARC Monographs classified UV-emitting tanning devices (sunlamps and sunbeds) as carcinogenic to humans (Group 1). Although commercial use of tanning devices is prohibited in some states of the USA, in almost all states and territories of Australia, and in some other countries, many people continue to use them. The association of sunbed exposure with predicted increased risk of induction of squamous cell carcinoma has been confirmed [6], and people should be aware of the risk associated with use of tanning devices.

Ultraviolet-induced DNA photolesions

The photon energy of UV radiation is not capable of causing ionization but results only in excitation at the atomic level. Therefore, all the biological consequences of UV radiation are attributable to excited chemical reactions in the molecules of the skin. DNA directly absorbs more energy from UVB photons than from UVA photons. UVB specifically acts on DNA by directly exciting the nucleobases, resulting in the instant formation of dimeric photoproducts at dipyrimidine sites. In contrast, UVA and visible light primarily exert a biological impact directly by participating in the formation of reactive oxygen species in the presence of photosensitizers, and indirectly produce oxidative DNA lesions. UVB produces dipyrimidine photoproducts by direct excitation, and also generates oxidative DNA lesions.

Studies have suggested that dipyrimidine photoproducts are the most important UV-induced DNA photolesions, because they are involved in cytotoxicity and mutagenesis [7]. Reactive oxygen species cause various biological effects via the redox signalling pathway and produce oxidative DNA lesions, which also play a role in carcinogenesis [8]. Among oxidative DNA lesions, 8-hydroxydeoxyguanosine (8-OHdG) has been established as a sensitive marker of oxidative DNA damage. The guanine base in genomic DNA is highly susceptible to oxidative stress, because guanine has the lowest oxidation potential of all the bases.

Recent work has shown that cyclobutane pyrimidine dimers are produced at higher yields than 8-hydroxyguanine (8-oxoG) after exposure to UVA in human skin cells and human skin in vivo [9]. The diuretic medication hydrochlorothiazide significantly increases the production of thymine dimers by UVA, independent of the presence of oxygen [10]. This indicates that excited hydrochlorothiazide molecules function as UVA-absorbing chromophores, which transfer energy to adjacent pyrimidines, thereby resulting in the formation of thymine dimers.

Ultraviolet-induced DNA lesions and mutations in skin cancers

The action spectrum for UV-induced carcinogenesis in animal experimental models is maximal within the UVB range, with the peak at 293 nm [11]. Formation of dipyrimidine photoproducts can lead to UV signature mutations in DNA. UV signature mutations are associated with transition-type mutations such as C:G → T:A at dipyrimidine sequences, where a transition is defined as a change from one pyrimidine (cytosine or thymine) or purine (guanine or adenine) to the other. The molecular changes observed in skin cancers have been analysed in many studies. In White people, TP53 mutations are present at much higher frequencies (~50–90%) in non-melanoma skin cancers than they are in internal malignancies [1]. These mutations are predominantly C:G → T:A at dipyrimidine sites, the UV signature mutations.

In Asian people, the UV signature mutations are significantly more frequent in skin cancers at sun-exposed body sites than in those at non-sun-exposed sites [12], suggesting that UV radiation is also closely involved in the development of non-melanoma skin cancer in Asian people. Several other reports have demonstrated that the types of mutations that are not considered to be caused by dipyrimidine photoproducts are frequently observed in human skin cancers at sun-exposed body sites [13], thereby suggesting that oxidative DNA lesions may also play a role to some extent in photocarcinogenesis.

Inflammation caused by sunburn promotes carcinogenesis, and particular DNA lesions are implicated

The sunburn process is dependent on several factors, including UV dose, UV wavelength, and photoskin type. After cellular molecules absorb UV radiation, photochemical reactions occur, and these processes are responsible for biological changes that culminate in sunburn. The findings of Devary et al. suggested that the UV response is initiated at or near the cell membrane rather than in the nucleus, and that the response may be elicited by oxidative stress caused by UV radiation [14]. There is plenty of evidence that various antioxidants attenuate erythema or oedema induced by UVB radiation [15]. Low levels of oxidants can modify cell signalling via redox regulation, and these signal modifications have functional consequences [16].

UV radiation triggers sequential molecular responses, thereby activating cell-surface growth factors and pro-inflammatory cytokine receptors. Mice deficient in tumour necrosis factor α (TNF-α), a pro-inflammatory cytokine, are resistant to skin carcinogenesis, although both deficient and wild-type mice exhibited the same c-Ha-ras mutations after treatment with 7,12-dimethylbenz[a]anthracene [17]. In animal photocarcinogenesis studies, some antioxidant nutrition that suppresses UV-induced inflammation has been shown to suppress cancer development.

Earlier, it was reported that in this mouse photocarcinogenesis model, the accumulation of 8-oxoG, an oxidative DNA photolesion, increases the development of skin cancers; this result is attributable to the upregulation of genes related to the inflammatory response pathway, such as Cxcl1 and Il-6, but not to the mutations caused by oxidative DNA lesions [8]. Rodier et al. reported that large doses of UV radiation, which cause irreparable damage to cells, induce DNA double-strand breaks and increase secretion of IL-6 [18].

Melanoma and ultraviolet-induced inflammation

Recently, much attention has been paid to melanoma formation and UV-induced inflammation. It is generally accepted that chronic inflammation increases the risk of cancer; this is consistent with the finding that excessive intense, intermittent sun exposure is one of the most important risk factors for melanoma.

In hepatocyte growth factor/scatter factor transgenic mice, a single dose of burning UV radiation to neonates, but not to adults, is necessary and sufficient to induce melanoma with a high incidence [19]. This provides an experimental basis for the epidemiological evidence that childhood sunburn is a major risk factor for the development of melanoma [20].

Whether UVA or UVB radiation is more dangerous for the development of melanoma is still controversial. Both non-melanocytic skin cancers and melanomas are induced by solar UV radiation, but there are some differences. Melanocytes show resistance to UVB-induced apoptosis. Consequently, melanocytes survive after acute sunburn, while harbouring high levels of DNA lesions, whereas keratinocytes tend to undergo apoptosis after large doses of UV radiation. The most frequent body sites for the development of superficial spreading melanoma, which is the most common type of malignant melanoma in the White population, are the trunk and thigh; these anatomical regions are often particularly exposed to the sun when sunbathing. Eumelanin protects the skin against UV-induced damage, whereas pheomelanin acts as a photosensitizer and causes oxidative DNA damage in melanocytes.

Role of UVA in photocarcinogenesis

Until recently, studies on carcinogenesis induced by UV radiation have focused on UVB-induced DNA mutations. However, the role of UVA in photocarcinogenesis is now receiving much more attention. One reason for this is increasing awareness of the involvement of UVA-induced reactive oxygen species in the development of melanoma. Another reason is that many studies have revealed that UVA generates not only reactive oxygen species but also cyclobutane pyrimidine dimers in vivo.

Cyclobutane pyrimidine dimers are now known to be produced at higher yields than 8-oxoG after UVA irradiation in rodent and human skin cells [9], prompting a paradigm shift in the theory of photocarcinogenesis. A recent series of studies demonstrating that UVA induces thymine dimers at much higher levels than other types of pyrimidine dimers, and that UVA does not induce (6–4) photoproducts [9], explains the mutation spectrum of the relevant genes in cancers at sun-exposed areas of the skin in humans [2]. An in vivo study analysing the action spectrum for photocarcinogenesis in a mouse model revealed that UVA is partly responsible for photocarcinogenesis [11].

UVA seems to cause cancer-promoting biological changes apart from DNA lesions that result in genomic mutations. Many of the carcinogenic functions of UVA have been attributed to the production of reactive oxygen species and the subsequent induction of the inflammatory signalling pathway. Reactive oxygen species generated by UV radiation upregulate the expression of many signalling molecules, including inducible nitric oxide synthase (iNOS), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), activator protein 1 (AP-1), signal transducer and activator of transcription (STAT), and cyclooxygenase 2 (COX-2), resulting in inflammation, which is followed, in turn, by generation of reactive oxygen species, depending on the strength of the inflammation.

Ultraviolet-induced immunosuppression

The immune system plays an important role in UV-induced carcinogenesis by contributing to host resistance to skin cancer development. However, UV radiation may circumvent immunosurveillance against skin cancers by modulating the immune response in a way that favours tumour development.

Skin cancers induced by UV radiation are highly antigenic, and can therefore be recognized by the immune system. This is evident from UV-induced murine skin cancers, many of which are immunologically rejected upon transplantation into normal syngeneic mice [3]. The exceptionally high incidence of skin cancers, particularly squamous cell carcinoma, in the sun-exposed skin of immunosuppressed renal transplant recipients or patients who received phototherapy together with an immunosuppressant [21] suggests that UV-induced human skin cancers are also highly antigenic.

However, despite the potential for immunological control, skin cancers occur with a high frequency in susceptible, sun-exposed populations. Earlier studies, mainly those using mouse models, have provided an explanation for this paradox by demonstrating that UV radiation not only transforms cells by inducing mutations but also interferes with host immunity against the developing skin tumours. These studies demonstrated that UV irradiation of the skin produces both local immunosuppression, which inhibits immune functions within the irradiated skin, and systemic immunosuppression against antigens introduced at a critical time after exposure to UV radiation.

Modulation of immune responses initiated at non-irradiated sites is now known to involve soluble mediators. Among such soluble mediators, IL-10 is crucial in the photocarcinogenesis pathway [22]. IL-10 polymorphisms and susceptibility to squamous cell carcinoma have been reported in several studies in humans.

Failure of immunosurveillance is closely related in photocarcinogenesis, and in this context, the use of a Toll-like receptor agonist recently emerged as a new strategy for cancer treatment. Imiquimod, an agonist for Toll-like receptor 7, is now clinically used worldwide for the therapy of actinic keratosis, a precancerous lesion caused by sun damage that has the potential to progress to squamous cell carcinoma.

Prevention of damage from solar ultraviolet radiation

The most effective way to reduce skin cancer incidence is to avoid unnecessary sun exposure and adopt personal preventive measures for protection from sunlight, such as wearing protective clothing, wearing a hat, applying sunscreen, and using shade. Minimizing the time spent outdoors between the hours of 9:00 a.m. and 3:00 p.m. – the period when the intensity of sunlight is the strongest – markedly reduces the risk of sun damage.

Members of the public should be advised that the strength of UV radiation does not correlate with the temperature. For example, in March in the Northern Hemisphere, the intensity of UV radiation is strong even though temperatures may be low. Even on cloudy days, about 80% of the solar UV radiation reaches ground level. About 10% of solar UVB radiation passes through glass windows.

In relation to photocarcinogenesis, the heritable disease xeroderma pigmentosum should be kept in mind. Xeroderma pigmentosum is characterized by an extreme sensitivity to sunlight and a greatly increased risk of developing skin cancers at sun-exposed areas from early childhood, because of deficiency in the repair of DNA photolesions [2].

Recently, accelerated photoageing and development of skin cancer have been reported in patients who developed severe photosensitivity disorders after being treated with voriconazole, an antifungal agent [23]. Use of the diuretic antihypertensive medication hydrochlorothiazide was associated with increased risk of non-melanoma skin cancer in a nationwide case–control study in Denmark [24]. This epidemiological result is consistent with the finding that hydrochlorothiazide significantly increased the production of thymine dimers after exposure to radiation in the UVA range [10]. Taking account of these data and results from studies in animals and in humans, increased attention should be paid to any severe inflammatory lesions that are subject to UV radiation.

Fig. 2.4.4

Crowds at Bondi Beach, Sydney, Australia. A relatively high incidence of melanoma and other skin cancers is attributable to exposure of fair-skinned populations to intense ultraviolet radiation in countries such as Australia. The incidence of both melanoma (more...)

Fig. 2.4.5

Sun protection during play. Avoiding unnecessary sun exposure is critical to avoiding sunburn and the associated risk of skin cancer.

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