**1. Introduction**

The prevalence of skin cancer varies greatly according to the geographic location and is developing rapidly in Western countries. This type of cancer is most frequent in fair-skinned people. In Australia, the rate of melanomas increased annually by 6.3% in men and 2.9% in women between 1959 and 1985. This type of cancer is the most frequent one in fair-skinned people. Since 1985, the rate has levelled off, which is reassuring even though the incidence of skin cancer in Australia is the highest in the world [1] (table 1) [2], followed by New Zealand and Norway [3]. As a comparison, we can look at the rate of non-melanoma skin cancer (NMSC) in Japan, which is between 1.2 and 5.4 per 100,000, that is to say a factor of 50 compared to Australia [4]. Skin cancer in children is rare. In teenagers (from 15 to 19 years old) the prevalence in England is 10 cases per million per year for melanomas and 24 cases per million per year for NMSC. The risk factors are: a family history of melanomas, *Xeroderma pigmento‐ sum* [5] and pathologies responsible for states of immunosuppression. Cases of congenital melanomas are extremely rare [6]. Excessive sun exposure has long been recognised as the most important environmental factor to be taken into account; indeed, ultra-violet radiation (UV) is the cause of 90% of NMSC and 67% of melanomas [7]. The high incidence of skin cancer in certain countries of the world is therefore not just down to chance but has a direct link to the population's skin type (fair-skinned, blue-eyed people who burn easily, who never tan and who often have freckles) [8] and to the level of sunshine [9]. Although UV rays only represent 3% of the total radiation which reaches Earth, from a point of view of energy, it is thought that they account for 10% of light energy [10]. Mountainous regions bring a greater risk of devel‐ oping sunburn, as the quantity of UVB increases by 4% every 300 metres [11], and in a similar way, the position with relation to the equator is of utmost importance, (the risk is greatest around the Tropics). UV radiation (UVA and B) causes alterations in DNA by either direct or indirect actions (by means of an oxidizing stress). The types which react to oxygen can cause either an increase in cell proliferation or their apoptosis, accordingly [12]. The notion of

© 2013 Couteau and Coiffard; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

phototypes, put forward by Fitzpatrick as early as 1975 within the framework of the care of patients treated with PUVA therapy, is linked to the concept of sun-reactive skin. This scale enables Caucasian subjects to be classed according to their sensitivity to UV rays. At first, 4 phototypes were established, called I, II, III and IV (Table 2), then this scale was later extended to include phototypes V (brown skin or Asian skin) and VI (black) [13]. A classification concerning Japanese people was also drawn up by Kawada [14]. The three corresponding groups are JI (always burn and rarely tan), JII (burn and tan moderately), JIII (never burn and always tan). These three groups should be linked to the Caucasian phototypes II, III and IV [15]. In the 1990s, JP Césarini introduced the notion of melano-compromised subjects (Photo‐ types I and II), melanocompetent subjects (Phototypes III and IV) and melanoprotected subjects according to their varying capabilities to protect themselves against skin cancer [16]. The best level of photoprotection is reached by black subjects, who are shown to have a low incidence of skin cancer (1 to 2% of cancers affecting black people are skin cancers compared to 20 to 30% for Caucasians). The phototypes are linked to melanin, which is a biopolymer functioning as a filter and which enables black people to produce an SPF (Sun Protection Factor) of around 13. The dispersion of melanosomes and their lack of degradation throughout the keratinization process forms an effective barrier. A black person's melanin filters twice as much UVB radiation as a Caucasian's melanin. The black epidermis is much more protected than a Caucasian one, as it transmits 7.4% of UVB radiation and 17.5% of UVA radiation compared to 24 and 55% for a Caucasian epidermis. In terms of Minimal Erythemal Dose (MED), it can be observed that this dose is between 6 and 33 times higher in black subjects [17]. It is important to create new classifications on a regular basis because of the interbreeding of races in the population. For example, in 1990, the US Census Bureau registered 6 races and 23 sub-types in the United States; 10 years later, the Census Bureau still counted 6 categories, but the number of sub-types had increased to 67, creating a multiplicity of sensitivities to the sun [18]. It seems that precautions taken by people who work outside to protect themselves from the sun are related to their phototype, as an American study shows that fair-skinned people are more aware in this respect [19]. The current way of life in industrialized countries goes hand in hand with an increase in the frequency of the length of exposure to the sun during leisure time. Contrary to previous centuries where pale skin tones were all the rage, the fashion of having a sun-tan, which began in the Thirties, is still current. The SUVIMAX study which was conducted in France in 1994 showed that in the cohort of 7,822 subjects questioned, 196 (110 women and 86 men) had travelled to a country with high levels of sunshine (high UV index) within the previous year and for a period of at least one month. Women, in particular, appear to be most concerned with daily exposure to sunshine (more than 2 hours per day) and admit that "getting a tan" is very important for them [20]. Sunbathing is still popular. Professor Dubertret is pessimistic and considers that if nothing is done in the way of prevention campaigns, the rate of skin cancer will double every ten years and a child born in 2000, if he behaves in the same way as his parents regarding his exposure to the sun, will have a 1 in 75 risk of developing a melanoma and a 1 in 7 risk of developing basocellular cancer [21]. The behavior of young Europeans tends towards improvement. Indeed, an increase in the use of sun products throughout exposure can be observed. In 10 years (between 1990 and 2000), the use of sun products increased from 52 to 63% in boys and from 80 to 87% in girls. It is a pity

that a minority is still so resistant to using sun products [22]. On the other hand, young Australians (from 12 – 17 years old) largely ignore prevention campaigns and the use of sun products decreased between 1993 and 2000 (going from 54 to 36% for teenagers in general and from 73 to 50% for girls in particular) [23]. A second more optimistic study praises the SunSmart television advertising campaign, which seems to be bearing fruit [24]. Indeed, the slogans are well-chosen and are likely to bring about a change of attitude; as proof: « Leave your hat on » (1991 – 1992), « How to remove a skin cancer » (1996 – 1998) and « No tan is worth dying for: Clare Oliver » (2008). In short, depending on the panels and on the authors, opinions differ [25]. The fact remains that young people in general, and more particularly young Americans (from the south of the USA) are stubborn and are still fond of exposing themselves to the sun. Sunburn at the end of the weekend is not uncommon [26]. A lot of efforts still have to be made, as only 1/3 of parents questioned say that they prefer activities for their children which avoid exposure to the sun and confirm that they apply sun products whilst doing beach-based activities [27]. Public awareness campaigns are necessary, as childhood is a key stage and it is important to understand that people who do not want to use sun products whilst continuing to expose themselves to the sun, do so for aesthetic reasons, in order to have a tan [28]. We set out, therefore, to present a method for topical skin protection: the use of sun products.

About Suncare Products http://dx.doi.org/10.5772/55411 129

**Countries Prevalence**

France 7/100000

Sweden 11/100000

Australia 50/100 000

**Table 1.** Prevalence of skin cancers - 1995 [2]

**Table 2.** Phototypes according to the Fitzpatrick classification

US 14/100000

**Phototypes Sensitivity to sunlight**

I Always burns, never tans

II Burns easily, tans minimally

III Burns moderately, tans gradually to light brown

V Rarely burns, tans profusely to dark

VI Never burns, deeply pigmented

IV Burns minimally, always tans well to moderately brown

that a minority is still so resistant to using sun products [22]. On the other hand, young Australians (from 12 – 17 years old) largely ignore prevention campaigns and the use of sun products decreased between 1993 and 2000 (going from 54 to 36% for teenagers in general and from 73 to 50% for girls in particular) [23]. A second more optimistic study praises the SunSmart television advertising campaign, which seems to be bearing fruit [24]. Indeed, the slogans are well-chosen and are likely to bring about a change of attitude; as proof: « Leave your hat on » (1991 – 1992), « How to remove a skin cancer » (1996 – 1998) and « No tan is worth dying for: Clare Oliver » (2008). In short, depending on the panels and on the authors, opinions differ [25]. The fact remains that young people in general, and more particularly young Americans (from the south of the USA) are stubborn and are still fond of exposing themselves to the sun. Sunburn at the end of the weekend is not uncommon [26]. A lot of efforts still have to be made, as only 1/3 of parents questioned say that they prefer activities for their children which avoid exposure to the sun and confirm that they apply sun products whilst doing beach-based activities [27]. Public awareness campaigns are necessary, as childhood is a key stage and it is important to understand that people who do not want to use sun products whilst continuing to expose themselves to the sun, do so for aesthetic reasons, in order to have a tan [28]. We set out, therefore, to present a method for topical skin protection: the use of sun products.

**Table 1.** Prevalence of skin cancers - 1995 [2]

phototypes, put forward by Fitzpatrick as early as 1975 within the framework of the care of patients treated with PUVA therapy, is linked to the concept of sun-reactive skin. This scale enables Caucasian subjects to be classed according to their sensitivity to UV rays. At first, 4 phototypes were established, called I, II, III and IV (Table 2), then this scale was later extended to include phototypes V (brown skin or Asian skin) and VI (black) [13]. A classification concerning Japanese people was also drawn up by Kawada [14]. The three corresponding groups are JI (always burn and rarely tan), JII (burn and tan moderately), JIII (never burn and always tan). These three groups should be linked to the Caucasian phototypes II, III and IV [15]. In the 1990s, JP Césarini introduced the notion of melano-compromised subjects (Photo‐ types I and II), melanocompetent subjects (Phototypes III and IV) and melanoprotected subjects according to their varying capabilities to protect themselves against skin cancer [16]. The best level of photoprotection is reached by black subjects, who are shown to have a low incidence of skin cancer (1 to 2% of cancers affecting black people are skin cancers compared to 20 to 30% for Caucasians). The phototypes are linked to melanin, which is a biopolymer functioning as a filter and which enables black people to produce an SPF (Sun Protection Factor) of around 13. The dispersion of melanosomes and their lack of degradation throughout the keratinization process forms an effective barrier. A black person's melanin filters twice as much UVB radiation as a Caucasian's melanin. The black epidermis is much more protected than a Caucasian one, as it transmits 7.4% of UVB radiation and 17.5% of UVA radiation compared to 24 and 55% for a Caucasian epidermis. In terms of Minimal Erythemal Dose (MED), it can be observed that this dose is between 6 and 33 times higher in black subjects [17]. It is important to create new classifications on a regular basis because of the interbreeding of races in the population. For example, in 1990, the US Census Bureau registered 6 races and 23 sub-types in the United States; 10 years later, the Census Bureau still counted 6 categories, but the number of sub-types had increased to 67, creating a multiplicity of sensitivities to the sun [18]. It seems that precautions taken by people who work outside to protect themselves from the sun are related to their phototype, as an American study shows that fair-skinned people are more aware in this respect [19]. The current way of life in industrialized countries goes hand in hand with an increase in the frequency of the length of exposure to the sun during leisure time. Contrary to previous centuries where pale skin tones were all the rage, the fashion of having a sun-tan, which began in the Thirties, is still current. The SUVIMAX study which was conducted in France in 1994 showed that in the cohort of 7,822 subjects questioned, 196 (110 women and 86 men) had travelled to a country with high levels of sunshine (high UV index) within the previous year and for a period of at least one month. Women, in particular, appear to be most concerned with daily exposure to sunshine (more than 2 hours per day) and admit that "getting a tan" is very important for them [20]. Sunbathing is still popular. Professor Dubertret is pessimistic and considers that if nothing is done in the way of prevention campaigns, the rate of skin cancer will double every ten years and a child born in 2000, if he behaves in the same way as his parents regarding his exposure to the sun, will have a 1 in 75 risk of developing a melanoma and a 1 in 7 risk of developing basocellular cancer [21]. The behavior of young Europeans tends towards improvement. Indeed, an increase in the use of sun products throughout exposure can be observed. In 10 years (between 1990 and 2000), the use of sun products increased from 52 to 63% in boys and from 80 to 87% in girls. It is a pity

128 Highlights in Skin Cancer

**Table 2.** Phototypes according to the Fitzpatrick classification


**Mechanisms of Collagen Network Organization in Response to Tissue/Organ Damage**

Takaoki Saneyasu, Saeko Yoshioka and Takao Sakai

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/63163

#### **Abstract**

Fibrosis is a part of the wound-healing response to tissue damage and characterized by excessive accumulation of mainly type I collagen-containing extracellular matrices (ECMs). Transforming growth factor beta (TGF-β) is a profibrogenic master cytokine responsible for promoting differentiation of tissue-resident fibroblasts into myofibro‐ blasts, upregulation of ECM production, and downregulation of ECM degradation. The formation of ECM is an essential response in wound healing. Fibronectin is an ECM glycoprotein substantially expressed during tissue repair. Based on *in vitro* findings, it has been widely accepted that collagen network organization was exclusively fibronec‐ tin matrix dependent. Unexpectedly, our fibronectin conditional knockout mouse models have demonstrated a fibronectin-independent mechanism of collagen fibril formation following injury and identified TGF-β signaling and type V collagen as essential elements for collagen fibrillogenesis. Interestingly, the targeting of the TGF-β signaling alone, as proposed in some recent antifibrotic therapies of chronic fibrotic diseases, is not sufficient to completely prevent liver fibrosis. In this chapter, we focus on the present knowledge of the mechanisms of the collagen network organization following tissue/organ damage and pathological processes of chronic fibrotic diseases.

**Keywords:** collagen, extracellular matrix, fibrogenesis, fibronectin, TGF-β


**5. Targeting the TMA/TMAO pathway as a therapeutic strategy to combat CVD risk-current research and future directions**

The gut microbiome is a growing area of research in metabolic health and its link to CVD risk. The development of high-throughput metagenomic tools has aided a new understanding of the gut microbiome's role in CVD risk [113]. The gut microbiome can be targeted to modify TMAO synthesis, according to recent fecal microbial transplant research [114] and as a result TMA/TMAO levels can be regulated. Based on research by Maisto et al., in healthy subjects, grape pomace polyphenolic extract has been found to lower serum levels of TMAO [115]. Resveratrol (RSV) reduces TMAO- induced atherosclerosis by lowering TMAO levels and enhancing hepatic bile acid synthesis through gut microbiota remodeling [116]. Antimicrobial phytochemicals, such as allicin, a dietary dosage derived from garlic, effectively neutralize the metabolic ability of gut microbiota to produce TMAO- induced by L-carnitine intake [117]. Luhong granules, a complex blend of herbs, flowers, animal parts, seeds, and roots, prolong ventricular remodeling after myocardial infarction by lowering TMAO and LPS levels in the bloodstream by increasing the gut microflora and intestinal barrier function [118]. A single oral dosage of a cutC/D inhibitor lowers plasma TMAO levels for up to three days and reverses diet-induced platelet reactivity and thrombus formation as studied in animal models, with no toxicity or increased bleeding risk [119]. In experiments with mice models, *Lactobacillus plantarum* ZDY04 significantly reduced serum TMAO and cecal TMA levels in mice by modulating the relative abundance of specific bacterial species, including *Bacteroids* and significantly inhibiting the development of TMAO-induced atherosclerosis in choline fed mice [120]. In high-fat diet-induced obese mice, capsanthin extract prevents obesity, lowers serum TMAO levels, and modifies the gut microbiota composition by decreasing serum triglycerides, total cholesterol, and TMAO levels and markedly increasing microbial diversity [121]. The ability of several oral probiotics to modify circulating TMAO levels in different cohorts, including healthy participants and patients with a CVDrelated disease, has been investigated [122–125]. None of them, however, appeared to have a significant effect on TMAO levels in the treatment groups as compared to the placebo groups. In another study, TMA-degrading microorganisms were used by Qiu et al. (2017) to investigate another promising technique for lowering TMA levels in the gut where oral administration of a TMA-metabolizing strain (*Enterobacter aerogenes* ZDY01) reduced TMA in the cecum and TMAO in the serum, as well as changing the microbial community composition in mice, according to their findings [126]. In human studies, changes in urine TMAO levels have been discovered in untargeted metabolomics investigations following supplementation with *Origanum dictamus* tea and *Curcuma longa* extract [127, 128].

## **6. Conclusions**

Diet has been shown to have an important role in the formation of TMAO because it offers the nutritional precursors needed to create TMA and TMAO. There is a positive correlation between circulating TMAO levels and the consumption of food rich in dietary precursors of TMAO like seafood, meat, eggs etc. Targeting the TMA/TMAO metabolism has emerged as a promising tool for cardiovascular disease prevention and treatment in recent years. Targeting the microbiota and host metabolic systems implicated in TMA and TMAO production shows potential for future intervention.

*Gut Microbial Metabolite Trimethylamine-N-Oxide and Its Role in Cardiovascular Diseases DOI: http://dx.doi.org/10.5772/intechopen.107976*

Animal models have largely established the capacity of specific diets, food ingredients, and phytochemicals found in herbs to reduce circulation of TMAO levels. The link between changes in TMAO levels and gut microbiota has only been shown in a few cases, and the exact processes behind the impacts of the dietary items under investigation are yet unknown. More importantly, there are few studies that suggest that lowering circulating TMAO levels has a favorable effect in humans. Because the majority of the studies have been conducted on animal models, the results are difficult to apply to humans. Future research in this area should address conventional microbial research obstacles as well as those more specific to the study of TMA/ TMAO metabolism, such as the substantial intra-individual variability of plasma TMAO levels observed in some humans. With the advancement and availability of next-generation sequencing and other omics technologies, a change from studies focusing on defining microbial community composition to more function-oriented research on the gut microbiota is envisaged. Bioinformatic approaches, shotgun metagenomics, meta-transcriptomics, meta-proteomics, and metabolomics, are all expected to be crucial in unraveling the intricate relationships between nutrition, microbial metabolism, and host health.

## **Acknowledgements**

All images in this manuscript were made using BioRender.


Section 5 Epstein-Barr Virus

**97**

**Chapter 6**

Therapy

**Abstract**

lymphoma

**1. Introduction**

*Emmanuel Drouet*

The Role of the Epstein-Barr Virus

Lytic Cycle in Tumor Progression:

The Epstein-Barr virus (EBV) reactivation corresponds to the activation of EBV global replication involving not only the origin of the latent viral replication but also that of the origin of lytic replication. During this reactivation, a minority of B cells infected with EBV in its latent form enter the lytic phase. During this phase, all EBV proteins are produced, enabling the assembly of complete virions that lysate their host cells and infect neighboring cells (lytic cycle). This horizontal EBV transmission seeks to increase the pool of EBV-infected B cells. This chapter seeks to review the role of the lytic EBV proteins (particularly that of the ZEBRA protein) *in tumor development*. This protein is the main transcription factor of EBV, expressed during the activation of the lytic cycle. Recently, we demonstrated that this immediate early protein can be detected in the soluble state (s-ZEBRA) in the serum of patients with posttransplant lymphoproliferative disorder. We highlighted the role of ZEBRA in EBV pathogenesis in transplanted subjects, not only as a key protein in the activation of EBV replication but also as a protein "toxoid" released into the extracellular milieu. This release could result in increased secretion of immunomodulatory cytokines and that of angiogenesis-promoting factors conducive to tumor progression.

**Keywords:** tumor progression, tumorigenesis, EBV, lytic cycle, Zta/ZEBRA protein,

Epstein-Barr virus (EBV) is a member of the herpesvirus family and only infects primates, with tropism for B cells and epithelial cells, which establishes a lifelong persistent infection in over 90% of the world's population [1]. After the resolution of the primary infection episode, EBV enters a latent phase. Following primary infection, the virus establishes lifelong persistence within the host memory B-cell compartment utilizing restricted latent gene expression programs [2–4]. Like all herpesviruses, EBV can choose between two alternative lifestyles: latent or lytic replication. EBV lytic replication, which is required for horizontal spread of the virus from cell to cell, and from host to host, occurs in both epithelial cells and B cells [5–7]. During latency, EBV exists in a dormant state where only a viral gene subset is expressed, facilitating the episomal persistence of the viral genome [8]. However,

Consequences in Diagnosis and