• SkinCancer

Vitamin D and skin cancer

Jenny Slight, Sanne L. Andersen, Lovisa Andersson

List of contents

General introduction

The most well-known function of vitamin D is its role in maintaining a proper ratio of calcium and phosphorus in the blood plasma, mainly in order to maintain a normal bone metabolism. The lack of vitamin D may cause osteoporosis in adults and rickets in young individuals (J. Swenson M., 1984). It also plays a role in the immune system and brain function. Recently it has been discovered that it also has an anticancer effect. This very important effect of vitamin D is a hot topic of today. It is investigated worldwide since cancer is one of the largest health threats in the Western world. A smaller portion of the required amount of vitamin D may be ingested with the food, but the largest part has to be synthesized in the skin with help of UVB light (Reichrath J., Reichrath S., 2012). What makes the situation complex is that UVB light also is the major cause of skin cancer. This essay will describe the general function of vitamin D and its connection with cancer. This is done by focusing on some of the mechanisms which vitamin D has a role in.

Figure 1 The connection between UVB regulated Vitamin D synthesis and UVB induced skin cancer. (Andersson L. 2012)

Vitamin D

Vitamin D is a group of fat solube steriods. It is not strictly a vitamin because it does not necessarily have to be ingested with the food. It can also be synthesized from cholesterol in presence of UV light in adequate amount. Among the members of the D vitamin family the most important are vitamin D2 and D3 (K. Murray R., et al., 2006).

VitaminD₂ is the vegetative form of vitamin D. Sterols, mainly ergosterol, in the plant cell is transformed into VitaminD₂ by an internal molecular rearrangement upon exposure to sunlight. VitaminD₂ has more or less the same biological role as vitamin D3 (Sjaastad, V.O., et al., 2010).

VitaminD₃ is the nonvegetable form of vitamin D, It can be ingested or produced from 7 dehydrocholesterol in the skin upon UVB light exposure. Dietary sources are a oil-rich fish, egg yolk and beef.

Vitamin D2 and D3 are the precursors for 1,25-hydroxvitamin D. The latter is the active form of vitamin D involved in different biological processes in the body, of which the most well known is the formation and resorption of bones. It acts on the kidneys, the mucosa of the small intestines and the osteoblast layer of the bones in order to maintain the proper ratio of calcium and phosphate for optimal bone formation (Boland R, 1986).

The role of 1,25-hydroxyvitamin D in maintenance of bone homeostasis

(J Swenson M,1984)

Vitamin D and regulation of epidermal immunity

Observations showing that vitamin D receptors are found in activated dendritic cells, macrophages and lymphocytes, make it possible for vitamin D and its active metabolites to play a role in the immune response. Both the adaptive and the initiate immune system are regulated by 1,25 hydroxyvitamin D (D. Bikle D., 2012).

The role of 1,25 hydroxyvitamin D in adaptive immune system

The suppressing of the adaptive immune system, as a consequence of 1,25 hydroxyvitamin D, is beneficial regarding autoimmune diseases and following transplants, but not in case of tumor control. However, 1,25 hydroxyvitamin D exert its inhibitory effect by suppressing the proliferation and immunoglobulin production, as well as retarding the differentiation of B-cell precursors into plasma cells. It also inhibits T-cell proliferation, maturation and its ability to present antigens to other cells of the immune system (D. Bikle D., 2012).

The role of 1,25 hydroxyvitamin D in the innitate immune system

The initiate immune system is the body’s first line of defense against pathogens. The activation of the initiate immune system involves the activation of Toll- Receptors in polynuclear cells, macrophages, monocytes and different epithelial cells including those in the epidermis. Activation of Toll-receptors leads to the release of a variety of substances killing the pathogens. 1,25 hydroxyvitamin D is believed to suppress the release of some of these substances (D. Bikle D., 2012).

Synthesis of Vitamin D3 and 1,25-hydroxyvitamin D

The cholesterol like substance, 7-dehydrocholesterol, is produced in the epithelial cells of the skin. It is the precursor in the synthesis of vitamin D₃ and its derivatives.

Upon exposure of UV light of about 300 nm the 7- Dehydroxycholesterol undergoes a non-enzymatic reaction which transforms it to pre vitamin D. During the next hours further heat mediated reactions takes place which transforms pre-vitamin D to vitamin D_3.

The vitamin D₃ derived from food sources or from the synthesis in the skin are bound to specific blood globulins. This is the major storage of vitamin D₃ for later use. A part of the vitamin D₃ is transported in the blood stream to the liver, were it is transformed into 25-hydroxyvitamin D. In the liver, the vitamin D₃ is hydroxylated by 25-OHase, to form 25-hydroxyvitamin D. This hydroxylated derivate, with low biological activity, is further released to the circulation and bound to the blood globulins again. Then, they are transported to the kidneys where the second hydroxylation takes place. Renal 1- OHase activation produces 1,25- hydroxyvitamin D, the most biological potent form of vitamin D. Whereas by the action of 24-OHase, the inactive 24-hydroxyvitamin D is produced (Figure 1) (D. Bikle D., 2012; J. Swenson M., 1984; K. Murray R., et al., 2006).

Cancer

In normal cells, the proliferation and differentiation are strictly controlled and in balance. Cancer is an abnormal state of the cell. Upon cancerogenic stimuli a rapid initial step affecting the gene material of the cell takes place. If the cell does not repair this change on its own, promoting factors of the cells may progress the cell toward malignant phenotype. This is the type of uncontrolled cell division referred to as cancer (Dunlop H. R., Malbert C-H., 2004).

Benign tumors

This type of tumor arises in a broad variety of tissues and grows locally. Their structure closely resembles the structure of the parent tissue. The clinical importance of this type of tumor is their ability to exert pressure, cause obstruction or form a space occupying lesion such as benign brain tumors. Hence the tumor itself is not necessarily a health risk, but the damages caused on surrounding tissues are (Dunlop H. R., Malbert C-H., 2004).

Malignant tumors

Malignant tumors differentiate in a broad way giving rise to abnormal structures. The range of growth may be rapid and they grow by infiltrating other tissues giving diffuse borders. Metastasis may occur in case of a malignant tumor.

The malignant tumors have the capability to spread via the blood and the lymph fluid and give rise to colonies and tumors in different places in the body. In 90 percent of deaths caused by cancer in animals and humans, malignant tumors are the cause (Dunlop H. R., Malbert C-H., 2004).

UV light and the formation of skin cancer

UV light is light of the wavelength 10nm to 400nm. It is essential for the synthesis of vitamin D, but it is also the major cause of skin cancer.

UVA: Light with wavelength 315nm to 400 nm. It does not stimulate vitamin D synthesis (Y. Tang J., et al., 2012).

UVB: Light with wavelength 280nm to 315nm. UVB light has energy enough to penetrate the skin, affect the cells and cause photochemical changes which are crucial for the synthesis of vitamin D, but also may give rise to cancer (Sjaastad, V. O., et al., 2010).

UVB induces cancer mainly due to oxidative processes affecting DNA cyclobutane pyrimidine dimers and pyrimidine photoproducts, which, if they not are repaired, cause mutations in the nucleotide sequence of DNA (C to T or CC to TT) (Figure 1.) (D. Bikle D., 2012).

Skin

The skin is our largest organ and has a broad variety of roles, such as protection, thermoregulation, sensation and, crucial for this topic, the synthesis of vitamin D. Most tumors appearing in the skin are benign and rarely transform into malign tumors.

The skin has several histological layers of which the basic knowledge is important since skin cancer can be obtained in these.

• Epidermis- the outermost layer of the skin with five sub layers from the outermost to the innermost:
  • Stratum corneum- Consist of flattened and fused remnants of the dead keratinocytes.
  • Stratum lucidum- Only present where the skin is very thick and consists of dead kerationocytes filled with eledin, an intermediate form of keratin.
  • Stratum granulosum- Consists of migrated kerationcytes from the underlying stratum spinosum and is here known as granulosa cells which promotes the final formation of keratin.
  • Stratum spinosum- Consists of prickle cells, kerationcytes connected by desmosomes, with very active protein synthesis.
  • Stratum basale- The innermost layer of epidermis, hence it is the boundary between epidermis and the underlying dermis. The stratum basale consists mainly of living keratinocytes. Melanocytes, which are the pigment producing cells in the skin, and merkel cells, which contain nerve endings, are receptors for touch, pain and other external stimuli.
• Dermis- Consists of fibrous connective tissue which makes the skin smooth, elastic and strong.
• Hypodermis- Transitional layer between the skin and the underlying fascia, muscles and bones. The hypodermis consists mainly of loose fibrous connective tissue and varying amount of adipose tissue. (Sjaastad, V. O., et al., 2010; Burkitt H. G., et al., 1993).

Skin Cancer

Different types of skin cancer may develop in different layers of the skin. The most common types are:

• Melanoma (other names include malignant melanoma and cutaneous melanoma).

Melanoma is the name for cancer present in cells producing melanin, the brown pigment giving skin the tan or the brown colour, the melanocytes. Melanoma tumors are usually black or brown, but they can even appear in lighter colours. Melanoma is less common than basal and squamous cell skin cancer, but is far more dangerous due to its high ability to spread to neighboring tissues (American Cancer Society, 2012).

• Keratinocyte cancer

Is more common than melanoma, but less dangerous.

• Basal cell carcinoma

The basal cell carcinomas share many common features with the cells of stratum basale. This type is rarely spread to other tissues and tends to grow slowly.

• Squamous cell carcinoma

The squamous cell carcinomas share many common features with the cells of stratum squamous cells. These cells are more likely to spread to surrounding tissue such as adipose and lymphatic tissue.

• Keratocanthomas

Dome shaped tumours that start growing quickly, but usually slow down. A few of them spread to other tissues.

These are some less common types of skin cancer that together make up less than 1% of non-melanoma skin cancers:

• Merkel skin cancer

Uncommon, developes from neuroendocrine cells in the skin, unlike basal and squamous cell carcinomas, merkel cell carcinomas often spread to neighbouring tissues.

• Karopsi sarcoma

Related to human herpes virus and may origin from the dermis or from internal organ.

• Cutaneous lymphoma

This type of cancer starts in different parts of the lymphatic system, including the part of the lymphatic system present in the skin.

• Skin adnexal tumora

This type of cancer starts in glands or hair follicles in the skin. Cancerous tumors are rare.

• Various types of sarcomas

Rarely develop from the connective tissue in the skin, more often from connective tissue deep to the skin (American Cancer Society. 2012)

Vitamin D receptors

For the 1,25 hydroxyvitamin D to be able to exert its affect in the body it has to bind to the vitamin D receptors. Vitamin D receptors (VDR) belong to the steroid nuclear receptor family. VDRs are present in most tissues and have a broad variety of biological actions, among others the regulation of gene transcription. One important action regarding this topic is the ability of VDR to decrease cellular proliferation of cancer cells (Y.Tang J., et al., 2012).

Vitamin D and skin cancer

The anticancer effect of vitamin D and its active metabolites has been investigated for several years. Most cell types contain receptors for 1,25 hydroxyvitamin D (VDR), including the basal cell, squamous cell carcinomas and melanomas, which means that they can be affected by 1,25 hydroxyvitamin D in different ways. It is shown that1,25 hydroxyvitamin D has a preventing effect for some types of cancer, e.g. colon cancer. It has also been indicated that 1,25 hydroxyvitamin D has a preventing effect on skin cancer. (Figure 1.)

The 1,25 hydroxyvitamin D is believed to prevent skin cancer by acting on several pathways, by regulation of epidermal immunity and by regulation of the DNA damage response. Two mechanisms where 1,25 hydroxyvitamin D plays a role in preventing cancer are described here, the hedgehog mechanism and the wnt/catenin pathway and also the role of 1,25 hydroxyvitamin D in repairing damaged DNA. (D. Bikle D, 2012).

The hedgehog mechanism

The hedgehog mechanism is important for cell proliferation and differentiation during embryonic development. The activity of this process diminishes during life after birth. If this process proceeds in an uncontrolled manner, cancer may develop in tissues where this pathway remains active, especially in the brain or skin tissue as basal cell cancer. 1,25 hydroxyvitamin D may regulate this pathway through genomic action and by direct inhibition, independent of the VDRs (D. Bikle D., 2012; Pasca di M., Hebrok M., 2003).

The wnt/B-catenin pathway

The wnt/B- catenin pathway is, as the hedgehog mechanism, a cell signaling pathway crucial for development. If this pathway is going on in an uncontrolled manner, cancer may develop.

Wnt signaling via activation of B-catenin has a complex role in the function of VDR. Wnt signaling increases the ability of b-catenin in the nucleus where it binds to transcription factors to promote gene expression important for the proliferation. B- catenin plays an important role in keratinocyte differentiation. VDR has been shown to bind B catenin and similar factors and reduce its transcriptional activity, hence, inhibit the proliferation of cancerogenous cells. The binding of VDR and B-catenin enhance the ability of 1,25 hydroxyvitamin D to activate the transcriptional activity of VDR and block the transcriptional activity of B catenin (D. Bikle D., 2012).

1,25 hydroxyvitamin D regulation of the DNA damage responce

The two enzymes, DNA damaging repair (DDR) and p53 have important roles in the prevention of UVB induced DNA mutation. DDR is responsible for damage recognition, repair and coordinate the cell cycle to DNA damage. Cancer makes the activity of DDR less controlled and mutations and proliferation of cancerogenic cells will increase.

Nucleotide expression repair (NER) is the most important way of repairing DNA. NER plays a major role in reducing the mutations since it is able to remove DNA damage before the replication starts.

It is shown that lack of VDR causes lack of DDR, which means that 1,25 hydroxyvitamin D signaling on DDR is involved in reduction of tumor formation (D. Bikle D, 2012).

Summary

It is clear that UVB light is the major cause of skin cancer and is crucial in the formation of vitamin D. Approximately 90% of the required amount of vitamin D has to be synthesized from 7-dehydrocholesterol in the skin by the action of UVB light. The remaining10% can be obtained from the food (Burkitt H.G., et al., 1993). However, the amount needed in order to gain the anticancer effect is not clear. Neither is it clear if a safe dose of UVB exist, meaning a dose that maximizes the synthesis of vitamin D while minimizing the DNA damage and formation of cancer (Dunlop H. R., Malbert C-H., 2004).

In today’s society, many dermatologists, health organizations and scientists recommend as much avoidance of UVB light as possible in order to prevent skin cancer. The recently discovered anticancer effect of vitamin D may give reason to revaluate this suggestion, but far more research is required.

In our essay we have tried to clarify the connection between Vitamin D and skin cancer by giving a broad knowledge of important factors. We have described UVB light to be able to see and understand the connection between vitamin D and skin cancer by focusing on the double role of UVB light.

List of references

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Figure

Figure 1: Andersson L, 2012