Anatomy Of The Skin And Cancer Biology Essay


1.1.1 The Anatomy of the Skin

Skin is the largest and one of the most multifaceted organs of the human body. It senses our surroundings and acts a protective barrier against many different insults, such as ultraviolet radiation, trauma, temperature extremes, toxins and pathogens. Other important functions include sensory perception, immunologic surveillance, thermoregulation and control of fluid loss. The skin. is composed of a several cell types of different embryonic origin. The ectoderm gives rise to the epidermis, hair follicles, sebaceous glands and the nails. The neural crest gives rise to melanocytes, nerves, and sensory receptors, while fibroblasts, adipocytes, blood vessels and immune cells are derived from mesoderm The skin is composed of two primary layers, the dermis and the epidermis, that encompass a fatty subcutaneous layer called the hypodermis. The epidermis represents the outermost layer of the skin. Most of the cells in the epidermis are keratinocytes (KCs). The epidermis consists of several distinct layers of keratinocytes at various stages of differentiation. These layers include the innermost basal layer, which contains self-renewing undifferentiated KCs, the intermediate spinous and granular layers, and the outermost layer, known as stratum corneum, which contains dead KCs (Dale and Holbrook, 1987; Presland and Dale, 2000). The stratum corneum provides a protective barrier against infections and the environment and maintains a waterproof layer that prevents loss of water from the human body. The epidermis also contains pigment producing melanocytes that are scattered throughout the basal layer, Langerhans' cells, which are part of the skin's immune system and the pressure-sensing Merkel Cells. The dermis, in contrast, is a thick, relatively acellular layer that comprises of extra-cellular matrix, nerve endings, fibroblasts, hair follicles, sebaceous glands (sweat and oil glands) and blood vessels.Immediately above the dermis lies the basement membrane, separating the epidermis and the dermis. It plays important roles in adhesion between basal layer of the epidermis and dermis and in controlling epidermal differentiation (Inoue S. Ultrastructure of Basement membranes. Int Rev Cytol 1989). The basement membrane is composed mainly of laminins, integrins, type IV collagen, type VII collagen, nidogen, and perlecan, etc (Burgeson Christiano. The dermal-epidermal junction. Curr Opin Cell Bio. 1997). In cancer, neoplastic KCs or melanocytes in the epidermis secrete matrix-mettaloproteases that degrade the basement membrane, aiding the invasion of the transformed cells into the dermis and eventually into the blood vessels.

1.1.2 Skin Cancer: Classification

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Cancer of the skin is the most common type of human malignancy, with more than a million new cases diagnosed every year in United States (American Cancer Society 2008). The incidence and mortality of skin cancer have increased exponentially during the past several decades, and every year the figure mounts. Ultraviolet (UV) radiation from the sun or the tanning beds is the main etiological agent of skin cancers (Epstein and Epstein, 1963; Fisher and Kripke, 2002; Cleaver and Crowley, 2002).. The alarming skin cancer statistics are further exacerbated by the increased UV irradiation reaching the earth’s surface due to increased ozone depletion in the earth’s atmosphere regions (de Gruijl, 1999).

Skin cancers are broadly classified into melanoma and non-melanoma, with non-melanoma skin cancers further divided into squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). Skin cancers are slow-growing, easy to recognize, and relatively easy to treat when detected early. BCC is the most common subtype of skin cancer affecting ~800,000 Americans each year. BCC is locally invading and originates in the basal layer or the hair-follicle derived KCs that almost never metastatizes (Fan et. al. 1997). BCCs occur mostly on the exposed parts of the body such as the face, ears, neck, scalp, shoulders and back and causes considerable morbidity. SCCs are the second most common subtype of skin cancer affecting more than ~250,000 Americans each year. SCCs arise of the transformed KCs from the upper layers of the epidermis that produce significant number of squamous differentiating KCs. SCCs can occur on all areas of the body including mucous membranes but mostly occur in areas exposed to the sun. SCC is also frequently curable with surgery and localized treatments, but it can metastatize and in some cases can also be fatal. Although the mortality rate from cutaneous malignancies is only 5-10% per year, the morbidity from treatment of non-melanoma skin cancers is tremendous in terms of cosmetic deformity, loss of function, medical treatment and adverse psychological effects {1381} {1382}. In contrast, Melanoma is a cancer of melanocytes and is highly malignant. Also, Melanoma has a much lower incidence than non-melanoma skin cancers, and is responsible for majority of the skin cancer deaths, estimated to be around ~8400 in 2008 in United States alone.

1.1.3 Histophatology of Human SCCs

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Cutaneous SCC arises from the malignant transformation of the KCs in the epidermis. The neoplasm develops predominantly on the sun-exposed areas of the skin. SCCs of the skin progress in stages with individual transformed KCs: SCC in situ where the neoplasm is confined to the epidermis, and Invasive SCC where the neoplasm extends beyond the epidermis {1338}. These two forms differ in the histology and carry different clinical features. SCC In Situ

Actinic Keratosis (AK), also known as solar keratosis, are the most common type of in situ SCC of the skin. These lesions are confined to the epidermis and develop solely on sun-exposed areas of the skin. Histopathological characterictics of AK include: thickening of the epidermis and sometimes epidermal dysplasia. In some cases AK, if left untreated, eventually progresses into an invasive SCC. Another form of SCC in situ is Bowen’s Disease (BD). BD is a type of SCC in situ with epidermal dysplasia at all levels. BD usually occurs on the mucosal surfaces. Ingested carcinogens, arsenic and HPV infections are the main cause of this internal malignancy. Invasive SCC

Histopathologically, invasive SCCs is characterized by the malignant proliferation of KCs from the epidermis into the dermis and deeper tissue. Based on the degree of differntaition, SCCs are classfied as well-differentiated, moderately-differentiated and poorly-differentiated. Well-differentiated SCCs are characterized by clusters of highly keratinized atypical KCs producing eosonophilic keratin pearls in the tissue. However, lack of keratinization, increased spindle shaped cells, increased cellular polymorphism, frequent atypical mitosis and occasional necrotic cells are the features of moderately to poorly-differentiated SCCs. In addition, depending on the depth and the age of the tumor, the inflammatory immune infiltrate, mainly comprising of lymphocytes and eosinophils is usually found in the dermis surrounding the neoplasm.

Mostly invasive SCCs are associated with or preceded by an AK or BD. However some SCC arise de novo and are not associated with an in situ component. Inhibition of Notch signaling or activation of Fyn kinase, a Src family kinase member, has shown to result in de novo spontaneous SCC formation, as well as AK-like lesions in the skin. De novo SCCs are considered high-risk lesions and are usually associated with poor prognosis. Another form of invasive SCC are keratoacanthomas (KA). These are neoplastic proliferation of KCs extending from the acanthotic epidermis into the dermis. Histologically the KA resembles well-differentiated SCCs. KAs usually self-regressing in couple of months as a result of host immune response.

SCCs can metastazie to lymph nodes and organs and can cause significant morbidity and even death. Prognostically, SCCs are divided into different risk categories based on the metastatic rate. Low risk SCCs include in situ SCCs, invasive SCCs derived from AK and keratoacanthomas. Intermediate risk SCC include acantholytic invasive SCC. High-risk subtypes include de novo invasive SCCs and SCCs associated with radiation, burns and immunosuppression. Well-differentiated SCCs have a cure rate of 99%, whereas the poorly differentiated invasive SCC have a success rate of 42%.

1.2 Skin Carcinogenesis

1.2.1 Apoptosis and Skin Carcinogenesis

Apoptosis, also referred to as programmed cell death, plays a central role in several processes such embryonic development and homeostasis. Apoptosis can be initiated through activation of death receptors (receptor pathway) or release of cytochrome-c from mitochondrial membrane (mitochondrial pathway), thus resulting in activation of appropiriate caspases (family of cysteine proteases) and ultimately cell death (Ferri Kroemer Nat cell. Bio. 2001). Apoptosis is the major form of defense mechanism against uncontrolled proliferation and un-repairable DNA damage. Amongst the three forms of UV radiation (UVA, UVB and UVC), the UVB form (290nm-320nm) is the most carcinogenic. UV light damages DNA by forming cross-links in the DNA (e.g. pyrimidine dimers). If un-repaired, cells undergo apoptosis thus inducing the formation of sun-burned or apoptotic KCs in the skin (Ziegler Jonason Nature 1994). Sometimes, cells can acquire UV-induced mutation in tumor suppressor genes (e.g. p53), thus decreasing the rate of apoptosis is these cells and providing them with a growth advantage over normal KCs (Ren hedrum oncogene 1996, Berg PNAS 1996), Over period of time these immortalized KCs expand and in case of excessive UV exposure, acquire oncogenic mutations (e.g. Ras), resulting in transformation leading to squamous cell carcinoma (Zhang Remenvick pnas 2001). The mechanism behind oncogene induced malignant transformation of human KCs is not completely understood.

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