Melanoma is a Dangerous Skin Cancer Associated with Melanocytes - Medical Science Assignment Help

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Introduction

Background

Melanoma is a dangerous skin cancer associated with melanocytes which produce melanin responsible for skin colour (Lerner and McGuire 1964). The most common forms of melanoma are cutaneous in origin but can occur in other parts such as ocular, mucosal and leptomeningeal melanoma (Mihajlovic et al. 2012). Metastasis is the primary cause of death in patients with Melanoma. According to data from (WHO) World Health Organization, there were 17,582 cases of melanoma skin cancer diagnosed in the UK in 2018 and 2,764 deaths from melanoma skin cancer. The melanoma is the 19th most common cause of cancer death in the UK, accounting for 1% of all cancer deaths (WHO, 2018). During their lifetime in UK 1 in 36 males and 1 in 47 females will be diagnosed with skin cancer. Almost 85% of melanoma are preventable. Melanoma is the 20th most common cancer around world, there were an estimated 287,723 new cases (1.6% of all cancers) and 60,712 deaths (0.6% of all cancer deaths) from melanoma in the year 2018, and a five-year prevalence of 965,623 cases (Bray et al. 2018). About half of the cases are diagnosed at ages 65+ years, and most cases occur on the trunk in males and on the lower limbs in females. Development Melanoma starts with gathering melanocytes to form a benign mole. This mole forms into atypical mole which can either undeveloped or develop into radial growth phase melanoma (RGP) (Miller and Mihm 2006).RGP grows horizontally in epidermis in skin and has no ability to metastatic (Crowson et al. 2006). In the later stage tumour develops vasculature, melanocytes increase in number, express integrin, and other adhesion molecules. At this stage tumour starts to thicken and melanocytes are attached to blood vessels and has capable of metastatic known as vertical growth phase melanoma (VGP) (Vacca et al. 1993). The depth of invasion by melanoma cells (Breslow depth) is a major determinant in patient prognosis, and the switch from RGP (indolent) to VGP (aggressive) is associated with poor prognosis. During conversion of melanoma from RGP to VGP, the expression of various integrins is altered (Vizkeleti et al. 2017) to enable cells to connect to the environment, gain new blood vessels, acquire migration, and invade other parts. Integrins play a major role in primary tumour aggressiveness and important mediators of metastasis (Hamidi and Ivaska 2018). Tumour metastasis is a consequent multistep process where tumour cells spread from the primary site to other parts. The tumours starts to metastasis through lymph angiogenesis and first metastasis at lymph node and later at lungs. (Harrell et al. 2007) This involves various cellular processes such as loss of cell adhesion, transmigration through the extracellular matrix (ECM) into the bloodstream, extravasation at the metastatic site, seeding and proliferation. (Arias-Mejias et al. 2020). (Slominski et al. 2018). Role of integrins and Vitamin D in Melanoma D 2 Cause Skin cancer is caused by exposure of UV rays because of its mutagenic effects which cause DNA damage and responsible in the loss of cellular homeostasis. The correlation of malignant melanoma and amount of sun exposure are crucial agents for causing disease (Gandini et al. 2005). The unnatural UV rays also responsible for the occurrence of the melanoma. The UV rays not only help in causing melanoma but also responsible for producing vitamin D under skin. Overall 7-15% of melanoma cases are hereditary, however this may not due to single genetic mutation transmitted from parents. (Goldstein and Tucker 2001). Nearly 45% of familial melanomas are due to germline mutations in CDKN2A, CDK4 and BAP1 (Leachman et al. 2017).The role of integrins and vitamin D in metastasis melanoma.

Integrins

Integrins are adhesion molecules made up of glycoproteins composed of 18? and 8? subunits together form 24 types of integrins in mammals. The integrins help in cell-cell and cell to environment interactions. Both ? and ? subunits have the extracellular domain, a transmembrane domain, and a cytoplasmic tail. (Campbell and Humphries 2011). In cancer cells, the extracellular domain acts as an receptor for adhesion proteins and growth factors to connect to the extracellular matrix (ECM) (Staunton et al. 2006). The cytoplasmic tail is linked to the cytoskeleton and cellular signalling pathways that trigger cell survival, proliferation such as focal adhesion kinase (FAK) and Src family kinases (Bendas and Borsig 2012).This process helps in tumour cell adhesion, invasion, migration, angiogenesis and metastasis. The development of metastasis depends on the upregulation of ?3 and ?1 integrins from RGP to VGP (Van Belle et al. 1999; Nikkola et al. 2004).The characteristics of metastasis are degradation of basement membrane, lack of apoptosis, angiogenesis, EMT transition. Degradation of basement membrane by ?v?3 is important for metastasis in melanoma. The next step in angiogenesis of tumour to provide nutrients is done by growth factors such as VEGF and FGF(Friedlander et al. 1995). VEGF and FGF helps in the degradation of basement membrane by expressing MMP2 and helps in the angiogenesis by Phosphoinositide-3 kinase pathway and P13/AKT dependent pathway. (Desch et al. 2012).M21 melanoma cell line lacking ?v can undergo apoptosis and helps in the reduction of tumour. When M21 cell line restore ?v expression then ?v?3 was able to restore tumour genic activity indicating ?v is responsible for the tumour activity in melanoma cells by Montgomery A.M et al 1994(Montgomery, 1994, Integrin alpha v beta 3 rescues melanoma cells from apoptosis in three-dimensional dermal collagen).

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