When the cells replicate in an uncontrolled manner they get transformed into a cancerous cells. When the cancer cells originate from the skin cells, it is said as skin cancer. Cancerous cells have different properties that make it different from the normal cells like accelerated cell cycle, dedifferentiation, invasiveness, changed cell surface, increased cell mobility, etc.( Abercrombaiende and Ambrose, 1962).
Skin cancer is mainly classified into 2 classes one is Melanoma and other is non melanoma skin cancer. Melanoma cancers are developing from melanocytes, the pigment-making cells of the skin. Melanocytes can also form benign growths called moles. While skin cancers not arising from melanoma are grouped together as non-melanoma skin cancers as they tend to rise from different cells apart from melanocytes. As compared to the non melanoma skin cancer like squamous cell carcinoma and basal cell carcinoma the occurrence of melanoma cancer is lower but melanoma cancer is more fatal than non melanoma cancers.
Melanoma mainly classified into 3 types namely cutaneous melanoma, mucosal melanoma and ocular melanoma depending on the area of origin. Further cutaneous melanoma is divided into four major types that are superficial melanoma, nodular melanoma, lentigo maligna melanoma, acral lentiginous melanoma.
' Superficial spreading melanoma is most common form of melanoma that grows along the top layer of the skin. It accounts for around 50-60% of the cases (Forman et al, 2006). Coalition of melanocytes at dermo-epidermal junction, horizontal growth which is eventually followed by vertical growth patterns are certain hallmark of superficial spreading melanoma (William et al, 2006).
' Nodular melanoma is the second most common type of melanoma accounting for 15-30% of the cases. It is the most invasive melanoma and its malignancy is recognized when it creates the bump at the site of spread. Nodular formation by melanocytes, with absence of radial growth phase and thin layer of epidermis are the hallmarks for nodular melanoma. (William et al, 2006)
' Lentigo maligna melanoma usually arises from lentigo maligna. It is usually found in older people in areas of skin that have had a lot of exposure to the sun over many years (most often the face and neck). This type of melanoma is developed from a slow-growing precancerous condition known as lentigo maligna or Hutchison's freckle, which looks like a stain on the skin (William et al, 2006). Lentigo melanoma accounts for 4-10% of total melanoma cases (Weinstock and Sober, 1987).
' Acral lentiginous melanoma is rarest type of melanoma that occurs on the palms, soles of the feet or beneath the nail beds. It is more common in darker-skinned patients. It accounts for 1-3 % of the melanoma cases (Bradford et al, 2009).
Second category of melanoma is mucosal melanoma. It accounts for about 1% of melanoma cases. It occurs in mucosal tissue, which lines body cavities and hollow organs. The most common sites are head and neck region (including the nasal cavity, mouth and oesophagus), rectum, urinary tract and vagina. It is often very difficult to detect (Mihajlovic et al, 2012).
Melanoma of the eye (ocular melanoma) is the third type of melanoma. Eyes contain melanocytes, and hence are susceptible to melanoma. Ocular melanoma occurs in eyes are of two types namely uveal melanoma and conjunctival melanoma. Uveal melanoma is the most common type of ocular melanoma. This occurs along the uveal tract of the eye, which includes the choroid, ciliary body and iris. The choroid is part of the lining of the eyeball. It's dark-coloured (pigmented) to prevent light reflecting around the inside of the eye. The ciliary body extends from the choroid and focuses the eye by changing the shape of the lens. The iris is the clearly visible, coloured disc at the front of the eye, which controls the amount of light entering the eye. All these structures are coloured with melanin. When melanoma occurs in the thin lining over the white part of the eye (the conjunctiva) or on the eyelid, it is known as conjunctival melanoma and occurs rarely (Singh et al, 2011).
Non-melanoma skin cancer is the most common form of skin cancers. They are called keratinocyte carcinomas because when seen under a microscope, their cells share some features of keratinocytes, the most common cell type of normal skin. Most keratinocyte cancers are basal cell carcinomas or squamous cell carcinomas.
' Basal cell carcinoma is the most common type of cancer in humans. About 30% of caucasians suffers from basal cell carcinomas (also called basal cell cancers) (Wong et al, 2003). They usually develop on sun-exposed areas, especially the head and neck. When seen under a microscope, basal cell carcinomas are seen to originate from the cells in the lowest layer of the epidermis, called the basal cell layer. These cancers tend to grow slowly. It is very rare for a basal cell cancer to spread to nearby lymph nodes or to distant parts of the body. But if a basal cell cancer is left untreated, it can grow into nearby areas and invade the bone or other tissues beneath the skin. The reoccurence of these cancer after treatment, are often seen at same place on skin. People who have had basal cell cancers are also more likely to get new ones elsewhere on the skin (Robinson, 1987).
' Another class of non melanoma skin cancer is Squamous cell carcinoma. The cells of this cancer, origins from the squamous cells which are seen in the outer layers of the skin. These cancers commonly appear on sun-exposed areas of the body such as the face, ears, neck, lips, and backs of the hands. They can be develop from scars or chronic skin sores. They often develop from actinic keratoses which is premalignant condition forming thick, scaly patches on skin (Prajapati and Barankin, 2008). Squamous cell carcinomas tend to grow and spread more than basal cell cancers. They are more likely to invade fatty tissues just beneath the skin, and are more likely to spread to lymph nodes and/or distant parts of the body, although this is still uncommon (Maula et al, 2003).
Other less common types of skin cancer that are quite different from keratinocyte cancers includes merkel cell carcinoma, kaposi sarcoma, cutaneous (skin) lymphoma, skin adnexal tumors, and various types of sarcomas. They accounts for less than 1% of non-melanoma skin cancers.
' Merkel cell carcinoma is type of skin cancer develops from neuroendocrine cells (hormone-making cells that resemble nerve cells in some ways) in the skin. They are most often found on the head, neck, and arms but can start anywhere. These cancers are thought to be caused in part by sun exposure and in part by Merkel cell polyomavirus (MCV). About 8 out of 10 Merkel cell carcinomas are thought to be related to MCV infection (Buck and Lowy, 2012). MCV is a common virus. Many people are infected with MCV, but it usually causes no symptoms as the virus shows the mutation only when found in cancer cells, while remains unchanged when affecting normal cells (Shuda et al, 2008)
' Kaposi sarcoma usually starts within the dermis but can also form in internal organs. It is related to infection with Kaposi sarcoma herpesvirus (KSHV), also known as human herpesvirus 8 (HHV8) (Phillips et al, 2008). This cancer is rare and found mostly in elderly people of Mediterranean descent. Kaposi sarcoma has become more common because it is more likely to develop in people with human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS) (Phillips et al, 2008).
' Skin lymphomas are cancers that start in lymphocytes, a type of immune system cell found throughout the body, including in the skin. Depending upon the type of immune cells affected they are categorized as B-cell cutaneous lymphoma and T-cell cutaneous lymphoma (William et al, 2006). Most lymphomas start in lymph nodes (bean-sized collections of immune system cells) or internal organs, but some types of lymphoma begin mostly or entirely in the skin and are called as Primary cutaneous lymphoma. The most common type of primary cutaneous lymphoma is cutaneous T-cell lymphoma (most of these are called mycosis fungoides) (Novelli et al, 2013).
' Adnexal tumors start in the hair follicles or glands (such as sweat glands) of the skin. Benign (non-cancerous) adnexal tumors are common, but malignant (cancerous) ones, such as sebaceous adenocarcinoma and sweat gland adenocarcinoma, are rare. Sarcomas are cancers that develop from connective tissue cells, usually in tissues deep beneath the skin. Much less often they may start in the skin's dermis and subcutis. Several types of sarcoma can start in the skin, including dermatofibrosarcoma protuberans (DFSP) and angiosarcoma (a blood vessel cancer) (William et al, 2006).
Factors responsible for skin cancer
Different factors are responsible of developing skin cancer namely UV radiation, Moles, genes present in family, immune suppression, Xeroderma pigmentosum.
1) UV Radiation: The UV radiation is mainly responsible for DNA damage of the skin cells that result into the mutation of the cells, transforming into the cancer cells. UV radiation is divided into 3 radiations that are UV-A, UV-B and UV-C. UV-A are long wavelength and low energy radiation that causes the tanning and damages the skin cells when exposed for longer period of time. UV-B are long wavelength and high energy radiation that causes sunburns, photo aging and are mainly responsible for skin cancer. UV-C does not pass through the earth's atmosphere and hence are not responsible for cancer development. UV radiation causes the direct cellular damage by damaging the DNA by formation of cyclobutane pyrimidine dimers, causes mutation, and increases the oxidative stress and inflammatory responses (Meeran et al, 2008). Mutation of p53 gene by UV radiation causes the dysregulation of the cell's DNA repair mechanism along with failure to cause apoptosis, and initiating the skin cancer (Benjamin and Ananthaswamy, 2007).
2) Dysplastic nevi: Dysplastic nevi also known as atypical moles, resembles closely to melanoma but are benign in nature. It results due to over proliferation of melanocytes and hence is brownish or blackish in color. It is found that chance of developing malignant melanoma from the pre-existing moles is 10 times higher, if the numbers of moles are more than 5 as compared to individual without moles (Friedman et al, 2009). Also people with fair complexion of skin have risk of melanoma 10 times more as compared to the black complexion peoples (Carlson et al, 2003).
3) Individual and family history of skin cancer: In men with a history of basal cell carcinoma (BCC), the subsequent squamous cell carcinoma (SCC) risk is 27% higher, while individuals with melanoma were 2.5 times more likely to report a subsequent SCC. (Cantwell et al, 2009). In case of melanoma, after diagnosis of primary melanoma risk of secondary melanoma is approximately 5%, while in case for older patients and males it is even greater than 5% (Goggins and Tsao, 1997). An individual with an history of SCC or BCC have increased risk of subsequent development of melanoma.
As per the review of the Swedish Family Center Database, individuals with at least one sibling or parent affected with SCC, insitu SCC (Bowen disease), or actinic keratosis had a twofold to threefold increased risk of invasive and in situ SCC relative to the general population (Hussain et al, 2009). It was found that incidence ratio of melanoma in offsprig of and affected individual is 2.62 while for siblings of the same is 2.94 (Brandt et al, 2011).
4) Immunosuppression: Immunosuppression also contributes to the formation of nonmelanoma skin cancers. Among solid-organ transplant recipients, the risk of SCC is 65 to 250 times higher, and the risk of BCC is 10 times higher than that observed in the general population, although the risks vary with transplant type (Jensen et al, 1999). Nonmelanoma skin cancers in high-risk patients (solid-organ transplant recipients and chronic lymphocytic leukemia patients) occur at a younger age, are more common and more aggressive, and have a higher risk of recurrence and metastatic spread than these cancers do in the general population (Glover et al, 1994). Melanoma has 1.6 to 2.5 time's greater risk of development in individuals with organ transplants in comparison to the general population (Dinh and Chong, 2007).
5) Xeroderma pigmentosum: Xeroderma pigmentosum is rare inherited condition resulting from the defect in the enzymes (nucleotide excision repair enzymes) that repairs the DNA. Since the people with this condition are not able to repair the damaged skin portion resulted from sunlight it results into melanoma. The incidence of nonmelanoma skin cancer in individuals younger than 20 years with xeroderma pigmentosum is 150 times increased as compared to normal individual (Kraemer et al, 1994).
6) Genetic changes affecting skin cancer: Mutation in various genes affects the development of disease in individuals. These mutations are often difficult to determine, and depends on the rarity of the genetic mutation. Major genes mutated like PTCH (Patched, drosophilia homolog) mutation in basal cell carcinoma and CDKN2A/p16 or p14/ARF mutation in melanoma development are seen in majority of cases. Presence of mutation in PTCH was seen in 30% of basal cell carcinoma (Halpern and Guerry, 1991). Mutation of CDKN2A results in 35-40% development of familial melanoma (Goldstein et al, 2006). CDKN2A is associated with development of melanoma-astrocytoma syndrome which involves the presence of cutaneous melanoma with increased likelihood of developing tumours in nervous system including astrocytoma, glioma, meningioma and other nerve cells (Azizi et al, 1995).
Following are the list of other few genes, along with its affecting conditions that is related to development of skin cancer.
Genes Condition with mutated gene Description
Xeroderma pigmentosum (XP) complementation group A (XPA), XP-group B(XPB), group C(XPC), group D(XPD), group E(XPE), group F(XPF) and group G(XPG). Xeroderma Pigmentosum These genes are part of nucleotide excision repair genes. Mutation of these genes causes increased sun sensitivity, increased risk of cutaneous carcinoma with photophobia and keratitis. (Kraemer and DiGiovanna, 2003)
GJB2 ( Gap junction protein, beta 2) Keratitis-ichthyosis-deafness syndrome (KID syndrome)
It is found that approximately 12 % of the people affected with KID syndrome develop squamous cell carcinoma with increased chances to affect the mucosal membrane. (van Steensel, 2006)
SDHB (Succinate dehydrogenase complex, subunit B), SDHD (Succinate dehydrogenase complex, subunit D), PTEN (Phosphatase and tensin homologue), and KLLN (Killin, p-53 regulated DNA replication inhibitor) Cowden-like syndrome.
Cowden-like syndrome is characterized by presence of multiple non-cancerous growth structures called as hamartomas. These growth structures are found mainly on skin and mucosal membranes and have increased risk of developing melanoma, colorectal cancer and breast cancer.
TYRP1 (tyrosinase related protein 1), SLC45A2 (solute carrier family 45, member 2) and MC1R (melanocortin 1 receptor) Oculocutaneous albinism These genes are responsible for production of melanin. Mutation in any of these genes destroys the ability of cells to produce melanin. Depending upon the type of gene mutated the oculocutaneous albinism is divided into 4 types (okulicz et al, 2003)
TERC (telomerase RNA component), TERT (telomerase reverse transcriptase), DKC1 (dyskerin) Dyskeratosis congenital It is telomere related disorder characterized by pigmentation, dysplastic nails and leukoplakia. Individuals with DS have increased risk of solid tumour formation like squamous cell carcinoma (Savage, 2009).
Many other genes like TMC-6 (transmembrane channel like protein 6), MYO5A (myosin va), LAMA3 (Laminin alpha-3) are also seen in development of various conditions and diseases which increases the risk of skin cancer.
Targets for skin cancer
Multiple tumor-promoting events like activation of oncogenes and inactivation of tumor suppressor genes, leads to transformation into cancer cells. Different pathways are responsible for development of skin cancer.
1) Role of P53 in skin cancer
The most prominent mutation studied in skin cancer is related to p53 tumor suppressor gene. It is suggested that as many as >90% of SCCs and >50% of BCCs have mutation in the p53 gene (Brash et al, 1996). The p53 protein is involved in programmed cell death (apoptosis), and it has been proposed that p53 serves to guard the genome by aiding DNA repair or causing elimination of cells with excessive DNA damage. Damage to p53 gene causes formation of mutated p53 protein which fails to protect the cell against the cell damage. Many p53 mutations are C to T transitions with a high frequency of CC to TT double base changes, thus being indicative of UV-radiation-induced mutations. In addition, the mutations do not appear to be at random but show a pattern of hot spots different from that of internal malignancies (Tornaletti, and Pfeifer, 1994). It is proposed that from these mutational hot spots mutations in codon 177 are specific only for BCCs while mutations in codon 278, although mutated at a lower frequency also in certain internal cancers, seem to be specific for skin SCCs. (Giglia-Mari. and Sarasin, 2003)
2) Role of RAS protein in skin cancer
Another pathway that is mainly mutated in many skin cancers is RAS (Rat sarcoma) pathway. In tumor condition RAS proteins are frequently mutated and hence are been targeted for treating different tumor condition. These proteins are the G-protein which are activated when bounded with GTP while stays inactive when bounded to GDP. Group of specialized protein known as GAPs (GTPase activating protein) causes the hydrolysis of GTP and hence the RAS pathway gets inactive. Activation of RAS proteins causes the stimulation of phosphotidyl inositol-3-kinase (PI3K), RAF proteins which regulates cell survival, proliferation and differentitation (Mitin et al, 2005). Activation of PI3K causes conversion of phosphatidylinositol-4,5-biphosphate (PIP2) to phosphatidylinositol-3,4,5-biphosphate
(PIP3) by phophorylation, which subsequently activates Akt that inactivates several proapoptotic proteins helping in survival of cell (Bello et al, 2013). Also activation of RAS proteins causes activation of MEK/ERK pathways that is responsible for cellular growth and proliferation (Marshall, 1995).
RAS superfamily consists of 3 members namely HRAS, NRAS, and KRAS. In case of melanoma it has found that mutation of NRAS is more frequent as compared to KRAS and HRAS (Hocker and Tsao, 2007) (Goel et al 2004). Though the specificity of NRAS getting mutated in melanoma is not known but it is suggested that NRAS might have unique role in development of melanoma (Whitwam et al 2007). Majority of skin cancer excluding melanoma involves mutation of HRAS is predominantly seen in general population with characteristic mutation at codons 12, 13 and 61. (Popps et al, 2002) Development of SCC and BCC through RAS protein mutation accounts for only 10-20% of the total mutation frequency (Schroeff et al, 1990).
3) Role of PTCH gene in skin cancer
Patched tumor suppressive gene (PTCH gene) is responsible in sonic hedgehog signaling that is needed in skin for hair follicle growth and morphogenesis. Patched1, the protein product of PTCH, is a cell surface receptor of the secreted signaling molecule SHH. In the absence of SHH, patched1 inhibits smoothened (SMO), a G-protein-coupled like receptor. SMO is released upon binding of sonic hedgehog (SHH) to patched1 and can initiate a signal transduction cascade that causes activation of the transcription factor GLI (Glioma associated oncogene). GLI is bounded with suppressor of fused (SUFU) in active state. On SHH binding SUFU gets inactivated and releases GLI. Unbounded GLI actively trasnlocates to nucleus and promotes the transcription of the target genes. Hence, dysregulation of this pathway by either the PTCH loss or the increased expression of SMO results in rising levels of the transcription factor Gli1 and, as a consequence, causes tumors (Grachtchouk, et al, 2000) by opposing cell cycle arrest and differentiation (Fan and Khavari, 1999). Mutations of either PTCH or SMO have been found in more than 70% of human BCCs (Xie et al, 1998).
Mechanism of action of PTCH pathway (Masoumi et al, 2011)
4) Role of BRAF gene in skin cancer
V-raf murine sarcoma viral oncogene homolog B1 (BRAF) gene codes for a proteins which are serine/threonine protein kinase that helps in regulating the MAP kinase/ERK pathways, which regulates cell division, differentiation and secretion. Rapidly accelerated fibrosarcoma (RAF) family are activated by the RAS proteins that are attached to inner layer of plasma membrane and gets activated in presence of external stimuli like growth factors via receptor tyrosine kinase (RTC) (Welbrock et al, 2004). Activation of RAF proteins causes phosphorylation of MEK and ERK (MAP Kinase proteins) leading to cell proliferation, metastasis, and tumour growth (Marshall, 1995)
Amongst RAF family BRAF is most easily activated by RAS. Also the basal kinases activity of the BRAF is higher than other RAF family members (Emuss et al, 2005). BRAF is highly expressed in melanoma and neuronal cells hence the mutation in BRAF leads to increased risk of melanoma (Chin et al, 2006). The most common mutation in BRAF gene is at T1799A point mutation which causes conversion from T to A amino acid resulting in glutamic acid formation in place of valine. This mutation is responsible in 90% of clinical pathology (Garnett and marais, 2006). Though BRAF mutation is common in dysplastic nevi and other melanomas but this mutation alone is not responsible for malignant transformation to melanoma (Kumar et al, 2004).
5) Role of PTEN gene in skin cancer
Mutation in PTEN gene also leads to formation of melanoma. PTEN gene is located on 10th chromosome. PTEN (phosphatase and tensin homolog) is a protein formed from the PTEN gene. Its phosphatase activity causes the degradation of the product of phosphatidylinositol 3-kinase (PI3K) by dephosphorylating phosphatidylinositol 3,4,5-triphosphate and phosphatidylinositol 3,4-bisphosphate at the 3' position (Simpsons and Parsons, 2001). This molecular change leads to change in cells to stop replicating and results in cell death (apoptosis). In case of melanoma it was found that 60% of the case resulted with deletion and mutation of this gene (Reifenberger et al 2000).With the mutation in PTEN gene the pathway controlling Akt signalling is nullified and hence the action of tumour suppressive gene and induction of apoptosis is neutralized, resulting in survival of cancer cells.
6) Role of GNAQ gene in skin cancer.
Yet another pathway named GNAQ pathway has been found to be responsible for development of skin cancer. Guanine nucleotide-binding protein G (q) subunit alpha is a protein that in humans is encoded by the GNAQ gene. Receptor activation causes the activation of GNAQ by catalyzing the release of GDP and binding of GTP. In its active form GTP-bound GNAQ causes the release of the beta and gamma subunits of the heterotrimeric G-protein. GTP-GNAQ and beta and gamma subunits transfer the receptor-mediated signal to downstream effectors through secondary messengers which participate in diverse signaling pathways to evoke different effectors. One of the effector pathway affected by GNAQ is activating the MAP kinase pathway, possibly via DAG-mediated activation of protein kinase C (Bello et al, 2013) Mutation of GNAQ results in mutated protein that remains activated for longer period along with the lost sensitivity to their inhibitors.
Mechanism of GNAQ signalling (Bello et al, 2013)
Model generation for skin cancer
Skin cancer is generally induced using mice, since the events of cancer in human can be replicated in mice with few exceptions. It is seen that in both species, point mutation in ras gene family members causes squamous cell carcinoma with predominant expression of H-ras mutation (Johannes L. Bos, 1998) (Stoler et al, 1993). Also the tumor events in mice undergo the similar sequential genetical changes as that of human including mutation in p53, retinoblastoma gene and p16INK4 (Balmain and Harris, 2000).
Skin cancer can be induced in mice by different ways like chemical method, radiation method, xenograft model, or by using genetically engineered mouse.
' Chemical Method
Chemical method involves use of chemical carcinogens that causes the specific mutation in specific cells to mimic the tumor events of human cancer (Balmain and Harris, 2000). These carcinogens are frequently subjected to different pathways of activation and detoxicification or might act directly on to the cells to produce the mutation. The action of certain carcinogen is variable since the difference in the metabolism governing the action of carcinogen is different in every individual (Weston and Harris, 2000). Mainly chemical carcinogenesis is divided into 4 sections namely cancer initiation, cancer promotion, malignant conversion and cancer progression (Weston and Harris, 2000). Cancer initiation stage causes the irreversible damage in genetic material of the cell. These process is mainly involves production of adducts between the carcinogen and the nucleotide of the DNA of the particular affected cell (Yuspa and Poirier, 1988). Further for clonal expansion of the mutated cells, increased rate of cell division ensures the production of cells with increased risk of malignant conversion (Verma and Boutwell, 1980). Malignant conversion causes the conversion of precancerous cells to the malignant. To increase the probability of malignant conversion increased exposure of DNA damaging agents causing activation of proto-oncogenes and deactivation of tumor suppressive gene to precancerous or benign cancer cells (Yuspa and Porier, 1988). Finally cancer progression stage involves metastasis of the tumor cells which enables it to secrete proteoses which allows it to invade other distance tissues in the body. Mainly for induction of skin cancer Dimethyl benz (a) anthracene is used as cancer initation along with tumour promoting agent either Tetradecanoyl phorbol acetate (TPA) or Croton oil. Thus two stage chemical method for inducing skin cancer produces skin papillomas at first, which are further transformed into deep squamous cell carcinoma in span of 18 weeks. The two-stage chemical carcinogenesis protocol includes an initiating application of DMBA for tumour initiation stage, followed by twice weekly dose of TPA for tumour development and progression stage. DMBA is a polycyclic aromatic hydrocarbon. Its application on skin causes an irreversible and specific mutation causing A-to-T transversion in codon 61 (second nucleotide) of the oncogene Ha-ras (Fujiki et al, 1989). The conversion results into CTA codon instead of CAA leading to missense mutation. DMBA is metabolised by CYP1A1 CYP1B1, the enzymeof CYP450 to the carcinogen 1, 2-epoxide-3, 4-diol DMBA which form adduct with DNA and further leads to mutation, which are prerequisite for the development of tumor (Di Giovanni J, 1992). TPA is a strong tumor promoter (Todd M. Kolb and Myrtle A. Davis, 2004). It is shown to increase production of ROS and hydroperoxides in keratinocytes both in vitro (Fischer et al, 1986) and in vivo (Perchellet & Perchellet, 1989) and organic peroxides have been shown to promote skin tumorogenesis (Slaga et al, 1982).
' Radiation Method
Radiation method involves application of UV radiation on the skin of mice to develop the tumor in span of 35-36 weeks. Use of UV radiation causes DNA damage and mutation. UV radiation is absorbed by DNA in range of 245-290 nm (Tornaletti & Pfeifer, 1996). UV radiation causes formation of mutagenic photoproducts or lesions in DNA between adjacent pyrimidines in the form of dimers. These dimers are of two main types: cyclobutane dimers between adjacent thymine or cytosine residues, and pyrimidine pyrimidone photoproducts between adjacent pyrimidine residues (Kripke, 1981). These dimers may interfere with important processes of cell cycle regulation involving DNA. UV radiation is categorized as UV -A, UV-B and UV-C. It was found that UVA was relatively ineffective as a carcinogen, but it increased the carcinogenic effects of UVB when mice were irradiated with both (Matsui & DeLeo, 1995). UV radiation also inhibits antigen presentation and stimulates the release of immunosuppressive cytokines.(Norval et al, 2008.) Thus UV radiation plays a dual role in the development of skin cancer. On one hand, UV radiation induces genetic alterations in keratinocytes, leading to their neoplastic transformation. On the other hand, UV radiation depresses the immune responses in the skin, which can permit the growth of emerging tumors produced by the effects of UV induced DNA damage.
' Xenograft models
Human tumor xenograft model involves use of human tumor cells which are transplanted under skin into immunocompromised mice which do not reject the human cells. Athymic nude mice, Severly compromised immunodeficient mice (SCID mice) or other immunodeficient mice can be used for tumor trasnplantation (Morton and Houghton, 2007). Tumor will be developed in mice withing span of 1-8 weeks depending on the number of cells or size of tumor transplanted. Using of xenograft models has several advantages like complexity of genetic and epigenetic malfunctions, invivo action of certain molecules on tumor cells and development of complete microenvironment which also involves presence of immune cells in 'humanized' mice by injecting human bone marrow cells. There are several disadvantages of xenograft model like expensive or complication of the model development in case of using humanized mice for tumor transplant. Also use of immunocompromised mice causes less realistic tumor environment which may not correctly justify the action of the drug (Richmond and Su, 2008).
' Genetically engineered model
The genetic profile of the mice is changed in such a way that one or several genes responsible for tumor formation are mutated, deleted or over expressed. The effects of these altered genes are studied for the response in the tumor development or for the invivo therapeutic responses with completely mirrored tumor microenvironment (Talmagde et al, 2007). For use of genetically modified model for human tumor, certain criteria's like homologous mutation in mice as compared to that in human tumors, mutation within the endogenous locus of the gene and should not be expressed as transgene, mutation should occur within specified group of tissues. Disadvantages like reproducibility of the model since tumor development is slow and variable. Development of such model consumes lot of time and is costly, also a limited target genes are modified which cannot reflect the complex heterogeneity of the human tumor cells (Richmond and Su, 2008).
Introduction to Cyclin Dependent Kinases (CDKs)
Regulation of cell cycle is an important step which maintains the balance of the cells between proliferation and apoptosis to maintain the functionality and integretiy of the tissues. Cell cycle is divided into four phases namely G1, S (DNA replication phase) , G2 and M (mitotic phase). For transition of cell from one phase to other it requires the complex of specific cdk and and its partner cyclin. CDKs are the protein kinases that consist only of a conserved catalytic kinase core of about 30 to 40 kDa, which is inactive by itself (Hanks and Hunter 1995). They require their cyclin partners for the activation of the kinase activity. Following is the table with role of different CDK's and their cyclin partners in cell cycle phases.
CDK Cyclin Cell cycle phase activity
CDK4 Cyclin D1, D2, D3 G1 phase
CDK6 Cyclin D1, D2, D3 G1 phase
CDK2 Cyclin E G1/S phase transition
CDK2 Cyclin A S phase
CDK1 Cyclin A G2/M phase transition
CDK1 Cyclin B Mitosis
CDK7 Cyclin H Cdk activating Kinase (CAK),all cell cycle phases
Role of CDK's in cancer cells and potential targets to block action of CDKs
In cancer cells there are variety of genetic and epigenetic responses causes the overexpression of different cdks. Because of deregulated CDK activation, cancer cells undergoes unscheduled proliferation along with genomic (defective DNA repair and DNA damage checkpoints) and chro??mosomal instability (defective mitotic che??ckpoints and chromosomal segregation) (Malumbres and Barbacid , 2009). In addition, mutations in such genes that encode these signaling proteins can make different protein molecules(eg. receptors or intermediate proteins) hyperactive, allowing them to relay proliferation signals to the nucleus even in the absence of signals from the extracellular matrix or from neighbo??ring cells. This uncontrolled signaling can lead to loss of cell cycle regulation and as a consequence to unrestrained cell division, a hallmark of cancer cells. (Malumbres and Barbacid , 2009). Most commonly in human cancer cells the overexpression of cdk 4/6 and cyclin D is found in majority (Shapiro, 2006). Different events like inactivation of p16INK4 (tumor suppresive gene), amplification and mutation of cdk4 and cyclin D are usually exclusive events taking part in cancer cells (Allen et al, 1994). Thus with help of different cdk inhibitors we can regulate the uncontrolled growth of the cancer cells.
Different strategies for targetting CDK proteins are developed, which involves the either direct action on CDK or on CDK-cyclin complex to inhibit its kinase activity or by indirect method which involves overexpression of CDK inhibitors, decrease levels of cyclin or modification of phoshorylated state of enzymes needed in reglation of CDK (Vermeulen et al, 2003). Till date the inhibitors of CDK discovered acts majorly through direct strategy, by producing competitive inhibition of ATP binding to CDK. Following table shows certain CDK inhibitors along with their IC50 on CDK. (Vermeulen et al, 2003)
Inhibitor IC50 (mM) Reference no.
Dimethylaminopurine 20 Meijer & Pondaven 1988;
Neant & Guerrier 1988
N6-isopentenyladenine 55 Rialet & Meijer 1991
Olomoucine 7 Vesely et al. 1994
Roscovitine 0.2'0.8 De Azevedo et al. 1997;
Meijer et al. 1997
Purvalanol A 0.004 Gray et al. 1998
Purvalanol B 0.006 Gray et al. 1998
Olomoucine II 0.02 Krystof et al. 2002
Butyrolactone 0.6 Kitagawa et al. 1993;
Kitagewa et al. 1994
Flavopiridol 0.4 Losiewicz et al. 1994
Oxoflavopiridol 0.13 Kim et al. 2000
Thioflavopiridol 0.110 Kim et al. 2000
Kenpaullone 0.4 Zaharevitz et al. 1999
Alsterpaullone 0.035 Schultz et al. 1999
Indirubin 10 Hoessel et al. 1999
Indirubin-3-monoxime 0.18 Hoessel et al. 1999
5-chloro-indirubin 0.4 Hoessel et al. 1999
Indirubin-5-sulphonic acid 0.055 Hoessel et al. 1999
Staurosporine 0.003'0.009 Gadbois et al. 1992
9-hydroxyellipticine 1 Ohasi et al. 1995
Suramin 4 Larsen, 1993
Hymenialdisine 0.022 Meijer et al. 2000
Toyocamycin 0.88 Park et al. 1996
Introduction to Linum usitatissimum L.
Flaxseed is commonly known as Alashi, Atasi, linseed, linen flax. These are the dried ripe seeds of Linum usitatissimum L, an annually growing erect herb of 0.6-1.2 m tall. It is cultivated throughout the plains of India ranging till an altitude of 800 m. Flowers are purple pale blue ranging with diameter of 15-25mm, with five petals. Fruit is round in shape in form of dried capsule of 5-9 mm diameter. Seeds are separated from the capsule when ripened by thrashing. Seeds are small and glossy with minutely pitted surface. It is elongated-oviod, rounded and flat at one end, while other end is pointed near which an enclosure of hilum and micropyle. Inner part of seed contains white thin layer of endosperm along with embryo having two yellowish flat planoconvex cotyledons with radical (Tanna et al, 2013).
Sweet mucilaginous taste with yellow colour and bland odour are certain organoleptic parameters.
Chemical components: Seeds consists of chemical components like alpha linolenic acid (ALA), cyanogenetic glycoside like linamarin, linustatin, neolinustin, unsaturated fatty acid (linolenic acid, linoleic acid, oleic acid), soluble flaxseed fiber mucilage (d-Xylose, L-Galactose, L-Rhamnose, d-galacturonic acid), lignans (secoisolariciresinol diglycoside (SDG)), monoglycerides, triglycerides, free sterols, sterol esters, hydrocarbons (protein), balast, phenylpropane (Ganorkar and Jain, 2012).
Certain microscopic characters involves presence of lignified sclerides, collenchymatous cells rounded in shape, aleurone grains, epidermal cells with presence of mucilage, oil globules and parenchymatous cells (Tanna et al, 2013).
Introduction to Secoisolariciresinol diglucoside
Secoisolariciresinol diglucoside (SDG) is a phytoestrogen molecule belonging to group of lignans. It is present in cereals (rye, wheat, oat), Curciferous vegetables (Broccoli, cabbage), fruits (apricot, strawberries) and seeds (Flaxseed, sesame seed) (Meagher and Beecher, 2000). Highest quantity of yield is obtain in flaxseed (Smeds et al, 2007). SDG get metabolized to form Enterolactone and Enterodiol (enterolignans) in colon by intestinal flora, which are further absorbed and distributed in the body through blood stream. Majorly two anaerobes, peptostreptococcus and eubacterium catalyzes the breakdown of SDG by demthylation and dehydroxylation (Wang et al, 2000). Further these enterolactones are absorbed by large intestine and enters blood stream. In blood it either conjugates with glucuronides or sulphatres or is present in free form ( Aldercreutz et al, 1993). They are excreated in urine mainly as monoglucuronides (85-95%) or monosulphates (2-10%) or as free aglycone (Aldercreutz et al, 1995). The mean residence time and half life measured after single dose of SDG (0.9mg/ kg of bodyweight) in healthy individual indicated that enterolignans accumalte in plasma when consumed 2-3 times a day and reach steady state. ( Kuijsten et al, 2005)
Different Pharmacological actions of SDG are
' Antioxidant activity: The plant lignans showed radical scavenging activity in both lipid and aqueous, in-vitro model systems SDG and its metabolites appeared as antioxidant. SDG along with their enterolignans showed significant inhibition of linoleic acid peroxidation at 10 and 100??M over a 24-48 h of incubation at 40??C. ( Prasad, 2000). However, it has been demonstrated that enterodiol and enterolactone were not effective in preventing H2O2 induced DNA damage in HT-29 cells and enterolactone did not reduced intracellular oxidative stress at similar concentration. (Pool-zobel et al, 2000).
' Antiatherosclerotic effect: It is seen that SDG decreases the release of inflammatory mediators such as interleukin (IL-1), tumor necrosis factor (TNF), leucotriene B4 (LTB4). These all mediators are known to stimulate polymorphonuclear leukocytes (PMNLs) and monocytes to produce oxidative free radicals (OFRs). Supplementation of flaxseed rich with SDG reduces the level of OFRs and hence, prevent the development of hypercholesterolemic atherosclerosis and aortic atherosclerosis by 46% markedly without lowering serum cholesterol. ( Prasad, 1997) ( Prasad, 2005)
' Anticancer activity: Supplementation of flaxseed reduced the epithelial cell proliferation by 38.8 - 55.4% and nuclear aberration by 58.8 - 65.9% in female rat (Thompson and serraino, 1991). SDG gets metabolized to enterolignans which can bind to estrogen receptor ?? and ?? and block or antagonize the effect of estrogen which plays important part in cancers like mammary carcinoma, and ovarian cancer . (Wang, 2002). Supplementations of SDG reduced the risk of breast cancer, and showed antiproliferative effect on the breast, positive effect on lipoprotein profile and bone density in post menopausal women.( Kitts et al, 1999) ( Haggans et al, 1919).It showed the suppression of mammary tumorigenesis by its partial estrogenic activity, antioxidant activity or reduction of plasma insulin like growth factor-1( Thompson et al,1996). Besides, its antioxidant and partial estrogenic activity of SDG and enterolignans also affect to beta glucouronidase activity, which may be the cause of protective effect against colon cancer. It has been observed that pretreatment of flaxseed decrease the risk of colon carcinogenesis, with reduced total number of aberrant crypts and foci significantly by 41-53% and 48-57% respectively (Sung et al, 1998) (Serriano and Thompson, 1992). Metabolites of SDG also appeared to influence steroid metabolism in- vitro, not only by acting on steroid receptor but also by steroid metabolism, for e.g. sex hormone binding globulin synthesis (Schottner et al, 1997 ) 5??-reductase and 17-?? hydroxyl-steroid dehydrogenase ( Evans et al, 1995).
' Anti-diabetic activity: It has been demonstrated that SDG prevented development of diabetes mellitus by 75%. It was mainly the antioxidant effect that reduced the generation of reactive oxygen radicals which plays important part in development if diabetes mellitus (Prasad et al, 2000).
' Effect on Cardiovascular system: SDG imparts its cardioprotective actions by several ways. It reduces the cholesterol levels , induces angiogenesis at peri infarcted areas and avoids ventricullar remodelling ( Penumathsa et al, 2007) . It also shows beneficial role in endotoxic shock (Pattanik and Prasad, 1998).
' Renoprotective effect: SDG rich flaxseed extract is seen to have renoprotective effect by reducing the radical generation in ischemic perfusion model in rats (Ghule et al, 2011).
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