Ivan+Liang

Picture in your mind a clear, sunny day in the middle of August. On this day, an elderly Taiwanese American man tends to his beloved garden, a passion that has given him meaning in his retirement days. Under the scorching sun, he toils without a shirt or shoes. What harm could possibly befall a man who had labored in the sun for 80 years of his life? Unbeknownst to him, the harsh UV rays from the sun have already wreaked havoc on his unprotected skin, causing irreparable damage to the cellular DNA. This man, like many millions around the world, has developed skin cancer, a cancer that affects one in five Americans (1). My grandfather, James Liang, was a part of that statistic, and had developed Bowen’s disease, an early stage of Squamous Cell Carcinoma (SCC) //in situ//. James, who is now 90 years old, first developed signs of SCC around 10 years ago.
 * The Sun: Friend or Foe **

My grandfather was born and raised in Taiwan, under the Japanese occupation during World War II. In his teens, he was drafted by the Japanese Army to fight in the war. After the war, he found work as a coal miner in Taiwan. Falling ill to a disease while in the mines, he left the job and became a sales manager in a textile mill. In his mid 50s, he moved to California and worked for Hitachi on automotive systems and retired at the age of 60. My grandfather has a family with his wife, three children, and four grandchildren. In the past, he was a chronic smoker but quit the habit after retirement. Since retirement, my grandfather has spent much of his leisure time outdoors in his garden as a primary hobby. The factor most likely to have brought on the cancer is his exposure to the sun while outdoors during his retirement years. While many of the events throughout his lifetime could be linked to cancer, the daily unprotected exposure to sun is most relevant to his development of Bowen’s disease. Skin cancer, especially nonmelanoma carcinomas, is incredibly common and has seen a marked increase in occurrence due to more leisure activities under UV exposure and tanning beds. It is important to understand the risk factors of skin cancer and the proper prevention methods and treatments.

Bowen’s disease is considered to be a non-critical form of Squamous Cell Carcinoma, and is the second most common type of skin cancer (2). This cancer develops as a growth of cancerous cells //in situ//, meaning their original place in the epidermis, and is non-invasive. Unlike more severe and dangerous forms of skin cancer, such as melanoma, SCC is usually contained in the epithelium and does not metastasize to other parts of the body (3). However, if left untreated, the cancer may penetrate into deeper layers of the skin. Bowen’s disease does not run in my family and my grandfather is an isolated case. Squamous Cell Carcinoma is more prevalent in males over the ages of 50, possibly due to more sun exposure in their occupations and the accumulated UV radiation over many years. Squamous Cell Carcinoma is not hereditary, but there can be genetic predisposition to it, and people with fair skin, hair, and eyes are at a higher risk of developing the disease. My grandfather does not exhibit any of the at risk physical features, but his activities in the garden and outdoors have exposed him to chronic and extreme levels of UV rays from sunlight, which is a significant risk factor for all forms of skin cancer. Overexposure to the sun causes UV photons to be absorbed by the DNA molecules of epithelial cells and can cause cell injury, uncontrollable division, and inflammation/sunburns (4). To be more specific, UV-B radiation generates photoproducts that impair DNA replication which then leads to genetic damage and mutation, and is the primary cause of lesions on the skin (5). In the case of my grandfather, he developed small lesions on the top of his feet and upper chest; both the affected areas were unprotected and open to sun exposure due to my grandfather usually wearing sandals and an unbuttoned shirt while working in the garden. The symptoms my grandfather experienced from the lesions caused by UV-B radiation were red, itchy, and scaly skin which eventually led him to consult a dermatologist.

The doctor’s prognosis of my grandfather’s disease was good, because Bowen’s disease is an early pre-cancerous stage to Squamous Cell Carcinoma and has many available treatments, especially if caught before the cancerous cells have a chance to metastasize. In most treatments of Squamous Cell Carcinoma, the cancerous growth can be removed successfully and survival rates for nonmelanoma cancers are extremely high. However, those who have had Squamous Cell Carcinoma are at a higher risk of recurring skin cancer and potentially more deadly types such as malignant melanoma. Since my grandfather’s cancer was still confined to the outer surface of skin cells, the doctor was confident that the affected areas of the epidermis could be removed without much destruction or disfigurement. The cancer was classified as “local, affecting only the skin” and had a skin biopsy to ensure the cancer was contained (6). The initial treatment for the tumor cells was cryosurgery by freezing the affected areas with liquid nitrogen. This technique causes the growth to crust and scab and eventually fall off, but it also causes redness and blistering of the skin. It is a general first treatment for Squamous Cell Carcinoma due to its low cost and ease of administration, but is overall less effective than other treatments, because it can only target skin at the very top layer of the epidermis and may miss growths that have penetrated deeper into the skin. My grandfather’s cancer went into remission, but about a year after the cryosurgery, the cancer recurred. This relapse may have occurred because of the lower cure rate of cryosurgery. The cancerous cells that had been missed by cryosurgery would have continued to divide uncontrollably and grow back. The treatment my grandfather underwent after relapse was excisional surgery, which involves cutting out the entire tumor growth along with a small area around the lesion to ensure complete removal of cancerous cells (1). This treatment is much more effective but also potentially damaging due to its invasive nature, and has a reduced cure rate for recurrent carcinomas. Along with the excisional surgery, my grandfather also received topical immunotherapy with Imiquimod (Aldara) cream for a few months. The treatment proved to be successful and the cancer never recurred. In 2015, my grandfather had a follow up with the dermatologist and the cancer was determined to be in complete remission. When caught early, most patients diagnosed with SCC can be effectively treated with little damage. However, there are those less fortunate patients where the cancer metastasizes to other parts of the body or even brings on a more aggressive form of skin cancer, such as malignant melanoma.

** Molecular Basis of Squamous Cell Carcinoma ** Squamous cell carcinoma (SCC) is one of the most prevalent cancers due to exposure to sunlight, a major contributing risk factor that affects the population indiscriminately and is unavoidable. Ultraviolet B radiation is a specific range of wavelengths (280-315 nm) present in sunlight that can be harmful with overexposure, because it is “a carcinogen [that] mutates a target gene (7).” UVB radiation promotes SCC through inactivation of the p53 tumor suppressor gene, resulting in resistance against damage induced cell death; SCC tumor cells can then initiate a metastatic cascade by promoting Vascular Endothelial Growth Factors (VEGF) and Matrix Metalloproteinases (MMPs), both of which are markers of tumor invasion and metastasis.

UVB radiation causes a loss of function mutation in the p53 tumor suppressor gene “at dipyrimidine sites, including a high frequency of C to T [nucleotide] substitutions (8),” granting the cancer cell selective advantages such as resistance to cell death, a main hallmark of cancer. Mutations caused by UVB radiation to p53 can affect the ability of p53 to regulate the cell cycle, transcription, genetic repair, and apoptosis. p53 is a protein that plays a central role in the cell cycle; it monitors the internal signals of the cell to assure that the cell is growing healthily. If p53 senses that there has been too much genetic damage to the cell, it will signal for the cell cycle to sl ow down or stop so that cellular repair can occur. p53 can also cause a series of events to happen that leads towards apoptosis, or programmed cell death in order to halt growth of tumors. UVB radiation can act as both the initiator and promoter of SCC by “permitting these apoptotic-resistant cells to continue to proliferate following UV exposures that inhibit neighboring cells (7).” Cells that have a single mutated p53 gene are more susceptible to receiving multiple mutations from sun exposure, because there is a flaw in the apoptotic regulation of the cell that allows it to survive the regulatory functions of p53. This is why age is a risk factor for SCC; the accumulation of mutations over decades of sun exposure is a leading cause in developing the cancer. The continued proliferation of the mutant tumor cells leads to a state of visibly abnormal skin, symptoms of early stage SCC.

Undiagnosed and untreated SCC has the potential to metastasize and invade the underlying dermal tissue, bones, lymph nodes, and other organs. Two factors that work in concert to bring on metastatic SCC are the expression of VEGF and MMPs. Tumor progression requires growth of the vascular network in order to supply nutrients and oxygen, and this is achieved through angiogenesis. VEGF is a protein that promotes angiogenesis and “can be constitutively expressed by human tumors (10).” Overexpression of angiogenic factors leads to increased chances of metastasis, because there is a higher density of vascular networks in which tumor cells can penetrate and circulate through to proliferate at secondary sites. VEGF can also up-regulate the expression of MMPs, which “promote tumor growth by degrading matrix barriers and by enhancing angiogenesis (11).” MMPs are able to break down the extracellular matrix (ECM) during growth, tissue repair, and angiogenesis. Malignant tumor cells must invade the stroma in order to gain access to the vascular network, and this is aided in part by MMPs which interact with neighboring stromal cells that regulate MMP expression. One method of treatment being researched to counteract the function of MMPs is the use of Tissue Inhibitors of Metalloproteinoases (TIMPs). “Overexpression of TIMPs by cancer cells or by the host reduces invasive and metastatic capacity of tumor cells,” but while TIMPs “reduced invasion and angiogenesis [they] also protected the melanoma cells from apoptosis… (11)” Invasion and metastasis of SCC relies largely on VEGF and MMPs, making them a prime target for treatment at the molecular basis.

** Treatment of Squamous Cell Carcinoma ** James was fortunate enough to catch his Squamous Cell Carcinoma (SCC) in the early stages and before it had the chance of metastasizing. For the less fortunate however, SCC invades the underlying tissue and the current standard of care, which is surgical excision, is not enough to completely treat the cancer. Metastatic cells that are embedded too deep to go under the knife must rely on more complex experimental therapies that target the Matrix Metalloproteinases (MMPs) and the Vascular Endothelial Growth Factors (VEGF). These experimental treatments show promise in increasing the overall survival of those afflicted with metastatic SCC by inhibiting MMPs and VEGF that are responsible for inducing angiogenesis and metastasis.

MMPs play a major role in metastasis and angiogenesis by degrading the extracellular matrix, thus allowing metastatic cells to proliferate at new sites in the body. There is a “strong causal relationship between MMP overexpression and tumour progression (12)” and pharmaceutical companies have attempted to target MMPs in the past on this basis. In the 1980s, small molecule MMP-inhibitor drugs were able to reach phase III clinical trials, but ultimately failed to increase survival rates. Modern day trials however, have found that failure in the past was a result of incomplete knowledge on the functions of MMPs. Research shows that “MMPs promote tumour progression not only through ECM degradation, as originally thought, but also through signaling functions,” and have “many host-protective functions” as well as general promotion of tumorigenesis (12). These host-protective functions are the anti-tumor functions of MMPs that restrict angiogenesis and metastasis. The current direction in MMP drug research has led to obstacles, specifically in distinguishing whether certain MMPs are target or anti-targets. Drugs that may inhibit the tumorigenesis effects of MMPs may also inhibit the protective qualities of the anti-tumor functions. In order to selectively inhibit the MMPs that promote metastasis, further research must be undertaken to identify the status of different MMPs. At its current stage, I would only recommend the use of experimental MMP targeted drugs for early stage metastatic SCC, because in later stages the effects of the cancer would require higher dosage, which has yet to be tested for effectiveness. Also, at higher doses, the small moleculeinhibitors of MMP are unable to be selective for the target vs. anti-target functions of MMPs.

VEGF is an angiogenesis factor that provides the necessary support for metastatic tumors to survive. VEGF is linked to metastasis, and “overexpression of angiogenesis factors in experimental tumors leads to enhanced tumor growth and vascularization, and therapeutic inhibition of VEGF activity has been shown to inhibit tumor growth and metastasis (13).” Tumor cells that have an abundant expression of epithelial growth factors and insulin growth factors “are able to promote the growth, survival, and migration of tumor cells, and induce the synthesis of VEGF… (14).” Two drugs, A12 and Cetuximab, have been shown to inhibit tumor-associated angiogenesis, and are even more effective when combined. A12 and Cetuximab dual-inhibit tyrosine kinases of EGFR and IG-FR and can decrease the tumor growth of SCC by inhibiting angiogenesis, which in turn leads to apoptosis of the tumor cells as shown in Figure 1. This dual drug combination treatment has shown to significantly inhibit SCC tumor growth and also “a combination of the 2 drugs resulted in a greater than 90% reduction in tumor volume (14).” This is promising for treating advanced cutaneous SCC, because it has the ability to stop overexpression of VEGF and angiogenesis. I would recommend this experimental treatment process for patients that have developed metastatic SCC with angiogenesis as the primary hallmark.

Skin cancer may not be flashy or impressive, but all cancers need to be given caution. SCC is relatively minor when caught early, but to let it progress untreated increases the risk of serious, and sometimes fatal, adverse health problems. Cancer can arise from all manners of carcinogens, and we forget that sunlight is a major risk factor for SCC. Don't be ignorant, and protect yourself from one of the most common types of cancer.

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