Basal cell skin cancer is a cancer that develops from the skin’s basal cells. The basal cells are located in the outermost layer of the skin called the epidermis and can be found in the deepest layer of the epidermis [1]. Basal cells constantly divide to form new cells in order to replace the squamous cells. As basal cells move up in the epidermis, the basal cells flatten and eventually become simple squamous cells. Separating the epidermis from deeper layers of the skin, the basement membrane is a barrier, which can be used as a protective mechanism for preventing cancer cells into the dermis or metastasis of cancer cells [2].
In the United States basal cell skin cancer is the most frequently occurring cancer. In 2010 the incidence rate in the United States was 2. 8 million people. The mortality rate for basal cell skin cancer is only 3000 and therefore the 5-year survival rate is very high. Although there is a high percentage of survival with the cancer, it should still be taken seriously because of skin disfigurations. There is a higher prevalence of basal cell skin cancer as people age, especially for Caucasians, Chinese, and the Japanese due to less melanin the melanocytes produce.
Melanin helps protect the skin against UV radiation; the predominant cause of basal cell skin cancer. A key factor for the increase in incidences each year is indoor UV tanning in which the individuals have a 69 percent increase risk of developing cancer earlier than normally [3]. Alcohol drinkers have a higher incidence rate, but counterintuitively there is a reduction in incidence rates among smokers and individuals that are obese. Though there is no dose-response relationship the social aspects of these cases determine the cause. For example, overweight individuals do not engage in physical activity and wear clothes that reveal less skin.
As a result, these factors lead to reduce of sun exposure [4]. As previously stated, the fact that basal cells are actively dividing, they are prone to environmental carcinogens. The leading mutagen of basal cell skin cancer is ionizing ultraviolet B radiation (290-320 nm). UVB causes pyrimidine dimers. When two pyrimidines are located on the same strand, UVB introduces a kink; therefore the two adjacent pyrimidines are connected rather than cross base pairing. Predominantly, most kinks are repaired by nucleotide excision repair, which utilizes the undamaged strand to provide a template for resynthesizes of the defective sequence.
However, if not repaired, pyrimidine dimer formation leads to a permanent mutation of (CC) to (TT). This particular conversion is found in the P53 gene. The mutated cell most likely undergoes apoptosis, and if any cell remains with the mutation, it can now proliferate and ultimately lead to tumorigenesis. In a sporadic basal cell skin cancer, P53 has been shown to be mutated in 100 percent of cases, and in hereditary cases 35 percent has shown a mutation of P53 [5]. The hedgehog pathway dysregulation is another signature cause of sporadic as well as heredity basal cell skin cancer.
In embryos, the pathway is upregulated for cell proliferation and differentiation; however, it is highly regulated and dormant in normal adults. The mechanism for hedgehog pathway is a ligand binding to the cell membrane bound receptor PTCH1, a tumor suppressor. The binding of the ligand to the receptor blocks the PTCH1 activity by inhibiting the SMO protein. Therefore, when the ligand is bound to the receptor, it upregulates the activity of SMO, which is post-translational modifications to allow translocation of transcription factors called GLI into the nucleus.
These transcription factors have binding sequences called Zinc fingers that initiate transcription for proteins that induce tumorigenesis e. g. c-MYC, cyclin, and vascular endothelial growth factor (VEGF). Roughly 75 percent of sporadic cases have displayed a mutation in PTCH1 [5]. In sporadic basal cell skin cancer, mutations to PTCH1 can lead to ligand independent activation of the hedgehog pathway. The mutation in the tumor suppressor protein, PTCH1, leads to constitutive activation of SMO and thus cell proliferation.
Potential targets impeding the hedgehog pathway will also target the SMO receptor with small molecule inhibitor thus preventing not to allow inactive SMO to convert into its active form. Although these are great mechanisms to prevent the activation of SMO, they are limited because activation could occur downstream of SMO by altering the signaling leads to an escape from the previously described approaches [6]. Vismodegib is a pharmacological treatment for basal cell skin cancer. This oral treatment is used when neither prophylactic radiation nor surgery is feasible for a patient and when the cancer has metastasized.
Vismodegib binds to SMO to inhibit the signal transduction. Vismodegib prevents the nuclear localization of the GLI transcriptions factors and halt target protein synthesizes causing inhibition of cell proliferation and angiogenesis [7]. Although it is FDA approved, but due to the high cost of $75,000 and the adverse effects of the drug, Vismodegib may not be the first option to cure basal cell skin cancer when alternates such as Mohs surgery, radiation therapy, and cryosurgery at lower expenses exist [8,9]. Vismodegib could potentially be attractive to treatments of other cancers involving the hedgehog pathway.
Sonidegib is another treatment for advanced basal cell skin cancer. Like Vismodegib, Sonidegib blocks hedgehog pathway by selective inhibition of SMO [10]. Gorlin syndrome, contributing to only 1 percent of the basal cell skin cancer, is an inherited autosomal dominant mutation in PTCH1. Only one inherited mutated copy of the gene would be enough to cause Gorlin syndrome. For basal cell skin cancer to develop, a mutation in the second copy of the PTCH1 gene needs to occur. The mutation inactivates PTCH1, which as a result, constitutive expression of the SMO protein.
Individuals with the syndrome may develop multiple basal cell cancer over their lifetime [11,12]. Xeroderma pigmentosum is an autosomal recessive disease only affecting one in a million people in the U. S. Because UV radiation causes thymine dimers and patients with the disease have a defective nucleotide excision repair mechanism as a result the damaged DNA is permanent. The accumulation of the permanent mutations leads patients with Xeroderma pigmentosum to skin cancer, including basal cell skin cancer [13,14].
Note that both Xeroderma pigmentosum and Gorlin syndrome make up a very small subset of basal cell skin cancer. Individuals once diagnosed with basal cell skin cancer are at risk for recurrence of the carcinoma. If the cancer recurs, the patient might be referred to another method of treatment. An excision is removal of the tumor by simply cutting it out along with normal skin. Mohs surgery has the best cure rate for the carcinoma. The surgery can be best used for larger tumors, however, it is more complex and time consuming compared to other methods.
Radiation therapy is an excellent approach to cure cancer in delicate spots e. g. eyelids, nose and ears. Radiation is a good therapeutic tool for individuals who developed cancer on their scalp because the only actively dividing cells would be the cancer cells. Although basal cell skin cancer has a very low mortality rate, great strides are still required to further understand cellular pathways involved to potentially use as a therapeutic tool to cure the metastasized basal cell cancer.
