Understanding Basal Cell Carcinoma

compiled by John G. Connor, M.Ac., L.Ac., edited by Barbara Connor, M.Ac., L.Ac.

Table of Contents

  • Introduction
  • Targeted Therapies Approach to Cancer
  • Conventional Medical Treatment Options
  • Molecular Pathways Involved in Basal Cell Carcinoma
  • Natural Compounds that May Target Growth Factors and Genes Involved in Basal Cell Carcinoma
  • Research on Natural Compounds that May be Skin Protective

Introduction
Basal cell carcinoma (BCC) is the most common type of cancer in people with European ancestry, and its incidence continues to increase steeply. The incidence of BCC varies geographically. For instance, in the Netherlands, the incidence rate is approximately 100 per 100 000 person-years, which is approximately one-tenth the risk in areas such as Australia. More than a million people in the United States develop BCC annually. Although BCC therapy is relatively straightforward and BCC mortality rates are extremely low, the high incidence of BCC and the high risk of developing multiple lesions put a major burden on limited health care resources, placing BCC in fifth place on the list of the most expensive cancers to treat in the United States. (Kiiski et al 2010)

The incidence of BCC is strongly associated with exposure to UV radiation; tumors develop primarily on the sun-exposed skin of elderly individuals with fair skin phototypes, are rarely found on palmoplantar surfaces or in children, and never appear on the mucosa. Additional established risk factors include ionizing radiation (IR), arsenic, and immune suppression. (Kasper et al 2012)

Individual risk factors for BCC include age, male sex, race, phenotypic characteristics, and genetic predisposition. These factors may interact with environmental exposures, such as UV light or iatrogenic exposures. In contrast to risk factors associated with incident BCC, the risk factor profile of those who develop multiple BCC lesions among patients with a prior lesion is not well documented. The strongest risk factor for developing multiple BCC lesions appears to be a history of a prior lesion, representing the accumulation of gene-environmental interactions. An estimated 40% to 50% of patients with a BCC lesion develop subsequent tumors. Previous studies have suggested that patients with BCC who had a truncal and/or superficial lesions, who have a sun-sensitive skin type, and who are unable to tan are at increased risk of developing subsequent tumors. (Kiiski et al 2010)

Ultraviolet B exposure is a significant factor in the development of basal cell and squamous cell carcinoma. The use of tanning beds is associated with a 1.5-fold increase in the risk of basal cell carcinoma and a 2.5-fold increase in the risk of squamous cell carcinoma. (Firnhaber JM 2012)

BCC can be locally invasive but it has a low metastatic potential. Red or blond hair, light-colored eyes, light skin, exposure to UV radiation, are all characteristics associated with an increased risk of BCC. Basal cell carcinoma subtypes include nodular, morpheaform, superficial, infiltrative, cystic, and basosquamous forms. Nodular basal cell carcinomas appear as pearly nodules, which are often ulcerated or crusted and are often described as the “sore that will not heal.” Superficial basal cell carcinoma (sBCC) presents as an erythematous patch that is slightly scaling and well demarcated. Morpheaform basal cell carcinomas are ill defined and typically present with a scar-like appearance. Occasionally, basal cell carcinomas may be pigmented and can resemble malignant melanoma or seborrheic keratosis depending on the degree of pigmentation. (Trandon & Brodell 2012)

Basal cell carcinoma is one of the most common skin neoplasms in humans and is characterized by local aggressiveness with little metastatic potential, though BCC may behave aggressively with deep invasion, recurrence and regional and distant metastasis. (Chu et al 2008) 

Targeted Therapies Approach to Cancer
We need to be thinking about targeting a biological network, not just a single molecule.  Any time you put pressure on cells and their dynamic signaling networks, you are inevitably challenging them to get around the problem they are experiencing.  (Louis Weiner, MD, Director, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center. Sept. 2010) 

Targeted therapy using hedgehog pathway and EGFR inhibitors shows significant promise in treatment of orbital and periocular basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (SCC), respectively. Such targeted therapy may be appropriate for patients who are not good candidates for surgery. (Yin et al 2013)

Conventional Medical Treatment Options
Nonmelanoma skin cancer, which encompasses basal cell and squamous cell carcinoma, is the most common cancer in the United States. Mohs micrographic surgery has the lowest recurrence rate among treatments, but is best considered for large, high-risk tumors. Smaller, lower-risk tumors may be treated with surgical excision, electrodesiccation and curettage, or cryotherapy. Topical imiquimod and fluorouracil are also potential, but less supported, treatments. Although there are no clear guidelines for follow-up after an index nonmelanoma skin cancer, monitoring for recurrence is prudent because the risk of subsequent skin cancer is 35 percent at three years and 50 percent at five years. (Firnhaber JM 2012)

The most commonly utilized surgical therapies for BCC are curettage and electrodesiccation (E and C) and surgical excision. Whereas surgical modalities have acceptable levels of morbidity and a high cure rate, effective non-invasive topical medical treatments of BCC are of great interest. (Trandon & Brodell 2012)

Vismodegib, a hedgehog pathway inhibitor, has recently been licensed by the US Food and Drug Administration for treatment of advanced BCC. Phase 2 trials have demonstrated efficacy in cases of locally advanced and metastatic BCC, as well as cases of hereditary basal cell naevus (Gorlin) syndrome. Side-effects are frequent and considerable and include myalgia, taste disturbance, alopecia, weight loss and fatigue. (Ali & Lear 2013)

The role of the immune system in the prevention and regression of cancer is significant. UV radiation, being the most important risk factor in the development of skin cancer, has a suppressive effect on local and systemic immune effectors. Different immunotherapeutic approaches have been used for the treatment of nonmelanoma skin cancer including adoptive T-cell therapies, vaccine-based strategies, cytokines and monoclonal antibodies. (Ghafouri-Fard S 2012)

Highly efficient treatment modalities such as surgery that aims at complete extirpation, radiotherapy, curettage, cryotherapy, photodynamic therapy, and topical applications of imiquimod or 5-fluorouracil are available and effective for the great majority of BCC patients. However, the occurrence of locally aggressive and invasive tumors, a bleak prognosis upon metastatic spread, a significant rate of recurrence often associated with increased aggressiveness, as well as the multitude of tumors appearing in high-risk populations such as basal cell nevus syndrome (BCNS) patients, provide compelling reasons to search for new preventive and therapeutic avenues. (Kasper et al 2012)

Molecular Pathways Involved in Basal Cell Carcinoma
The Wnt pathway has a well-established role in normal hair follicle development and cycling, and both human and mouse BCCs have increased levels of β-catenin, a critical mediator of Wnt signaling. In accordance with these observations, overexpression of the potent Wnt antagonist, Dkk1, in mouse epidermis resulted in the inhibition of benign Hh-driven hamartomas, showing that active Wnt signaling is required for their growth. (Kasper et al 2012)

In line with its importance in epidermal development, the EGFR/MEK/ERK pathway has been shown to modulate GLI-dependent transcription in human keratinocytes and to synergistically induce oncogenic transformation of human keratinocytes. Additionally, the tumor suppressor p53 may influence BCC development. The complete loss of p53 was shown to result in upregulated expression of the Hh pathway mediator smoothened (Smo) in the interfollicular epidermis (IFE) in mice, thereby making these keratinocytes receptive to BCC induction. (Kasper et al 2012)

MicroRNAs (miRNAs), small regulatory RNAs with pleiotropic function, are commonly misregulated in cancer. Here we identify miR-203, a miRNA abundantly and preferentially expressed in skin, to be downregulated in BCCs. We show that activation of the Hedgehog (HH) pathway, critically involved in the pathogenesis of BCCs, as well as the EGFR/MEK/ERK/c-JUN signaling pathway suppresses miR-203. We identify c-JUN, a key effector of the HH pathway, as a novel direct target for miR-203 in vivo. (Sonkoly et al 2012)

The HH signaling pathway is currently thought to be of vital importance for the maintenance of cell growth in BCC. Sporadic BCCs in human predominantly develop due to deregulation of HH pathway by inactivation of PTCH1 and subsequent activation of the GLI transcription factors. (Sonkoly et al 2012)

Although LKB1 is historically known as a tumor suppressor, our study provides evidence that it may drive proliferation in UVB-induced BCCs. In this study, we assessed LKB1 expression and its downstream signaling pathways in UVB-induced basal cell carcinomas (BCCs) derived from Ptch1+/− mice. Our data suggest that LKB1 expression and -dependent downstream signaling are dysregulated in UVB-induced murine BCCs. In summary, we show that LKB1 activation along with the activation of multiple signaling pathways, including AMPK/ACC, mTOR/S6K/4E-BP1, and AKT/GSK3β/β-catenin, occur during the pathogenesis of BCCs. While some of these pathways appear to be directly regulated by LKB1, others are overridden by oncogenic stimuli that contribute to the tumor pathogenesis. (Byekova et al 2011)

The fundamental initiation of BCC development is typically due to mutation of genes in the sonic hedgehog (Shh) signaling pathway. Mutation of the Shh pathway associated genes, SHH, PTCH, SMO, GLI1, or GLI2, can promote BCC tumorigenesis. Such genomic alteration has been found in >70% of BCC cases studied. (Lo et al 2010)

We found that stromal cell-derived factor 1α (SDF-1α) induced angiogenic activity in human BCC cells, both in vitro and in vivo. SDF-1α significantly upregulated several angiogenesis-associated genes such as interferon-alpha-inducible protein 27, interleukin (IL)-6, bone morphogenetic protein (BMP)-6, SOCS2 and cyclooxygenase 2 (COX)-2 in human BCC cells. Among them, IL-6 was the earliest and highest upregulated gene whose induction was observed within 6 h of the commencement of SDF-1α–CXCR4 interaction. The mechanisms behind the SDF-1α-induced time and dose-dependent upregulation of messenger RNA expression and protein secretion of IL-6 were investigated. The transcriptional regulation of IL-6 by SDF-1α was mediated by phosphorylation of extracellular signal-related kinase 1/2 and activation of the nuclear factor-κB complex. The identification of the angiogenic profiles induced through SDF-1α–CXCR4 interactions in human BCC cells may contribute further insights into the mechanisms involved in the angiogenic potential of SDF-1α (CXCL12). (Chu et al 2008)

This study was conducted to determine the elemental composition of a cell tumor classified as basal cell carcinoma in skin. We conclude from these data that basal cell carcinoma has a characteristic elemental composition. It is possible that increased potassium and magnesium levels have a stimulatory effect on this tumor type, in contrast to other types of cancer cells where elevated sodium and chlorine and lowered potassium levels have frequently been found. (Wallberg et al 2000)

Natural Compounds that May Target Growth Factors and Genes Involved in Basal Cell Carcinoma
Curcumin – In basal cell carcinoma, curcumin promotes de novo synthesis of p53 protein or some other proteins for stabilization of p53, and hence enhances its nuclear translocation to transactivate Cip1 and Gadd45 indicating that p53-associated signaling pathway is critically involved in curcumin-mediated apoptotic cell death. (Sa & Das 2008)

Diallyl trisulfide an active component of garlic oil – Our findings suggest that diallyl trisulfide exerts chemopreventive potential via ER stress and the mitochondrial pathway in basal cell carcinoma cells. (Wang et al 2012)

Eicosapentaenoic acid (EPA) – Reduction in this range of early markers, i.e. sunburn, ultraviolet radiation (UVR)-induced p53 in skin and strand breaks in peripheral blood lymphocytes, indicate protection by dietary eicosapentaenoic acid against acute UVR-induced genotoxicity; longer-term supplementation might reduce skin cancer in humans. (Rhodes et al 2003) 

Omega-3 (n-3) PUFAs- Oral n-3 PUFAs appear to abrogate photoimmunosuppression in human skin, providing additional support for their chemopreventive role; verification of study findings is required. (Pilkington et al 2013)

Vitamin D3 has been shown to block hedgehog signaling in vitro and in murine basal cell carcinomas in vivo, presumably at the level of SMO, in a manner independent of vitamin D receptor (VDR) activation. (Kasper et al 2012)

Research on Natural Compounds that May be Skin Protective
Ashwagandha (Withania somnifera) – Pretreatment of the animals with 1-oxo-5beta, 6beta-epoxy-witha-2-enolide (20 mg/kg bwt.), isolated from the roots of Withania somnifera, prior to exposing the animals to UV B radiation, prevents the incidence of skin carcinoma. The administration of 1-oxo-5beta, 6beta-epoxy-witha-2-enolide, to the animals after exposing them to UV B radiation/UV B radiation and benzoyl peroxide also prevents the occurrence of malignancy in the cutaneous tissue. (Mathur et al 2004) 

Grape seed proanthocyanidins – Administration of dietary grape seed proanthocyanidins inhibited acute and chronic UVB irradiation-induced phosphorylation of ERK1/2, JNK1/2 and p38 proteins of MAPK family, which seems to be mediated through reactivation of MAPK phosphatases in the mouse skin compared with non-GSP-treated but UVB-exposed mice. (Afaq & Katyar 2011)

Green tea polyphenols (GTPs), silymarin, retinoids, grape seed proanthocyanidins (GSPs), and delphinidin – Plant polyphenols possess anti-inflammatory, immunomodulatory, anti-oxidant properties and DNA repair activities, and that can be exploited for the prevention of variety of skin disorders caused by excessive exposure to solar UV light. Recent advances in our understanding at the cellular and molecular levels of photocarcinogenesis have led to the development of promising strategies for the skin photoprotection including photocarcinogenesis. Studies have shown the photoprotective potential of several plant polyphenols, such as green tea polyphenols (GTPs), silymarin, retinoids, grape seed proanthocyanidins (GSPs), and delphinidin, etc. against UV radiation-induced adverse effects. (Afaq & Katyar 2011) 

Ocimum sanctum (Holy Basil or Tulsi) – Preclinical studies have also shown that Tulsi and some of its phytochemicals eugenol, rosmarinic acid, apigenin, myretenal, luteolin, β-sitosterol, and carnosic acid prevented chemical-induced skin, liver, oral, and lung cancers and to mediate these effects by increasing the antioxidant activity, altering the gene expressions, inducing apoptosis, and inhibiting angiogenesis and metastasis. (Baliga et al 2013)

Pomegranate – Consumption of pomegranate, rich in antioxidants, was associated with decreased basal cell carcinoma and squamous cell carcinoma risk, also after correcting for multiple testing. (de Vries et al 2012)

Pomegranate fruit extract (PFE) is a rich source of anthocyanins, ellagitannins and hydrolyzable tannins and possesses strong antioxidant activity. Oral feeding of PFE to SKH-1 hairless mice in a UVB initiation-promotion protocol resulted in reduced tumor incidence, delay in the latency period of tumor appearance, and lower tumor body burden compared to that of non-PFE-treated and UVB-irradiated control animals. (Afaq & Katyar 2011)

Silymarin – Chemoprevention of skin cancer by consumption of naturally occurring botanicals appears a practical approach and therefore world-wide interest is considerably increasing to use these botanicals. . Wide range of in vivo mechanistic studies indicated that silymarin possesses antioxidant, anti-inflammatory and immunomodulatory properties which may lead to the prevention of skin cancer in in vivo animal models. The available experimental information suggests that silymarin is a promising chemopreventive and pharmacologically safe agent which can be exploited or tested against skin cancer in human system. Moreover, silymarin may favorably supplement sunscreen protection and provide additional anti-photocarcinogenic protection. (Katiyar SK 2005)

Sulforaphane (SF) inhibited TPA-induced ornithine decarboxylase activity in mouse skin, an obligate step in TPA-induced promotion of carcinogenesis. These data link this molecular mechanism to SF-dependent inhibition of the promotion of tumorigenesis. (Gills et al 2006)

Vitamin E – A substantial protective effect on non-melanoma skin cancer was found in exploratory analyses for the fat soluble antioxidant vitamin E. (Davies et al 2002) 

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