Non-melanoma skin cancers in New Zealand--a neglected problem

Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the commonest types of non-melanoma skin cancer (NMSC). The incidence of NMSC has been increasing globally with Australia recording a 1.5-fold increase over the last 17 years. Given that Australia and New Zealand share similar latitude, sun exposure levels, population skin types, and other risk factors, it is conceivable that this increase has also occurred in New Zealand. However, the incidence of NMSC in New Zealand is unknown. The cost of treating NMSC in New Zealand is estimated to be more than NZ$50 million annually, based on extrapolated Australian data. In Australia, NMSC is the most costly burden to its healthcare system, and therefore the Australian Government has allocated resources to improve epidemiological research, and preventative efforts. Currently within New Zealand there is a lack of focus on the NMSC problem. The absence of New Zealand data on the incidence of NMSC has hampered the development of consistent healthcare policies (including preventative measures), that achieve an integrated and sustainable service delivery. A critical analysis of this problem based on longitudinal data is now vitally important to address this neglected problem.     

Non-melanoma skin cancer in mouse and man

As a frontier organ, skin is exposed to different environmental and/or occupational chemicals which cause cutaneous cancers in experimental animals. In mice, 7,12-dimethylbenz[a]anthrancene (DMBA) and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) are frequently used as skin model tumor initiator and promoter, respectively. The sequential administration of DMBA and TPA leads to the appearance of a large number of benign papillomas, of which some convert later into invasive squamous cell carcinomas (SCC). At the molecular level, initiation of carcinogenesis in mouse skin consists in the mutational activation of the Ha-ras oncoprotein. HA-RAS mutations are rare in human SCC, but HA-RAS-mutated tumors appear in melanoma patients treated with B-raf inhibitors, indicating that initiated, HA-RAS-mutated stem cells also reside in human skin. Similarly, UV-induced human SCC show footprint mutations in the tumor suppressor gene TP53 which are also observed in UV-induced mouse SCC. Strong species differences exist with respect to phorbol ester-mediated tumor promotion. While certain mouse strains are very susceptible, other rodent species are much less sensitive. Likewise, humans appear to be much more resistant to phorbol ester-mediated skin toxicity. Papilloma formation as a result of a chemical insult is uncommon in men, questioning the relevance of this preneoplastic lesion for humans. However, skin tumorigenesis in the experimental situation and in humans appears to follow common molecular mechanisms, even though there are species differences in the morphological correlates to the preneoplastic state. Therefore, we recommend not simply labeling them as irrelevant for human risk assessment.     

Non-melanoma skin cancer: new and future synthetic drug treatments

Introduction: Non-melanoma skin cancers (NMSC) mainly comprise two different entities: basal cell carcinoma (BCC) and squamous cell carcinoma (SCC); beneath these two entities, Merkel cell carcinoma, adnexal tumors, dermatofibrosarcoma protuberans, angiosarcoma, and cutaneous lymphoma belong to NMSC. These rare skin tumors are not the topic of this review.

BCC and SCC are the most common cancers diagnosed in humans. The preferred treatment is surgery, which in most cases is curative. Although a high recurrence rate is seen, these cancers rarely metastasize. Therefore, systemic treatments were not a priority for these patients. It is long known that the abnormal activation of Hedgehog and epidermal growth factor receptor pathways were involved in BCC and SCC. In the last decade, metastatic disease became an important area of research, mostly because new therapies that targeted components of these two pathways became available.

Areas covered: Here we cover the available therapeutic options for patients diagnosed with BCC and SCC, focus on systemic and targeted therapies.

Expert opinion: BCC and SCC are common cancers, with good prognosis. More than the metastatic disease, advanced local disease and recurrent disease pose clinicians a great challenge. Albeit there are promising results with targeted therapies, resistance development has already been described.     

Imiquimod and superficial skin cancers

Topical imiquimod has opened an entirely new area of dermatology that previously did not exist: medical therapy for skin cancers. While surgery will continue to play a vital role in treating more aggressive tumors and in patients who may not be imiquimod candidates, the availability of a viable medical therapy that can be used independently or in combination with other modalities will considerably enhance our ability to treat skin cancer successfully.     

Virologic and genetic evaluation of vemurafenib-induced skin cancers

We describe the occurrence of a giant squamous cell carcinoma in a patient receiving vemurafenib for the treatment of late melanoma mestastases. Although the development of keratoacanthomas and squamous cell carcinomas (SCC) has been described during vemurafenib therapy, most of the reported cases are treated with surgical excision. In the present case, SCC regressed after drug withdrawal.     

Metallothionein isoform 3 expression in human skin,related cancers and human skin derived cell cultures

Human skin is a well known target site of inorganic arsenic with effects ranging from hyperkeratosis to dermal malignancies. The current study characterizes the expression of a protein known to bind inorganic, As³⁺, metallothionein 3 (MT-3). Expression of this protein was assessed immunohistochemically with a specific MT-3 antibody on human formalin-fixed, paraffin-embedded biopsy specimens in normal skin, squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and melanoma. Assessment in normal skin using nine normal specimens showed moderate to intense MT-3 staining in epidermal karatinocytes with staining extending into the basal cells and moderate to intense staining in melanocytes of nevi. MT-3 immunoexpression was shown to be moderate to intense in 12 of 13 of SCC, low to moderate in 8 of 10 BCC, and moderate to intense in 12 melanoma samples. MT-3 expression in cell culture models (normal human epidermal keratinocytes, normal human melanocytes, and HaCaT cells) showed only trace expression of MT-3, while exposures to the histone deacytalase inhibitor, MS-275, partially restored expression levels. These results indicate that the epidermis of human skin and resulting malignancies express high level of MT-3 and potentially impact on the known association of arsenic exposure and the development of skin disorders and related cancers.     

The hedgehog pathway inhibitor GDC-0449 shows potential in skin and other cancers

Background: The hedgehog signalling pathway is vital in early development, but then becomes dormant, except in some cancer tumours. Hedgehog inhibitors are being developed for potential use in cancer.

Objectives/methods: The objective of this evaluation is to review the initial clinical studies of the hedgehog inhibitor, GDC-0449, in subjects with cancer.

Results: Phase I trials have shown that GDC-0449 has benefits in subjects with metastatic or locally advanced basal-cell carcinoma and in one subject with medulloblastoma. GDC-0449 was well tolerated.

Conclusions: Long-term efficacy and safety studies of GDC-0449 in these conditions and other solid cancers are now underway. These clinical trials with GDC-0449, and trials with other hedgehog inhibitors, will reveal whether it is beneficial and safe to inhibit the hedgehog pathway in a wide range of solid tumours or not.     

Multiple nonmelanoma skin cancers in a patient with epidermolytic hyperkeratosis on long-standing retinoid therapy

Epidermolytic hyperkeratosis is a rare genetic disorder of keratinization. In childhood, patients are erythrodermic and have a compromised stratum corneum, replaced with generalized hyperkeratosis as the patients age. Treatment consists of topical emollients as well as, topical and oral retinoids. Ultraviolet (UV) light, often in combination with psoralen ultraviolet A (PUVA) is widely used as a therapeutic modality for a multitude of hyperproliferative disorders. Although not strictly indicated for epidermolytic hyperkeratosis, it has been utilized as experimental treatment, particularly in the days prior to retinoids. Psoralen ultraviolet A has also been implicated in the development of nonmelanoma skin cancers, especially, squamous cell carcinoma (SCC). Retinoids are well-known to protect against nonmelanoma skin. A patient with epidermolytic hyperkeratosis with multiple nonmelanoma skin cancers, previously treated with PUVA and long-standing oral retinoids is reported.     

New advances on the functions of epidermal growth factor receptor and ceramides in skin cell differentiation, disorders and cancers

Recent advances in understanding of the biological functions of the epidermal growth factor and epidermal growth factor receptor (EGF-EGFR) system and ceramide production for the maintenance of skin integrity and barrier function are reported. In particular, the opposite roles of EGFR and ceramide cascades in epithelial keratinocyte proliferation, migration and terminal differentiation are described. Moreover, the functions of ceramides in the epidermal permeability barrier are reviewed. The alterations in EGFR signaling and ceramide metabolism, which might be involved in the etiopathogenesis of diverse skin disorders and cancers, are described. New progress in understanding of skin organization, which might provide the basis for the design of new transcutaneous drug delivery techniques as well as for the development of new therapies of skin disorders and cancers, are reported.     

癌细胞中钙离子通道的研究进展

质膜通道参与细胞的基本功能,在癌细胞中亦是如此。特别是钙离子通道与癌细胞的关系逐渐受到重视。该文以近年来钙离子通道对肿瘤细胞增殖、凋亡、转移和血管生成的影响研究作一综述,将为肿瘤的研究和诊疗提供一个新视角。