Faculty Bibliography

The pathogenesis of BCC is associated with sonic hedgehog (SHH) signaling. Vismodegib, a smoothened inhibitor that targets this pathway, is now in clinical use for advanced BCC patients, but its efficacy is limited. Therefore, new therapeutic options for this cancer are required. We studied gene expression profiling of BCC tumour tissues coupled with laser capture microdissection to identify tumour specific receptor tyrosine kinase expression that can be targeted by small molecule inhibitors. We found a >250 fold increase (FDR<10-4) of the oncogene, anaplastic lymphoma kinase (ALK) as well as its ligands, pleiotrophin and midkine in BCC compared to microdissected normal epidermis. qRT-PCR confirmed increased expression of ALK (p<0.05). Stronger expression of phosphorylated ALK in BCC tumour nests than normal skin was observed by immunohistochemistry. Crizotinib, an FDA-approved ALK inhibitor, reduced keratinocyte proliferation in culture, whereas a c-Met inhibitor did not. Crizotinib significantly reduced the expression of GLI1 and CCND2 (members of SHH-pathway) mRNA by approximately 60% and 20%, respectively (p<0.01). Our data suggest that ALK may increase GLI1 expression in parallel with the conventional SHH-pathway and promote keratinocyte proliferation. Hence, an ALK inhibitor alone or in combination with targeting SHH-pathway molecules may be a potential treatment for BCC patients.

Organ transplant recipients suffer from an increased incidence and recurrence rate of nonmelanoma skin cancers. These cancers are often more aggressive than those in the general population, resulting in significant morbidity and mortality. Often times, routine treatment modalities are not adequate and the use of different management strategies is necessary. Treatment modalities, including surgical excision, Mohs micrographic surgery, physically destructive modalities, topical therapy, and photodynamic therapy may be used. Combinations of these therapies may be used in rotation for treatment of extensive field disease. Chemoprophylaxis with oral retinoids and alteration of the immune suppression regimen may be indicated for specific cases. In addition, newly emerging therapies for squamous cell carcinomas including cetuximab and capecitabine may offer heightened control in organ transplant patients with significant cutaneous disease.

The development of vismodegib and its recent approval by the United States Food and Drug Administration for use in patients with locally advanced or metastatic basal cell carcinoma (BCC) carries with it a renewed sense of optimism. Once BCC has progressed to an advanced, or so-called inoperable stage, there has been a paucity of effective therapies, making the new small molecule inhibitors targeting the hedgehog pathway particularly hopeful prospects. In order to better understand the utility of these new treatments, it is important to assess the existing economic, physical, and psychological burden of advanced BCC. This review aims to recognize the impact of inoperable and metastatic BCC, as well as to better characterize the various types of advanced BCC. The use of vismodegib as a prophylactic treatment in patients with basal cell nevus syndrome is also addressed, including possible adverse events, tumor resistance, and new onset malignancies.

During wound healing, stem cells provide functional mature cells to meet acute demands for tissue regeneration. Simultaneously, the tissue must maintain a pool of stem cells to sustain its future regeneration capability. However, how these requirements are balanced in response to injury is unknown. Here we demonstrate that after wounding or ultraviolet type B irradiation, melanocyte stem cells (McSCs) in the hair follicle exit the stem cell niche before their initial cell division, potentially depleting the pool of these cells. We also found that McSCs migrate to the epidermis in a melanocortin 1 receptor (Mc1r)-dependent manner and differentiate into functional epidermal melanocytes, providing a pigmented protective barrier against ultraviolet irradiation over the damaged skin. These findings provide an example in which stem cell differentiation due to injury takes precedence over stem cell maintenance and show the potential for developing therapies for skin pigmentation disorders by manipulating McSCs.

OBJECTIVE: To characterize the presence of CD200 and CD200 receptor (CD200R) in the human cutaneous squamous cell carcinoma (SCC) microenvironment and to define a possible role for the CD200 axis in immune evasion by SCC. DESIGN: Gene expression in SCC vs normal skin was studied. Laser capture microdissection was used to determine differential expression of CD200 in normal skin vs actinic keratosis vs SCC in situ vs invasive SCC. Immunofluorescence microscopy was used to define expression of CD200R on macrophages, myeloid dendritic cells, natural killer cells, and T cells in SCC vs normal skin. The effects of SCC supernatant on induction of CD200 in human blood endothelial cells was also examined. SETTING: Academic Medical Center with an established Section of Mohs and Dermatologic Surgery and an active Cutaneous Biology Research Program. PARTICIPANTS: Surgical discard tissue from deidentified patients and samples of normal skin from healthy volunteers were used in this study. MAIN OUTCOME MEASURES: Expression of CD200 on SCC-associated blood vessels; expression of CD200 receptor on SCC-associated macrophages and T cells; and induction of CD200 on endothelial cells by SCC supernatants. RESULTS: CD200 gene and message were upregulated in SCC stroma. Immunostaining revealed a higher number of CD200(+) cells in SCC stroma than in normal dermis (180.8 cells/mm(2) vs 24.6 cells/mm(2)) (P<.01). CD200 was further identified mainly on blood vessel endothelium in SCC. Tumor supernatant was able to induce CD200 expression on human dermal blood endothelial cells in culture. CD200R was identified on macrophages and dendritic cells in SCC microenvironment. CONCLUSIONS: CD200 expression on local blood vessels may promote tumor progression by suppressing CD200R myeloid cells during diapedesis. These data highlight a previously unrecognized mechanism of immune evasion by SCC and may provide guidance for the development of targeted therapy.