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The general transcription factor E2F1 reportedly functions in a protumorigenic manner in several cancer models. We show that the genetic context of cancer cells influence E2F1's role to impede the protumorigenic role. Thirty to fifty percent of melanoma patients carry mutant BRAF with about 90% of mutant BRAF melanomas being V600E mutation. Tissue microarrays from melanoma patients were used to establish an association between E2F1 and BRAFV600E . We show for the first time that low E2F1 levels in BRAFV600E melanomas are associated with lymph node metastasis. Genetic manipulation of E2F1 in BRAFV600E and BRAFwt cells were used to determine its role in malignant melanoma progression by examining effects on migration and invasion. E2F1-mediated negative regulation of myosin light chain kinase (MYLK) increased migration and invasion in BRAFV600E cells by phosphorylating myosin light chain and increased stress fiber formation. We show that E2F1 inhibits extracellular signal-regulated kinase (ERK) activation in BRAFV600E cells and provide evidence for a negative feedback loop between E2F1 and ERK in these cells. This study shows for the first time that E2F1 has a cancer protective role in oncogenic BRAF-activated melanoma cells and that loss of E2F1 can allow disease progression through a novel mechanism of E2F1-mediated MYLK regulation. This study has implications for oncogenic BRAF-activated tumors and resistance to targeted oncogenic BRAF therapy.

Background Acantholytic squamous cell carcinoma (Acantholytic SCC) are epithelial tumors characterized by a loss of cell adhesion between neoplastic keratinocytes. The mechanism underlying loss of cell-cell adhesion in these tumors is not understood. Methods A retrospective analysis of acantholytic SCC (n = 17) and conventional SCC (n = 16, controls not showing acantholysis) was conducted using a set of desmosomal and adherens junction protein antibodies. Immunofluorescence microscopy was used to identify tumors with loss of adhesion protein expression. Results The vast majority of acantholytic SCC (89%) showed focal loss of at least one desmosomal cell adhesion protein. Most interestingly, 65% of these tumors lost expression of two or more desmosomal proteins. Conclusions Loss of cell adhesion in acantholytic SCC is most likely linked to the focal loss of desmosomal protein expression, thus providing potential mechanistic insight into the patho-mechanism underlying this malignancy.

Psoriasis is a chronic inflammatory skin disease that affects 2.2% of Americans and is a substantial detriment on the quality of life. Psoriasis is a complex interaction between numerous immune cells and has been considered largely a T-helper type 1 (Th1) T-cell-mediated response. Although numerous cytokines, including tumor necrosis factor-αβ, interleukin 1β, and interferon-γ, have been identified with distinct roles in skin inflammation and psoriasis, proinflammatory functions of newly identified cytokines have been linked recently to the alternative T-cell subsets Th17 and Th22 that are distinct in their functions and cytokine profiles. This review summarizes the basic research, translational applications, and new therapeutic developments contributing to the understanding of the diversity of human effector CD4+ Th1, Th17, and Th22 T cells, as well as the proinflammatory cytokines associated with these subsets in psoriasis.

Invisible (or blacklight) tattoos are fast becoming the trend in the world of tattoo art, and with their rise comes the onset of associated complications. Though there have been many reports of cutaneous reactions to traditional tattoo pigments, literature regarding reactions to invisible tattoos is scarce. We report the case of a 28-year-old man who presented with an inflammatory eruption of 2 months' duration confined to the area of a recently placed invisible tattoo; the eruption was diagnosed as granulomatous dermatitis to a foreign material. Under fluorescent light, a refractile foreign material was identified in the biopsy specimen, which we believe to be melamine, one of the invisible tattoo's five ingredients. Previous cases of cutaneous reactions to invisible tattoos were attributed to polymethylmethacrylate, not a component of the tattoo in this case. To our knowledge, this is the first case implicating melamine as the cause of a granulomatous tattoo reaction. Given the rising popularity of invisible tattoos, we present this case to raise awareness of the risks associated with this alternative tattoo trend.

RhoA controls changes in cell morphology and invasion associated with cancer phenotypes. Cell lines derived from melanoma tumors at varying stages revealed that RhoA is selectively activated in cells of metastatic origin. We describe a functional proteomics strategy to identify proteins regulated by RhoA and report a previously uncharacterized human protein, named “mediator of RhoA-dependent invasion (MRDI),” that is induced in metastatic cells by constitutive RhoA activation and promotes cell invasion. In human melanomas, MRDI localization correlated with stage, showing nuclear localization in nevi and early stage tumors and cytoplasmic localization with plasma membrane accentuation in late stage tumors. Consistent with its role in promoting cell invasion, MRDI localized to cell protrusions and leading edge membranes in cultured cells and was required for cell motility, tyrosine phosphorylation of focal adhesion kinase, and modulation of actin stress fibers. Unexpectedly MRDI had enzymatic function as an isomerase that converts the S-adenosylmethionine catabolite 5-methylribose 1-phosphate into 5-methylribulose 1-phosphate. The enzymatic function of MRDI was required for methionine salvage from S-adenosylmethionine but distinct from its function in cell invasion. Thus, mechanisms used by signal transduction pathways to control cell movement have evolved from proteins with ancient function in amino acid metabolism.

Aurora kinase A (Aurora-A) belongs to a highly conserved family of mitotis-regulating serine/threonine kinases implicated in epithelial cancers. Initially we examined Aurora-A expression levels at different stages of human skin cancer. Nuclear Aurora-A was detected in benign lesions and became more diffused but broadly expressed in well and poorly differentiated squamous cell carcinomas (SCC), indicating that Aurora-A deregulation may contribute to SCC development. To mimic the overexpression of Aurora-A observed in human skin cancers, we established a gene-switch mouse model in which the human variant of Aurora-A (Phe31Ile) was expressed in the epidermis upon topical application of the inducer RU486 (Aurora-AGS). Overexpression of Aurora-A alone or in combination with the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA), did not result in SCC formation in Aurora-AGS mice. Moreover, Aurora-A overexpression in naive keratinocytes resulted in spindle defects in vitro and marked cell death in vivo, suggesting that the failure of Aurora-A to initiate tumorigenesis was due to induction of catastrophic cell death. However, Aurora-A overexpression combined with exposure to TPA and the mutagen 7,12-dimethylbenz(a)anthracene accelerated SCC development with greater metastastic activity than control mice, indicating that Aurora-A cannot initiate skin carcinogenesis but rather promotes the malignant conversion of skin papillomas. Further characterization of SCCs revealed centrosome amplification and genomic alterations by array CGH analysis, indicating that Aurora-A overexpression induces a high level of genomic instability that favors the development of aggressive and metastatic tumors. Our findings strongly implicate Aurora-A overexpression in the malignant progression of skin tumors and suggest that Aurora-A may be an important therapeutic target. [Cancer Res 2009;69(18):7207–15]

Clear cell sarcoma (CCS) is a rare tumor classically associated with the tendons and aponeuroses of distal extremities of young adults. CCS and malignant melanoma (MM) share immunohistochemical profiles and ultrastructural features, but classic CCS has characteristic morphology with low mitotic activity and minimal pleomorphism. Occasional cases show pleomorphism, high mitotic index, and/or melanin pigmentation, making CCS indistinguishable from MM based on morphology. However, CCS is genetically distinct owing to its consistent association with a t(12;22)(q13;q12) chromosomal translocation, leading to the formation of the EWS/ATF1 fusion transcript. This translocation has never been documented in cutaneous melanoma, and thus is regarded as specific for CCS. Recent evidence suggests that primary "malignant melanomas" in unusual anatomic sites, most notably the gastrointestinal (GI) tract, may be CCS. This is supported by 11 cases of primary GI CCS with the t(12;22) translocation. We used reverse-transcription polymerase chain reaction and fluorescence in situ hybridization to examine whether a proportion of cases diagnosed as MM of the GI tract in patients without a history of cutaneous MM actually represent primary GI CCS. In total, we examined 7 cases: Four with no prior history of MM, 2 with histories of cutaneous MM, and 1 with an anal MM. All 4 cases for which there was no history of cutaneous/mucosal MM harbored the EWS/ATF1 fusion transcript. We report the largest series of GI CCS and have shown that molecular studies may be warranted in cases that otherwise seem to represent MM of unusual primary locations.

We present a patient with subungual melanoma of the thumb who, during radioisotope-guided selective sentinel lymphadenectomy, was found to have black, hard lymph nodes at multiple axillary node levels. This finding was interpreted intraoperatively as clinical evidence of metastasis and a formal axillary dissection was carried out. Pathological examination of excised nodes failed to demonstrate metastasis but instead showed collections of tattoo pigment.

Background: Granular cell tumors (GCTs) are benign neural tumors with a distinct histologic appearance on light microscopy, characterized by eosinophilic cytoplasmic granules. Pustulo-ovoid bodies of Milian (POB) are larger granules surrounded by a clear halo. There have been no histologic studies to document their prevalence in GCT. Methods: We examined the sections of 47 cases of GCT stained with hematoxylin and eosin to determine the frequency of POB within this tumor. POB were measured per 10 high-power fields (HPFs) and were divided into the following categories: less than 10 POB per 10 HPFs, 10–30 per 10 HPFs, 30–50 per 10 HPFs and greater than 50 per 10 HPFs. Results: POB were present in 100% of the specimens examined. Eleven cases (23%) had between 1 and 9 POBs per 10 HPFs, twelve cases (26%) had between 10 and 29 POBs per HPFs, five cases (11%) had between 30 and 50 POBs per HPFs and nineteen cases (40%) had greater than 50 POBs per HPFs. When grouped according to clinical characteristics, there was an even distribution of POB by age, sex and site of the tumor. Conclusions: In our series, POB were present in varying numbers in all the tumors studied. They appear to represent the heterogeneity of the lysosomes, giving the appearance of large granules that have partially detached from the adjacent cytoplasm. POB are an easily recognizable component of GCTs.