c-KIT signaling as the driving oncogenic event in sub-groups of melanomas.

As we enter the era of targeted therapy for melanoma, attempts are being made to sub-group tumors on the basis of their driving oncogenic mutations, with the hope of developing truly personalized therapeutic regimens. c-KIT is a receptor tyrosine kinase whose aberrant activation is implicated in the progression of gastrointestinal stromal tumors and some acute myeloid leukemias. The role of c-KIT signaling in melanoma has been controversial; although c-KIT activity is critical to melanocyte development, its expression tends to be lost in most melanomas. Some reports have even shown that the re-expression of c-KIT induces apoptosis in melanoma cell lines. The recent publication of work showing the presence of activating c-KIT mutations in acral and mucosal melanomas, as well as melanomas arising on skin with chronic sun damage, has renewed interest in c-KIT signaling in melanoma. Recent work from our own laboratory has further identified melanomas with constitutive c-KIT signaling activity resulting from c-KIT receptor overexpression. Although the initial clinical trials of the c-KIT inhibitor imatinib mesylate in melanoma were negative, some dramatic responses have been seen in patients with very high c-KIT expression and/or documented activating mutations, fostering the belief that focused studies in patients selected on the basis of c-KIT mutational status will yield more encouraging results. The current review discusses the role of c-KIT signaling in melanoma progression and how this new information can be applied to the targeted therapy of melanoma.

Methionine-dependence phenotype of tumors: metabolite profiling in a melanoma model using L-[methyl-13C]methionine and high-resolution magic angle spinning 1H-13C nuclear magnetic resonance spectroscopy.

Tumors frequently have abnormal L-methionine (Met) metabolism, the so-called Met-dependence phenotype that refers to the inability to proliferate in the absence of Met. However, the origin of this phenotype is still unknown and may arise from one of several pathways of Met metabolism. To help characterize the metabolic features of Met-dependent/independent phenotypes, the fate of the methyl carbon of L-[methyl-13C]Met was chased in a murine model of malignant melanoma (B16-F1) in vitro and in vivo. Growth curves under Met restriction showed that melanoma cells in vitro were Met-independent, whereas implanted melanoma tumors in vivo were Met-dependent. Label-assisted high-resolution magic angle spinning 1H-13C NMR spectroscopy metabolite profiling showed that, in vitro, creatine and phosphatidylcholine 13C-enrichments were poor, but S-adenosyl-Met and posttranslationally N-methylated protein signals were strong. In contrast, in vivo, creatine and phosphatidylcholine enrichments were strong but S-adenosyl-Met and N-methylated protein signals were poor. In addition, in vivo, transsulfuration was very efficient, consumed one-carbon units originating from the methyl carbon of Met, and yielded taurine labeling. From these data, the Met-dependent/independent phenotypes appear closely related to the source of one-carbon units. Thus, L-[methyl-13C]Met-assisted NMR spectroscopy metabolite profiling allowed the discrimination between Met-dependence and Met-independence and provided novel mechanistic information on their origin.

Array comparative genome hybridization for tumor classification and gene discovery in mouse models of malignant melanoma.

Chromosomal numerical aberrations (CNAs), particularly regional amplifications and deletions, are a hallmark of solid tumor genomes. These genomic alterations carry the potential to convey etiologic and clinical significance by virtue of their clonality within a tumor cell population, their distinctive patterns in relation to tumor staging, and their recurrence across different tumor types. In this study, we showed that array-based comparative genomic hybridization (CGH) analysis of genome-wide CNAs can classify tumors on the basis of differing etiologies and provide mechanistic insights to specific biological processes. In a RAS-induced p19(Arf-/-) mouse model that experienced accelerated melanoma formation after UV exposure, array-CGH analysis was effective in distinguishing phenotypically identical melanomas that differed solely by previous UV exposure. Moreover, classification by array-CGH identified key CNAs unique to each class, including amplification of cyclin-dependent kinase 6 in UV-treated cohort, a finding consistent with our recent report that UVB targets components of the p16(INK4a)-cyclin-dependent kinase-RB pathway in melanoma genesis (K. Kannan, et al., Proc. Natl. Acad. Sci. USA, 21: 2003). These results are the first to establish the utility of array-CGH as a means of etiology-based tumor classification in genetically defined cancer-prone models.

Acción del piroxicam en ratones hembras CEPA C57BL/6 con melanoma B16F1 / Action of the piroxicam in the females mices of C57BL/6 with inoculated melanoma B16F1

El melanoma maligno es un cáncer cutáneo grave, cuya frecuencia ha aumentado rápidamente en los últimos años. Debido al éxito limitado de la quimioterapia en el tratamiento del melanoma nos propusimos demostrar la acción del piroxicam, un analgésico no esteroide, sobre el melanoma B16F1, tumor experimental ampliamente utilizado en el estudio de células cancerosas, para lo cual nos planteamos la hipótesis de que el piroxicam administrado a ratones hembras de la cepa C57BL/6 inoculados con melanoma B16F1 ejerce una acción antitumoral. Se utilizaron 33 hembras de la cepa C57BL/6 distribuidos en dos grupos, un grupo tratado durante un mes con una dosis diaria de piroxicam de 8mg/kg y un grupo control el cual recibió una solución de agua destilada más el vehículo de la droga utilizada. Los resultados obtenidos se analizaron mediante la prueba "t" de Student. Se demostró que el Piroxicam no inhibió el desarrollo del melanoma B16F1; por el contrario aumentó el crecimiento diario del tumor primario "in situ" y las dimensiones del tumor primario "in situ" y las dimensiones del tumor primario disecado, debido probablemente al efecto inhibidor de las prostaglandinas sobre la replicación celular del melanoma B16F1. Concluimos con estos resultados que el piroxicam estimula el desarrollo del melanoma B16F1 en ratones de la cepa C57BL/6

Melanomas multiples primitivos sincronicos / Synchronous primitive multiple melanomas

Comunicamos un caso en un paciente de 46 años del sexo masculino de tres melanomas multiples primitivos cutaneos sicronicos localizados todos en el dorso.Los niveles y espesores fueron:lV y 2,77 mm,"in siru" y lll Y 0,73 mm respectivamente.No presentaba nevos displasicos ni otros precursores y/o marcadores. Resaltamos la necesidad de comunicar estos casos excepcionales para adquirir experiencia en su comportamiento biologico que algunos autores consideran diferente y estable en su incidencia a pesar del aumento global en el numero de melanomas en todo el mundo.

Melanomas multiples primitivos sincronicos / Synchronous primitive multiple melanomas

Comunicamos un caso en un paciente de 46 años del sexo masculino de tres melanomas multiples primitivos cutaneos sicronicos localizados todos en el dorso.Los niveles y espesores fueron:lV y 2,77 mm,"in siru" y lll Y 0,73 mm respectivamente.No presentaba nevos displasicos ni otros precursores y/o marcadores. Resaltamos la necesidad de comunicar estos casos excepcionales para adquirir experiencia en su comportamiento biologico que algunos autores consideran diferente y estable en su incidencia a pesar del aumento global en el numero de melanomas en todo el mundo.AU

Discriminant analysis for classification of murine melanomas and human cervical epithelial cells.

Computer analysis of cell images offers many advantages over routine visual examination. It leads to quantitative and accurate detection of subvisual information and provides reproducible measures so that objective decisions in cancer diagnosis become possible. Such diagnostic decisions usually follow partly from a classification process. In this paper two multivariate discriminant analysis methods--namely, linear discriminant analysis (LDA) and quadratic discriminant analysis (QDA)--are presented. LDA and QDA were used to classify cytologic data based on some morphodensitometric measurements. The cytologic data constituted two samples, one representing B16 cell lines and the other including three types of normal human cervical epithelial cells. LDA and QDA were assessed both individually and in comparison to each other, mainly on the basis of the rate of correct classification and robustness. The measurements extracted from the cytologic data employed were shown to be stable and consistent. The statistical results obtained from experiments on cervical cells look particularly promising and encouraging for future work. It has also been shown in this study that the classification techniques employed are valid and that LDA performed almost as well as QDA.