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Subpopulations of tumor infiltrating leukocytes in immunogenic skin tumors were identified with monoclonal antibodies. The tumors studied included primary UV-induced tumors and JB/MS melanomas, which survive in the host by immunosuppression of the immune response. The proportions of nucleated cells in primary UV-induced tumor cell suspensions which reacted with monoclonal antibodies were: 52% Mac-1+, 21% Lyt-1+, 13% Lyt-2+, 7% L3T4+, and 8% IL-2R+. Thus there was a high proportion of cells of the macrophage lineage in the growing UV-induced tumors. In JB/MS melanoma cell suspensions the mean proportion of macrophages was 6.4%, and total T lymphocytes (Lyt-1) averaged only 5.5%. Thus, there was little leukocytes infiltration into JB/MS melanoma, suggesting that chemotaxis was defective. The high level of macrophages and T cells in the primary UV-induced tumors indicates that chemotaxis was intact. Therefore, either the tumorcidal capacities of the macrophages and Tc were insensitive to activated macrophages and to Tc cells.

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Visando o tratamento tópico de tumores cutâneos, desenvolvemos micro e nanoemulsões para a co-localização cutânea de paclitaxel e ceramida C6. A nanoemulsão mostrou-se mais eficaz em promover penetração de ambos os compostos nas camadas viáveis da pele, com aumentos de 11,5 (paclitaxel) e 3,5 (ceramida) vezes comparado a uma solução controle, e não reduziu significativamente a viabilidade de equivalentes epidérmicos, sugerindo sua segurança para aplicação tópica. A incorporação na nanoemulsão diminuiu as concentrações de paclitaxel e ceramida necessárias para reduzir a viabilidade de células de melanoma a 50% em 6 a 15 vezes, respectivamente, sendo que a co-encapsulação desses compostos promoveu uma nova redução (4 vezes) nessas concentrações, demonstrando aumento da eficácia decorrente da associação dos compostos. A administração tópica do nanocarreador contendo paclitaxel e ceramida co-encapsulados promoveu desorganização e morte celular em equivalentes cutâneos com melanoma, demonstrando o potencial desta formulação para o tratamento tópico de tumores cutâneos. / Nano and microemulsions were developed in this study for cutaneous co-localization of the active agents paclitaxel and C6 ceramide for topical treatment of skin cancer. The nanoemulsion was more effective in promoting the penetration of the compounds into viable skin layers, with increases of 11.5- (paclitaxel) and 3.5- fold (ceramide) being observed. The nanoemulsion did not reduce the viability of human epidermis equivalents, suggesting its safety for topical application. Incorporation in the nanoemulsion reduced the concentration of paclitaxel and ceramide required to decrease viability of human melanoma cells to 50% by 6 to 15-fold compared with their solutions; co-encapsulation of the compounds promoted a further reduction of 4-fold. Topical administration of the nanocarrier with co-encapsulated paclitaxel and ceramide to skin equivalents with melanoma promoted disorganization and intense cytotoxicity. These results demonstrate the potential of nanoemulsions for association of paclitaxel and ceramide C6 to improve their cytotoxic effect and skin localization.

One of the most challenging questions in the study of cancer is the origin and the nature of the cells that initiate cancer. Accumulated studies have provided many molecular origins of cancers but we still do not know what kind of cells in the tissues transform to cancer cells. Therefore, identifying the cellular origin of these cells is critical for the development of better prognosis, diagnosis and treatment of cancer. A stem cell origin of cancer has been postulated over 150 years. Recent cancer stem cell studies have opened a new window on aspects of the cellular origin of cancer. In this communication, we will address two possible cellular origins of cancer in epithelial tumor development using mouse skin cancer model: tissue specific stem cells, and cells from other organs. To demonstrate contribution of the tissue specific stem cells in tumor development, we monitored the contribution of keratin-15 positive hair follicle bulge stem cells to skin tumor development in the multistage skin carcinogenesis model with Krtl- 15CrePRl;R26R transgenic mice. We found that labeled progeny of the keratin-15 positive bulge stem cells migrate into papillomas and these cells contribute to almost all papilloma samples by 20 weeks of promotion. Additionally, in contrast to the transient contribution of bulge-derived cells in skin wound healing, consistent percentage of the bulge-derived cells stay in the papillomas over 20 weeks. Furthermore, papillomas have heterogeneous expression of the codon 61 signature Ha-ras mutation, with approximately 30 percent of bulge-derived regions expressing the mutation. To determine the contribution of exogenous sources in skin tumor development, we examined bone marrow-derived cells (BMDCs) in the skin tumors from the allogeneic gender-mismatched bone marrow transplantation recipient mice after chemical skin carcinogenesis. We observed that genetically marked (EGFP) BMDCs were detected in the epithelial part of skin wounds and also skin tumors, and we found greater degree of BMDC contribution in chronic ulcer-related skin lesions. Lastly, an in-vitro assay demonstrated plasticity of BMDCs by inducing keratin-14 expressing cells from mesenchymal stem cells. These results demonstrated that hair follicle bulge stem cells and also BMDCs are able to contribute to skin tumor development.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Equine sarcoid is a locally aggressive cutaneous neoplasm, described and characterized as a clinical entity by Jackson in 1936. The neoplasm has a worldwide distribution and affects several equine species. It is believed that the cause of sarcoid is this infection by bovine papillomavirus 1 or 2. The combination of certain factors, including cutaneous trauma, genetic predisposition and viral exposure, seem to be involved in the development of the lesions. Sarcoid have no seasonality, no predilection by color or type hair and is considered the most common skin tumor of horses. Due to the lack of data which could characterize this tumor under the sphere of influence of the Laboratório de Patologia Veterinária (LPV) of the Universidade Federal de Santa Maria (UFSM), this dissertation determines the epidemiological aspects and the anatomic distribution of the different clinical forms of equine sarcoid in the state of Rio Grande do Sul. The files of histopathological exams carried out by the Laboratório de Patologia Veterinária of the Universidade Federal de Santa Maria (LPV-UFSM), between January 2000 and March 2010, were reviewed in search of cases of equine sarcoid. Forty cases were selected to determine epidemiological aspects and the anatomical distribution of the various clinical forms of these neoplasms in horses from Rio Grande do Sul. Out of the cases in which the ages were registered in the histopathological reports, 73,0% (27/37) were 1-5 years-old horses. Multiple sarcoids were observed in most of the affected horses (29/40 [72,5%]). The fibroblastic was the most observed clinical form and it occurred in 42,2% (27/64) of the cases. In more than half of the cases (22/40 [55,0%]), sarcoids had a multifocal distribution. Twenty two (55%) out of the 40 horses evaluated had the tumors in the limbs. / O sarcoide equino é um neoplasma cutâneo, localmente agressivo e foi descrito e caracterizado como uma entidade clínica por Jackson em 1936. Tem distribuição mundial e afeta várias espécies equídeas. Acredita-se que a causa seja a infecção pelo papilomavírus bovino tipo 1 ou 2. A combinação de alguns fatores, incluindo trauma cutâneo, predisposição genética e exposição ao vírus, parecem estar envolvidas no aparecimento das lesões. Não tem predileção por cor ou tipo da pelagem ou da pele e nem por estação do ano. O sarcoide é considerado o tumor mais comum de pele dos equinos. Devido a escassez de dados que caracterizam esse tumor na região de abrangência do Laboratório de Patologia Veterinária (LPV) da Universidade Federal de Santa Maria (UFSM), essa dissertação determina os aspectos epidemiológicos e a distribuição anatômica das diferentes formas clínicas do sarcoide no Rio Grande do Sul. Foram revisados todos os protocolos de exames histopatológicos, arquivados no LPV-UFSM, realizados entre janeiro de 2000 e março de 2010, na busca de casos de sarcoide equino. Quarenta casos foram selecionados com o objetivo de determinar os aspectos epidemiológicos e a distribuição anatômica das diferentes formas clínicas deste tumor em equinos no Rio Grande do Sul. Dos casos que tiveram suas idades anotadas nos protocolos, 73,0% (27/37) eram de equinos entre 1 e 5 anos de idade. Múltiplos sarcoides foram observados na maioria dos equinos afetados (29/40 [72,5%]). A forma clínica mais observada foi a fibroblástica, que ocorreu em 42,2% (27/64) dos casos. Em mais da metade dos casos (22/40 [55,0%]), os sarcoides tinham distribuição multifocal. Equinos que apresentavam tumores nos membros totalizaram 22 dos 40 (55%) casos analisados.

The dissertation is focused on the study of intercellular interactions in skin tumors. It is based on 5 original publications that cover several topics. We studied the origin of tumor-associated fibroblasts concerning the primary tumor population. We demonstrated using a mouse model that tumor-associated fibroblasts are produced from the host organism and thus did not arise from transformation directly from tumor cells. We also investigated the relationship between tumor-associated fibroblasts and keratinocytes. We have shown that tumor-associated melanoma fibroblasts affect keratinocytes which, under their influence, acquire the features typically observed in migrating cells and cells undergoing epithelial-mesenchymal transition. We studied the interactions between healthy fibroblasts and tumor cells. We have demonstrated that fibroblasts acquired from healthy skin from a patient suffering from melanoma are significantly different from control fibroblasts of healthy donors in the expression profile. Changes in distal fibroblasts support the view of melanoma as a systemic disease. We have further demonstrated that melanoma-associated fibroblasts do not carry a BRAF mutation, in contrast to BRAF positivity of melanoma cells. And therefore, they did not arise from the transition from melanoma. The...