Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors.

Nonmelanoma skin cancer is one of the most common malignancies in humans. Different therapeutic strategies for the treatment of these tumors are currently being investigated. Given the growth-inhibiting effects of cannabinoids on gliomas and the wide tissue distribution of the two subtypes of cannabinoid receptors (CB(1) and CB(2)), we studied the potential utility of these compounds in anti-skin tumor therapy. Here we show that the CB(1) and the CB(2) receptor are expressed in normal skin and skin tumors of mice and humans. In cell culture experiments pharmacological activation of cannabinoid receptors induced the apoptotic death of tumorigenic epidermal cells, whereas the viability of nontransformed epidermal cells remained unaffected. Local administration of the mixed CB(1)/CB(2) agonist WIN-55,212-2 or the selective CB(2) agonist JWH-133 induced a considerable growth inhibition of malignant tumors generated by inoculation of epidermal tumor cells into nude mice. Cannabinoid-treated tumors showed an increased number of apoptotic cells. This was accompanied by impairment of tumor vascularization, as determined by altered blood vessel morphology and decreased expression of proangiogenic factors (VEGF, placental growth factor, and angiopoietin 2). Abrogation of EGF-R function was also observed in cannabinoid-treated tumors. These results support a new therapeutic approach for the treatment of skin tumors.

A critical role for ras-mediated, epidermal growth factor receptor-dependent angiogenesis in mouse skin carcinogenesis.

Epidermal growth factor receptor (EGFR) plays a critical role in epidermal biology. Abnormal EGFR function has been described in epithelial tumors including those induced by two-stage chemical carcinogenesis in mouse skin. A large body of evidence indicates that in this model, activation of Ha-ras is the critical event in papilloma formation, a process that involves epidermal proliferation and stroma remodeling, which includes angiogenesis. This study reports that activated Ha-ras results in a dramatic induction of EGFR in epidermal tumor cells and provides experimental evidence that EGFR signaling is responsible for Ha-ras-dependent vascular endothelial growth factor (VEGF) induction, as well as for the repression of other angiogenic factors such as angiopoietin 1. The pivotal role of functional EGFR in throwing the angiogenic switch necessary for tumor growth was confirmed by s.c. injection of immunodeficient mice with epidermal tumor cells carrying a dominant negative (dn) EGFR and by in vivo chemical skin carcinogenesis assays in transgenic mice expressing the same dn EGFR form in the epidermis. Immunohistochemical analysis of the tumors obtained by both ex vivo and in vivo approaches showed that dn EGFR expression abolished the changes in blood vessels that occurred during tumor progression. A strong reduction of VEGF expression in dn EGFR tumors appears to be the key event responsible for angiogenesis and tumor growth suppression. The apoptotic rate was increased, and Akt activity was decreased, suggesting that impaired nutrient and oxygen supply might contribute to diminished cell survival in dn EGFR tumors. Support for this mechanism is provided by the fact that the ectopic expression of VEGF in dn EGFR-expressing tumor cell lines restored tumor growth capacity. Although ras activation might suffice for epidermal transformation and the stroma-remodeling events of tumor induction, such effects may not be operative without a functional upstream EGFR. It is tempting to speculate that EGFR family members may function as angiogenic regulators in other epithelial tumors such as those of the colon, breast, and prostate, reinforcing their value as targets for therapeutic intervention.

Epidermal abnormalities and increased malignancy of skin tumors in human epidermal keratin 8-expressing transgenic mice.

Keratins K8 and K18 are the major components of the intermediate filament cytoskeleton of simple epithelia. Increased levels of these keratins have been associated with invasive growth and progression to malignancy in different types of human and murine epithelial tumors (including skin tumors), and even in tumors from nonepithelial origin. However, it has not yet clarified whether K8/K18 expression in tumors is cause or consequence of malignancy. Given the increasing incidence of epidermal cancer in humans (40% of all tumors diagnosed), we generated a mouse model to examine the role of simple epithelium keratins in the establishment and progression of human skin cancer. Transgenic mice expressing human K8 in the epidermis showed severe epidermal and hair follicle dysplasia with concomitant alteration in epidermal differentiation markers. The severity of the skin phenotype of these transgenic mice increases with age, leading to areas of preneoplastic transformation. Skin carcinogenesis assays showed a dramatic increase in the progression of papillomas toward malignancy in transgenic animals. These results support the idea that K8 alters the epidermal cell differentiation, favors the neoplastic transformation of cells, and is ultimately responsible of the invasive behavior of transformed epidermal cells leading of conversion of benign to malignant tumors.

Inhibition of tumor angiogenesis by cannabinoids.

Cannabinoids, the active components of marijuana and their derivatives, induce tumor regression in rodents (8). However, the mechanism of cannabinoid antitumoral action in vivo is as yet unknown. Here we show that local administration of a nonpsychoactive cannabinoid to mice inhibits angiogenesis of malignant gliomas as determined by immunohistochemical analyses and vascular permeability assays. In vitro and in vivo experiments show that at least two mechanisms may be involved in this cannabinoid action: the direct inhibition of vascular endothelial cell migration and survival as well as the decrease of the expression of proangiogenic factors (vascular endothelial growth factor and angiopoietin-2) and matrix metalloproteinase-2 in the tumors. Inhibition of tumor angiogenesis may allow new strategies for the design of cannabinoid-based antitumoral therapies.

Paratesticular desmoplastic small round cell tumor: case report.

BACKGROUND: The desmoplastic small round cell tumor has recently been separated from other small round cell tumors because of its characteristic pathological and clinical features. They are usually intra-abdominal tumors affecting young people and have classically been associated with a bad prognosis. However, in recent years there have reports on desmoplastic small round cell tumors affecting other body regions, including the paratesticular area. CASE PRESENTATION: We report the case of a 23-year-old male, that consulted on a progressive enlargement of the right hemiscrotum in the last year and a half. He referred no previous urological symptoms and had no systemic symptomatology. Physical examination revealed a round elastic firm 2 to 3 cm mass distal to the tail of the epididymis, which was excised with a preoperative diagnosis of adenomatoid tumor. However, histological and immunohistochemical diagnosis confirmed a desmoplastic small round cell tumor. The extension study included a computed tomography scan and a plain chest radiograph, that showed no metastasis. The patient received chemoradiation therapy with methotrexate, dacarbacin, cyclophosphamide, actinomycin D and vincristin, but had to be changed to a vincristin, actinomycin D, cyclophosphamide and adriamicin scheme on severe toxicity. He completed five cycles of the chemotherapy with moderate toxicity. Today, 6 years after diagnosis the patient remains well and free of disease. CONCLUSIONS: Recent reviews on desmoplastic small round cell tumor affecting the paratesticular area have shown a better prognosis for tumors of this origin compared to abdominal ones. We should include this lesion among the differential diagnosis of paratesticular tumors, mainly in children and adolescents.

Um estudo sobre jovens e violência no espaço escolar / Un estudio sobre juventud y violencia en la escuela / A study on youth and violence at school

Este texto é resultado de um projeto de pesquisa sobre a temática do jovem, violência e escola. O objetivo desse projeto foi investigar a interpretação dos jovens sobre a violência na sociedade, na escola e na sua própria vida. O pressuposto é o de que conhecer a perspectiva de agressores e vítimas sobre as suas experiências de violência contribui para esclarecer os universos simbólicos e normativos que regulam as condutas violentas e as possíveis formas de reduzir sua incidência. Os dados foram coletados por meio de grupos focais. Um dos grupos foi constituído por alunos qualificados pela escola como protagonistas de situações de violência. O outro grupo foi constituído por jovens considerados bons alunos. A análise dos dados mostra uma diferença entre a lógica da violência à escola e da escola, e a violência na escola.

Este texto es el resultado de un proyecto de investigación sobre el tema de la violencia juvenil y la escuela. El objetivo de este proyecto fue investigar la interpretación de los jóvenes sobre la violencia en la sociedad, en la escuela y en su propia vida. El supuesto es que el conocimiento de la perspectiva de los agresores y de las víctimas acerca de sus experiencias de violencia ayuda a clarificar los universos normativos y simbólicas que regulan el comportamiento violento y las posibles maneras de reducir su incidencia. Los datos fueron recolectados a través de grupos de enfoque. Un grupo fue formado por la escuela calificada como protagonistas de los estudiantes situaciones de violencia. El otro grupo estaba formado por los jóvenes considerados buenos estudiantes. Análisis de los datos muestra una diferencia entre la lógica de la violencia hacia y desde la escuela y la violencia escolar.

This paper is the result of a research project on the subject of youth, violence and school. The purpose of this project was to investigate the understanding of the young people on the violence in society, at school and in their own lives. The assumption is that knowing the aggressors' and victims' perspective about their experiences of violence helps to clarify the symbolic and the normative universes that rule violent conducts and the possible ways to reduce the incidence of violence. Data were collected through focus groups. One of the groups was composed by students qualified by their school's board as protagonists in situations of violence. The other group was consisted by those considered as good students. Data analysis shows the differences between the logic of violence at school, the school violence and violence against the school.

IKKalpha enhances human keratinocyte differentiation and determines the histological variant of epidermal squamous cell carcinomas.

Squamous cell carcinomas (SCCs) of the skin display different clinical features according to their epithelial differentiation grade and histological variant. Understanding the causes of these divergences might increase the curability of SCCs. Therefore, it is important to study the mechanisms of differentiation in keratinocytes. IKK (IkappaB kinase) alpha is an important protein for epidermal morphogenesis, although the pathways through which it exerts its function are unknown and controversy exists about its role in cancer development. We show that enhanced IKKalpha expression increases both early and terminal differentiation of human keratinocytes through an E-cadherin-dependent mechanism. Increased expression of IKKalpha in mouse tumorigenic epidermal cells leads to changes in the differentiation pattern of the resulting SCCs, originating a distinct histological variant that resembles the human acantholytic SCC (ASCC) variant. Although human ASCCs have an aggressive clinical course and high risk of metastasis, nothing is known about their etiology. We show that human ASCCs, as observed in the counterpart IKKalpha murine tumors, express high levels of both IKKalpha and E-cadherin, with absence of keratins K1 and K10, usually co-expressed with IKKalpha and E-cadherin. The tight correlation between the properties of both murine and human ASCC variants strongly suggests that IKKalpha is responsible for the development of this human SCC variant.

Extramedullary hematopoiesis in an adult.

Cutaneous extramedullary hematopoiesis is a rare disease, affecting mainly children with intrauterine viral or hematologic disorders. To our knowledge, only about 30 cases have been reported in adults, mainly associated with myelofibrosis. We report a new case of this entity in a 79-year-old woman and comment on the clinical and histologic differential diagnosis.