ROR2 promotes epithelial-mesenchymal transition by hyperactivating ERK in melanoma.

Receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a protein with important functions during embryogenesis that is dysregulated in human cancer. An intriguing feature of this receptor is that it plays opposite roles in different tumor types either promoting or inhibiting tumor progression. Understanding the complex role of this receptor requires a more profound exploration of both the altered biological and molecular mechanisms. Here, we describe that ROR2 promotes Epithelial-Mesenchymal Transition (EMT) by inducing cadherin switch and the upregulation of the transcription factors ZEB1, Twist, Slug, Snail, and HIF1A, together with a mesenchymal phenotype and increased migration. We show that ROR2 activates both p38 and ERK mitogen-activated protein kinase pathways independently of Wnt5a. Further, we demonstrated that the upregulation of EMT-related proteins depends on the hyperactivation of the ERK pathway far above the typical high constitutive activity observed in melanoma. In addition, ROR2 also promoted ERK phosphorylation, EMT, invasion, and necrosis in xenotransplanted mice. ROR2 also associates with EMT in tumor samples from melanoma patients where analysis of large cohorts revealed that increased ROR2 levels are linked to EMT signatures. This important role of ROR2 translates into melanoma patient' s prognosis since elevated ROR2 levels reduced overall survival and distant metastasis-free survival of patients with lymph node metastasis. In sum, these results demonstrate that ROR2 contributes to melanoma progression by inducing EMT and necrosis and can be an attractive therapeutic target for melanoma.

ROR2 has a protective role in melanoma by inhibiting Akt activity, cell-cycle progression, and proliferation.

BACKGROUND: Receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a Wnt5a receptor aberrantly expressed in cancer that was shown to either suppress or promote carcinogenesis in different tumor types. Our goal was to study the role of ROR2 in melanoma. METHODS: Gain and loss-of-function strategies were applied to study the biological function of ROR2 in melanoma. Proliferation assays, flow cytometry, and western blotting were used to evaluate cell proliferation and changes in expression levels of cell-cycle and proliferation markers. The role of ROR2 in tumor growth was assessed in xenotransplantation experiments followed by immunohistochemistry analysis of the tumors. The role of ROR2 in melanoma patients was assessed by analysis of clinical data from the Leeds Melanoma Cohort. RESULTS: Unlike previous findings describing ROR2 as an oncogene in melanoma, we describe that ROR2 prevents tumor growth by inhibiting cell-cycle progression and the proliferation of melanoma cells. The effect of ROR2 is mediated by inhibition of Akt phosphorylation and activity which, in turn, regulates the expression, phosphorylation, and localization of major cell-cycle regulators including cyclins (A, B, D, and E), CDK1, CDK4, RB, p21, and p27. Xenotransplantation experiments demonstrated that ROR2 also reduces proliferation in vivo, resulting in inhibition of tumor growth. In agreement with these findings, a higher ROR2 level favors thin and non-ulcerated primary melanomas with reduced mitotic rate and better prognosis. CONCLUSION: We conclude that the expression of ROR2 slows down the growth of primary tumors and contributes to prolonging melanoma survival. Our results demonstrate that ROR2 has a far more complex role than originally described.

BCL2L10 Is Overexpressed in Melanoma Downstream of STAT3 and Promotes Cisplatin and ABT-737 Resistance.

The anti-apoptotic proteins from the Bcl-2 family are important therapeutic targets since they convey resistance to anticancer regimens. Despite the suspected functional redundancy among the six proteins of this subfamily, both basic studies and therapeutic approaches have focused mainly on BCL2, Bcl-xL, and MCL1. The role of BCL2L10, another member of this group, has been poorly studied in cancer and never has been in melanoma. We describe here that BCL2L10 is abundantly and frequently expressed both in melanoma cell lines and tumor samples. We established that BCL2L10 expression is driven by STAT3-mediated transcription, and by using reporter assays, site-directed mutagenesis, and ChIP analysis, we identified the functional STAT3 responsive elements in the BCL2L10 promoter. BCL2L10 is a pro-survival factor in melanoma since its expression reduced the cytotoxic effects of cisplatin, dacarbazine, and ABT-737 (a BCL2, Bcl-xL, and Bcl-w inhibitor). Meanwhile, both genetic and pharmacological inhibition of BCL2L10 sensitized melanoma cells to cisplatin and ABT-737. Finally, BCL2L10 inhibited the cell death upon combination treatments of PLX-4032, a BRAF inhibitor, with ABT-737 or cisplatin. In summary, we determined that BCL2L10 is expressed in melanoma and contributes to cell survival. Hence, targeting BCL2L10 may enhance the clinical efficacy of other therapies for malignant melanoma.

Consejo genético y detección de vías moleculares en pacientes con cáncer hereditario / Genetic advice and molecular pathways detection in patients with hereditary cancer

INTRODUCCIÓN: El cáncer de mama es la primera causa de muerte de la mujer en la Argentina, con una incidencia estimada de más de 19.000 casos nuevos por año. Dentro de estos, el tipo de cáncer hereditario más común es el de mama/ovario hereditario, provocado por mutaciones en los genes BRCA 1(Breast cáncer) y BRCA 2. A su vez el cáncer colorrectal es la segunda causa de muerte en Argentina, con una incidencia estimada de más de 11.000 casos nuevos por año. OBJETIVO: de la presente investigación es evaluar la utilidad de la realización de los estudios genéticos en personas con cáncer hereditario en el contexto del consejo genético, con un asesoramiento antes y después de realizarse la prueba genética POBLACIÓN Y MÉTODOS: Se estudiaron 34 mujeres con diagnóstico de cáncer de mama/ovario y 31 pacientes de ambos sexos con diagnóstico de cáncer colorrectal (CCR). En las mujeres se analizaron los genes BRCA 1 y 2 por secuenciación de próxima generación (NSG) y grandes rearreglos de los genes BRCA 1 y 2 por amplificación de sonda dependiente de la ligadura multiplex (MLPA). En las personas de ambos sexos se determinó la Inestabilidad de Microsatelites(IMS), el análisis de mismatch repair (MMR) por MLPA y la mutación del gen BRAF (Protooncogen B-Raf) RESULTADOS: Los resultados mostraron que las pacientes con cáncer de mama / ovario con antecedentes familiares tienen un alto porcentaje de BRCA negativo. En cuanto a los cambios fenotípicos, el más predominante en este estudio, fue el subtipo triple negativo y la paciente con BRCA 2 positivo presentó este fenotipo. Con respecto al estudio del cáncer de colon detectamos cuatro pacientes con IMS-alta y mutación del V600E del gen BRAF. Cuando se les realizó el análisis de MLPA en los genes MSH6, MLH1, MSH2 y PMS2 a los efectos de establecer la diferencia entre CCR y síndrome de Lynch, los resultados fueron negativos, por lo tanto, estos pacientes fueron diagnosticados como CCR esporádico. CONCLUSIONES: Como lo demuestra este trabajo, para el consejo genético, el estudio de vías moleculares en pacientes con cáncer hereditario es un instrumento de ayuda para la valoración del riesgo génico. (AU)

INTRODUCTION: Breast cancer is the leading cause of death of women in Argentina, with a estimated incidence of more than 19,000 new cases per year. Among these, the most common type of inherited cancer is the breast /ovarian caused by mutations in the BRCA1 and BRCA 2 genes. At the same time, the cancer colorrectal is the second cause of death in Argentina, with an estimated incidence of more than 11,000 new cases per year. OBJECTIVE: of the present investigation is to evaluate the usefulness of the realization of the genetic studies in people with hereditary cancer in the context of genetic counseling, with a advice before and after the genetic test. POPULATIONS AND METHODS: We studied 34 women diagnosed with breast / ovarian cancer and 31 patients of both sexes with diagnosis of colorectal cancer (CRC). In women, the BRCA 1 and 2 genes by next generation sequencing (NSG) and large rearrangements of BRCA 1 and 2 genes by probe amplification dependent on multiplex ligation(MLPA). The instability of microsatellites (IMS) was determined in people of both sexes, the analysis of mismatchrepair (MMR) by MLPA and the mutation of the BRAF gene. RESULTS: There results showed that patients with breast / ovarian cancer with a history family members have a high percentage of negative BRCA. As for the changes phenotypic, the most predominant in this study, was the triple negative subtype and the patient with positive BRCA 2 presented this phenotype. With respect to the study of colon cancer detected four patients with IMS-high and mutation of the V600E of the BRAF gene. When the MLPA analysis was performed on the MSH6, MLH1, MSH2 genes and PMS2, in order to established difference between CRC and Lynch syndrome, the results were negative and therefore these patients were diagnosed as sporadic CRC. CONCLUSIONS: As this work demonstrates, for him genetic counseling, the study of pathways molecules in patients with hereditary cancer is a helpful instrument for risk assessment. (AU)

Adenoacantoma del esofago superior: presentacion de un caso / Adenocanthoma of the upper esophagus: report of a case

We report 72 years old woman, with adenoacamthoma of the upper osophagus who was admitted in Hospital israelita "EZRAH" in April of 1991. We performed a review of the literature on this rare tumour, that is the reason of presenting this case (AU)

Adenoacantoma del esofago superior: presentacion de un caso / Adenocanthoma of the upper esophagus: report of a case

We report 72 years old woman, with adenoacamthoma of the upper osophagus who was admitted in Hospital israelita "EZRAH" in April of 1991. We performed a review of the literature on this rare tumour, that is the reason of presenting this case

Distúrbios inmunológicos, inmunodefiencia y sarcoma angioblástico de tipo Kaposi: aspectos lesionales en los ganglios linfáticos / Immunological disorders, immunodeficiency and angioblastic sarcoma of Kaposis type: lesional aspects in the lymph nodes

Se describen los cambios hitológicos en los ganglios linfáticos en pacientes con evidencias de inmunodeficiencia y sarcoma angioblástico de tipo Kaposi, destacando las modificaciones previas y concomitantes a la instalación de la neoplasia y relacionando las mismas con el disturbio inmunológico. Se realizan consideraciones sobre la histogénesis de las células neoplásicas en los angiosarcomas de tipo Kaposi y se concluye que las mismas muestran caracteres hemangiopericitoides y endoteliales combinados (AU)

Distúrbios inmunológicos, inmunodefiencia y sarcoma angioblástico de tipo Kaposi: aspectos lesionales en los ganglios linfáticos / Immunological disorders, immunodeficiency and angioblastic sarcoma of Kaposis' type: lesional aspects in the lymph nodes

Se describen los cambios hitológicos en los ganglios linfáticos en pacientes con evidencias de inmunodeficiencia y sarcoma angioblástico de tipo Kaposi, destacando las modificaciones previas y concomitantes a la instalación de la neoplasia y relacionando las mismas con el disturbio inmunológico. Se realizan consideraciones sobre la histogénesis de las células neoplásicas en los angiosarcomas de tipo Kaposi y se concluye que las mismas muestran caracteres hemangiopericitoides y endoteliales combinados