Signal transducer and activator of transcription 3 and cancer associated fibroblasts jointly generate chemo-resistance and affect prognosis in epithelial ovarian cancer / 中华妇产科杂志

Objective: To investigate the mechanism of signal transducer and activator of transcription 3 (STAT3) and cancer associated fibroblasts (CAF) jointly generate chemo-resistance in epithelial-ovarian cancer and their effect on prognosis. Methods: A total of 119 patients with high-grade ovarian serous cancer who received surgery in Cancer Hospital of Chinese Academy of Medical Sciences from September 2009 to October 2017 were collected. The clinico-pathological data and follow-up data were complete. Multivariate Cox regression model was used to analyze the prognostic factors. Ovarian cancer tissue chips of patients in our hospital were prepared. EnVision two-step method immunohistochemistry was used to detect the protein expression levels of STAT3, the specific markers of CAF activation, fibroblast activating protein (FAP), and type Ⅰ collagen (COL1A1) secreted by CAF. The relationship between the expression of STAT3, FAP, COL1A1 protein and drug resistance and prognosis of ovarian cancer patients was analyzed, and the correlation between the expression of three proteins was analyzed. These results were verified through the gene expression and prognostic information of human ovarian cancer tissues collected in the GSE26712 dataset of gene expression omnibus (GEO) database. Results: (1) Multivariate Cox regression model analysis showed that chemotherapy resistance was an independent risk factor for overall survival (OS) of ovarian cancer (P<0.001). (2) The expression levels of STAT3, FAP, and COL1A1 proteins in chemotherapy resistant patients were significantly higher than those in chemotherapy sensitive patients (all P<0.05). Patients with high expression of STAT3, FAP, and COL1A1 had significantly shorter OS than those with low expression (all P<0.05). According to the human ovarian cancer GSE26712 dataset of GEO database, patients with high expression of STAT3, FAP, and COL1A1 also showed shorter OS than patients with low expression (all P<0.05), the verification results were consistent with the detection results of ovarian cancer patients in our hospital. (3) Correlation analysis showed that the protein level of STAT3 was positively correlated with FAP and COL1A1 in our hospital's ovarian cancer tissue chips (r=0.47, P<0.001; r=0.30, P=0.006), the analysis of GEO database GSE26712 dataset showed that the expression of STAT3 gene and FAP, COL1A1 gene were also significantly positively correlated (r=0.31, P<0.001; r=0.52, P<0.001). Conclusion: STAT3 and CAF could promote chemotherapy resistance of ovarian cancer and lead to poor prognosis.

Estaniocalcina 2 modula eventos importantes para a tumorigênese oral e é um marcador prognóstico para pacientes com carcinoma de células escamosas oral / Staniocalcin 2 modulates important events for oral tumorigenesis and is a prognostic marker for patients with oral squamous cell carcinoma

O hormônio glicoproteico estaniocalcina 2 (STC2) está envolvido na carcinogênese e progressão de muitos tipos de câncer. No entanto, seu significado clínico e mecanismos moleculares no carcinoma de células escamosas oral (CCEO) foram pouco estudados e permanecem incertos. O presente estudo investigou associações da expressão da STC2 com parâmetros clinicopatológicos e de sobrevida em pacientes com CCEO. Além disso, foram avaliados os efeitos biológicos causados pela redução dos níveis de STC2 em linhagens celulares de CCEO e fibroblastos associados ao câncer (do inglês CAF ­ carcinoma associated fibroblasts). A análise imunoistoquímica em 100 casos de CCEOs primários indicou que a superexpressão da STC2 foi associada com o parâmetro N do sistema TNM e foi um fator de risco independente para sobrevida específica da doença e sobrevida livre de doença em pacientes com CCEO. Usando ensaios in vitro, foi demonstrado que o silenciamento da STC2 em linhagens de CCEO promoveu a apoptose e reduziu a proliferação celular, migração, invasão e transição epitélio-mesenquimal. Análises adicionais revelaram que o CAF expressa maiores níveis de STC2 do que as células de CCEO. O silenciamento da STC2 no CAF reduziu a invasão celular do CCEO, sugerindo que a STC2 liberada por CAFs contribui para um fenótipo mais invasivo no CCEO. Esses resultados sugerem que a STC2 modula eventos importantes para a tumorigênese oral e pode ser um biomarcador prognóstico para pacientes com CCEO (AU).

The glycoprotein hormone stanniocalcin 2 (STC2) is involved in carcinogenesis and progression of several cancer types. However, its clinical significance and molecular mechanisms in oral squamous cell carcinoma (OSCC) have been partially studied and remain uncertain. In the present study, we investigated associations of STC2 expression with clinicopathological and survival parameters of OSCCs patients. We also determined the biological effects caused by STC2 downregulation in OSCC and cancer associated fibroblasts (CAF) cell lines. Immunohistochemical analysis in 100 cases of primary OSCC indicated that STC2 overexpression was associated with N stage (TNM staging) and was an independent risk factor for disease-specific survival and disease-free survival in patients with OSCC. Using in vitro assays, we demonstrated that STC2 knockdown in OSCC cell lines promoted apoptosis, and reduced cell proliferation, migration, invasion and epithelial-mesenchymal transition. Further analysis revealed that CAF expresses higher levels of STC2 than OSCC cells. Knockdown of STC2 in CAF reduced OSCC cell invasion, suggesting that STC2 released by CAF contributes to a more invasive phenotype in OSCC. These results suggest that STC2 modulates important events for oral tumorigenesis and can be a prognostic biomarker for OSCC (AU).

Histological changes implicated in metastasis / Cambios histológicos implicados en metástasis

The process of malignancy emergence is associated with the acquisition of the capacity to invade other tissues. Several different biological processes have been described as involved in this process. Specifically, epithelial mesenchymal transition (EMT), a mechanism associated with embryogenesis and wound repair but also with mobility acquisition, is one of the concerned processes. In EMT an epithelial cell loses its epithelial characteristics, its junctions with neighbor cells and with the basal lamina and acquires mobility and mesenchymal characteristics. Also, factors of the tumor microenvironment have been described as involved. Tumor presence triggers a response in the surrounding tissue known as reactive stromal. It shows particular characteristics similar to those found in wound healing stroma: an increase of the fibroblast number and enhancing of the capillary density. The notable difference is the chronicity in the tumoral process. Of a high relevance seems to be the role of activated macrophages with a characteristic phenotype. Finally, cancer associated fibroblasts (CAF) are a type of cells found in tumors, developed from local tissue or possibly from bone marrow. CAF characteristically show a distinct morphology and secrete a high number of metalloproteases allowing tumoral cells advance through the tissue. Additionally, CAF have a direct effect on the survival of the epithelial cells. The three processes are interrelated and metastasis is probably caused by the effect of all of them and probably by other additional factors.

El desarrollo de malignidad está asociado con la adquisición de la capacidad de invadir otros tejidos. Varios procesos diferentes han sido asociados con la aparición de metástasis. Concretamente, la transición epitelio mesénquima (TEM), un mecanismo asociado con embriogénesis y reparación de heridas pero también con adquisición de movilidad, es uno de ellos. En la TEM, una célula epitelial pierde sus características epiteliales, sus uniones con las células vecinas y con la lámina basal y adquiere movilidad y características mesenquemáticas. También han sido asociados factores del microambiente del tumor. La presencia del tumor produce una respuesta en el tejido que lo rodea descrito como estroma reactivo. Sus características son similares a las del estroma de las heridas en proceso de curación: un incremento del número de fibroblastos y un aumento de la densidad de capilares. La gran diferencia es la cronicidad del proceso tumoral. De gran relevancia es el papel de los macrófagos activados que muestran un fenotipo característico. Finalmente, los fibroblastos asociados a cáncer (FAC) son un tipo de células encontradas en tumores, que se desarrollan a partir del tejido local o quizá de la médula ósea. Los FAC, de modo característico muestran una morfología diferente y secretan una gran cantidad de metaloproteasas permitiendo a la célula tumoral avanzar a través del tejido. Además, los FAC ejercen un efecto directo sobre la supervivencia de las células epiteliales. Los tres procesos están interrelacionados y la metástasis es causada probablemente por el efecto de todos ellos y probablemente por otros factores adicionales.