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Simvastatin interferes with cancer 'stem-cell' plasticity reducing metastasis in ovarian cancer.
Kato, S; Liberona, M F; Cerda-Infante, J; Sánchez, M; Henríquez, J; Bizama, C; Bravo, M L; Gonzalez, P; Gejman, R; Brañes, J; García, K; Ibañez, C; Owen, G I; Roa, J C; Montecinos, V; Cuello, M A.
Afiliación
  • Kato S; Division of Obstetrics and GynecologyFaculty of Medicine, Pontificia Universidad Católica de Chile (PUC), Santiago, Chile.
  • Liberona MF; Division of Obstetrics and GynecologyFaculty of Medicine, Pontificia Universidad Católica de Chile (PUC), Santiago, Chile.
  • Cerda-Infante J; Department of Hematology and OncologyFaculty of Medicine, PUC, Santiago, Chile.
  • Sánchez M; Department of Cellular and MolecularFaculty of Biological Sciences, PUC, Santiago, Chile.
  • Henríquez J; Department of Hematology and OncologyFaculty of Medicine, PUC, Santiago, Chile.
  • Bizama C; Department of Hematology and OncologyFaculty of Medicine, PUC, Santiago, Chile.
  • Bravo ML; Department of PathologyFaculty of Medicine, PUC, Santiago, Chile.
  • Gonzalez P; Department of Physiological SciencesFaculty of Biological Sciences, PUC, Santiago, Chile.
  • Gejman R; Millennium Institute on Immunology and ImmunotherapyPUC, Santiago, Chile.
  • Brañes J; Department of Physiological SciencesFaculty of Biological Sciences, PUC, Santiago, Chile.
  • García K; Department of PathologyFaculty of Medicine, PUC, Santiago, Chile.
  • Ibañez C; Division of Obstetrics and GynecologyFaculty of Medicine, Pontificia Universidad Católica de Chile (PUC), Santiago, Chile.
  • Owen GI; Division of Obstetrics and GynecologyFaculty of Medicine, Pontificia Universidad Católica de Chile (PUC), Santiago, Chile.
  • Roa JC; Department of Hematology and OncologyFaculty of Medicine, PUC, Santiago, Chile.
  • Montecinos V; Millennium Institute on Immunology and ImmunotherapyPUC, Santiago, Chile.
  • Cuello MA; Department of Physiological SciencesFaculty of Biological Sciences, PUC, Santiago, Chile.
Endocr Relat Cancer ; 25(10): 821-836, 2018 10.
Article en En | MEDLINE | ID: mdl-29848667
Cell plasticity of 'stem-like' cancer-initiating cells (CICs) is a hallmark of cancer, allowing metastasis and cancer progression. Here, we studied whether simvastatin, a lipophilic statin, could impair the metastatic potential of CICs in high-grade serous ovarian cancer (HGS-ovC), the most lethal among the gynecologic malignancies. qPCR, immunoblotting and immunohistochemistry were used to assess simvastatin effects on proteins involved in stemness and epithelial-mesenchymal cell plasticity (EMT). Its effects on tumor growth and metastasis were evaluated using different models (e.g., spheroid formation and migration assays, matrigel invasion assays, 3D-mesomimetic models and cancer xenografts). We explored also the clinical benefit of statins by comparing survival outcomes among statin users vs non-users. Herein, we demonstrated that simvastatin modifies the stemness and EMT marker expression patterns (both in mRNA and protein levels) and severely impairs the spheroid assembly of CICs. Consequently, CICs become less metastatic in 3D-mesomimetic models and show fewer ascites/tumor burden in HGS-ovC xenografts. The principal mechanism behind statin-mediated effects involves the inactivation of the Hippo/YAP/RhoA pathway in a mevalonate synthesis-dependent manner. From a clinical perspective, statin users seem to experience better survival and quality of life when compared with non-users. Considering the high cost and the low response rates obtained with many of the current therapies, the use of orally or intraperitoneally administered simvastatin offers a cost/effective and safe alternative to treat and potentially prevent recurrent HGS-ovCs.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Ováricas / Células Madre Neoplásicas / Inhibidores de Hidroximetilglutaril-CoA Reductasas / Simvastatina / Plasticidad de la Célula / Metástasis de la Neoplasia Aspecto: Patient_preference Límite: Female / Humans Idioma: En Revista: Endocr Relat Cancer Asunto de la revista: ENDOCRINOLOGIA / NEOPLASIAS Año: 2018 Tipo del documento: Article País de afiliación: Chile Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Ováricas / Células Madre Neoplásicas / Inhibidores de Hidroximetilglutaril-CoA Reductasas / Simvastatina / Plasticidad de la Célula / Metástasis de la Neoplasia Aspecto: Patient_preference Límite: Female / Humans Idioma: En Revista: Endocr Relat Cancer Asunto de la revista: ENDOCRINOLOGIA / NEOPLASIAS Año: 2018 Tipo del documento: Article País de afiliación: Chile Pais de publicación: Reino Unido