Simvastatin interferes with cancer 'stem-cell' plasticity reducing metastasis in ovarian cancer.

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.

Lipophilic but not hydrophilic statins selectively induce cell death in gynaecological cancers expressing high levels of HMGCoA reductase.

Recent reports have suggested that statins induce cell death in certain epithelial cancers and that patients taking statins to reduce cholesterol levels possess lower cancer incidence. However, little is known about the mechanisms of action of different statins or the effects of these statins in gynaecological malignancies. The apoptotic potential of two lipophilic statins (lovastatin and simvastatin) and one hydrophilic statin (pravastatin) was assessed in cancer cell lines (ovarian, endometrial and cervical) and primary cultured cancerous and normal tissues. Cell viability was studied by MTS assays and apoptosis was confirmed by Western blotting of PARP and flow cytometry. The expressions of key apoptotic cascade proteins were analysed. Our results demonstrate that both lovastatin and simvastatin, but not pravastatin, selectively induced cell death in dose- and time-dependent manner in ovarian, endometrial and cervical cancers. Little or no toxicity was observed with any statin on normal cells. Lipophilic statins induced activation of caspase-8 and -9; BID cleavage, cytochrome C release and PARP cleavage. Statin-sensitive cancers expressed high levels of HMG-CoA reductase compared with resistant cultures. The effect of lipophilic statins was dependent on inhibition of enzymatic activity of HMG-CoA reductase since mevalonate pre-incubation almost completely abrogated the apoptotic effect. Moreover, the apoptotic effect involved the inhibition of synthesis of geranylgeranyl pyrophosphate rather than farnesyl pyrophosphate. In conclusion, lipophilic but not hydrophilic statins induce cell death through activation of extrinsic and intrinsic apoptotic cascades in cancerous cells from the human female genital tract, which express high levels of HMG-CoA reductase. These results promote further investigation in the use of lipophilic statins as anticancer agents in gynaecological malignancies.

[Serous peritoneal papillary tumor of low malignancy potential. Report of a case]. / Tumor papilar peritoneal seroso de bajo potencial maligno. Comunicación de un caso.

Papillary serous carcinoma with low malignant potential, similar to those described in the ovary, can also originate in the peritoneum. Characteristically they show peritoneal spread without involvement of the ovary and, if present, it corresponds to a superficial implant similar to those seen in the rest of the peritoneal cavity. Histologically they correspond to a low malignant potential tumor; they are slow growing and have good prognosis. They are common in young women, usually they present few symptoms and are frequently discovered during other surgical procedures. The treatment is surgical and it can be conservative in cases of women who want to preserve their fertility, without coadjuvant therapy. We report a 34 years old woman with a primary peritoneal serous carcinoma with low malignant potential and discuss its management.

[Frozen-section biopsy in ovarian neoplasm diagnosis: diagnostic correlation according to diameter and weight in tumors of epithelial origin]. / Biopsia rápida por congelación en el diagnóstico de tumores de ovario: correlación diagnóstica según diámetro y peso en tumores de origen epitelial.

BACKGROUND: Adequate management and treatment of ovarian carcinoma requires a complete surgical staging supported by frozen-section examination. To achieve this goal it is necessary a high level of accuracy. AIM: To evaluate the accuracy of frozen-sections in ovarian carcinoma considering the influence of tumor diameter and weight. PATIENTS AND METHODS: Retrospective study of frozen-sections performed in patients with ovarian tumors who underwent surgery. Frozen- and permanent-sections were divided into three categories (benign, borderline and malignant) and stratified by diameter (< 10 cm, 10 to 20 cm, > 20 cm) and weight (< 700 g, 700 a 1400 g, > 1400 g). The diagnostic correlation, sensitivity, specificity, predictive values and accuracy of each frozen-section diagnosis were determined. RESULTS: Eight hundred forty two ovarian tumors that underwent frozen-sections between January 1988 and October 1998 were studied. Final diagnosis was 86.7% benign, 2.7% low malignant potential (LMP) and 10.6% malignant. The diagnosis correlation between frozen- and permanent-sections was 98.2%. Misdiagnosis was in epithelial ovarian tumors, particularly in LMP tumors. Sensitivity, specificity, positive- and negative-predictive values and accuracy of the four hundred eighty nine epithelial tumor were 92.6%, 99.2%, 96.7%, 98.2% and 97.9%, respectively. Diagnostic correlation was higher in epithelial ovarian tumors with diameter < 10 cm (98.2% v/s 93.8%) and weight < 700 g (96.9% v/s 88.9%). CONCLUSIONS: Diagnostic correlation with permanent-section examination, sensitivity, specificity and predictive values of frozen-sections are high in ovarian tumors. Accurate diagnosis at frozen sections of epithelial ovarian tumors with diameter > 10 cm or weight > 700 g (particularly in LMP tumors) is difficult because of the extensive sampling required. Frozen-sections diagnoses are important to determine the type and extent of surgery performed at the initial operation.