Browsing by Author "Branes, Jorge"

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    Body Composition and Metabolic Dysfunction Really Matter for the Achievement of Better Outcomes in High-Grade Serous Ovarian Cancer
    (2023) Cuello, Mauricio A.; Gomez, Fernan; Wichmann, Ignacio; Suarez, Felipe; Kato, Sumie; Orlandini, Elisa; Branes, Jorge; Ibanez, Carolina
    Simple Summary Current evidence supports a negative impact of obesity-associated metabolic dysfunction in several cancers. However, the evidence is still controversial regarding high-grade serous ovarian cancer (HGSOC). In this study, we demonstrated that body composition, particularly the presence of high visceral adiposity (with or without sarcopenia) estimated by aCT scan, is associated with worse survival in HGSOC. As a molecular proxy to CT-scan-based assessment of nutritional status and to identify putative biomarkers of metabolic disorders, we evaluated the expression levels of a set of 425 obesity- and lipid-metabolism-disorder-related genes across 273 tumor samples. We identified two obesity- and lipid-metabolism-related clusters with marked differences in survival and that were associated with molecular features predictive of immune checkpoint blocker response. Finally, we assessed the impact of nutritional/pharmacologic interventions affecting body composition/lipid metabolism on patient survival. We observed that the reduction of visceral adiposity, the increase of muscle mass, and the use of metformin/statins improve survival. Although obesity-associated metabolic disorders have a negative impact on various cancers, such evidence remains controversial for ovarian cancer. Here, we aimed to evaluate the impact of body composition (BC) and metabolism disorders on outcomes in high-grade serous ovarian cancer (HGSOC). Methods: We analyzed clinical/genomic data from two cohorts (PUC n = 123/TCGA-OV n = 415). BC was estimated using the measurement of adiposity/muscle mass by a CT scan. A list of 425 genes linked to obesity/lipid metabolism was used to cluster patients using non-negative matrix factorization. Differential expression, gene set enrichment analyses, and Ecotyper were performed. Survival curves and Cox-regression models were also built-up. Results: We identified four BC types and two clusters that, unlike BMI, effectively correlate with survival. High adiposity and sarcopenia were associated with worse outcomes. We also found that recovery of a normal BC and drug interventions to correct metabolism disorders had a positive impact on outcomes. Additionally, we showed that immune-cell-depleted microenvironments predominate in HGSOC, which was more evident among the BC types and the obesity/lipid metabolism cluster with worse prognosis. Conclusions: We have demonstrated the relevance of BC and metabolism disorders as determinants of outcomes in HGSOC. We have shone a spotlight on the relevance of incorporating corrective measures addressing these disorders to obtain better results.
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    Leptin stimulates migration and invasion and maintains cancer stem-like properties in ovarian cancer cells: an explanation for poor outcomes in obese women
    (2015) Kato, Sumie; Abarzua-Catalan, Lorena; Trigo, Cesar; Delpiano, Ana; Sanhueza, Cristobal; Garcia, Karen; Ibanez, Carolina; Hormazabal, Katherine; Diaz, Daniela; Branes, Jorge; Castellon, Enrique; Bravo, Erasmo; Owen, Gareth; Cuello, Mauricio
    The evidence linking obesity with ovarian cancer remains controversial. Leptin is expressed at higher levels in obese women and stimulates cell migration in other epithelial cancers. Here, we explored the clinical impact of overweight/obesity on patient prognosis and leptin's effects on the metastatic potential of ovarian cancer cells. We assessed clinical outcomes in 70 ovarian cancer patients (33 healthy weight and 37 overweight) that were validated with an external cohort from The Cancer Genome Atlas (TCGA) database. Progression-free and overall survival rates were significantly decreased in overweight patients. Similarly, a worse overall survival rate was found in TCGA patients expressing higher leptin/OB-Rb levels. We explored serum and ascites leptin levels and OB-Rb expression in our cohort. Serum and ascites leptin levels were higher in overweight patients experiencing worse survival. OB-Rb was more highly expressed in ascites and metastases than in primary tumors. Leptin exposure increased cancer cell migration/invasion through leptin-mediated activation of JAK/STAT3, PI3/AKT and RhoA/ROCK and promoted new lamellipodial, stress-fiber and focal adhesion formation. Leptin also contributed to the maintenance of stemness and the mesenchymal phenotype in ovarian cancer cells. Our findings demonstrate that leptin stimulated ovarian cancer cell migration and invasion, offering a potential explanation for the poor prognosis among obese women.
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    Pelvic intravenous leiomyomatosis with intracardiac extension. Report of two cases
    (SOC MEDICA SANTIAGO, 2012) Mertens, Renato; Valdes, Francisco; Munoz, Cecilia; Irarrazaval, Manuel; Branes, Jorge; Riquelme, Carlos; Marine, Leopoldo; Bergoeing, Michel; Kraemer, Albrecht
    Intravenous leiomyomatosis with extension into the heart is an infrequent entity described in 1907. Its clinical presentation is non-specific, although cardiac symptoms predominate. Diagnosis is based on clinical findings and appropriate imaging. We report two females, aged 35 and 51 years. One of them presented with a pelvic mass and dyspnea, the other patient had severe cardiac failure on admission. Computed axial tomography scan allowed an accurate preoperative diagnosis on both patients. Successful one stage resection of the tumor was performed under cardiopulmonary bypass. Both patients are asymptomatic on follow up at 6 months and 25 years. (Rev Med Chile 2012; 140: 906-909).
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    The oestrogen metabolite 2-methoxyoestradiol alone or in combination with tumour necrosis factor-related apoptosis-inducing ligand mediates apoptosis in cancerous but not healthy cells of the human endometrium
    (BIOSCIENTIFICA LTD, 2007) Kato, Sumie; Sadarangani, Anil; Lange, Soledad; Villalon, Manuel; Branes, Jorge; Brosens, Jan J.; Owen, Gareth I.; Cuello, Mauricio
    Cancers of the reproductive tract account for 12% of all malignancies in women. As previous studies have shown that oestrogen metabolites can cause apoptosis, we characterised the effect of oestrogen and oestrogen metabolites on non-cancerous and cancerous human endometrial cells. Herein, we demonstrate that 2-methoxyoestradiol (2ME), but not 17 beta-oestradiol, induces apoptosis in cancer cell lines and primary cultured tumours; of endometrial origin. In contrast, 2ME had no effect on cell viability of corresponding normal tissue. This ability of 2ME to induce apoptosis does not require oestrogen receptor activation, but is associated with increased entry into the G2/M phases of the cell cycle and the activation of both the intrinsic and the extrinsic apoptotic pathways. The selective behaviour of 2ME on cancerous as opposed to normal tissue may be due to a reduction in 17 beta -hydroxysteroid dehydrogenase type 11 levels in cancer cells and to a differential down-regulation of superoxide dismutase. Furthermore, we demonstrate that pre-treatment with 2ME enhances the sensitivity of reproductive tract cancer cells to the apoptotic drug tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), without the loss in cell viability to normal cells incurred by currently chemotherapeutic drugs. In conclusion, 2ME, alone or in combination with TRAIL, may be an effective treatment for cancers of uterine origin with minimal toxicity to corresponding healthy female reproductive tissue.