Browsing by Author "Kato, Sumie"
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- ItemBody 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, CarolinaSimple 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.
- ItemLeptin 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, MauricioThe 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.
- ItemProgesterone promotes focal adhesion formation and migration in breast cancer cells through induction of protease-activated receptor-1(BIOSCIENTIFICA LTD, 2012) Diaz, Jorge; Aranda, Evelyn; Henriquez, Soledad; Quezada, Marisol; Espinoza, Estefania; Loreto Bravo, Maria; Oliva, Barbara; Lange, Soledad; Villalon, Manuel; Jones, Marius; Brosens, Jan J.; Kato, Sumie; Cuello, Mauricio A.; Knutson, Todd P.; Lange, Carol A.; Leyton, Lisette; Owen, Gareth I.Progesterone and progestins have been demonstrated to enhance breast cancer cell migration, although the mechanisms are still not fully understood. The protease-activated receptors (PARs) are a family of membrane receptors that are activated by serine proteases in the blood coagulation cascade. PAR1 (F2R) has been reported to be involved in cancer cell migration and overexpressed in breast cancer. We herein demonstrate that PAR1 mRNA and protein are upregulated by progesterone treatment of the breast cancer cell lines ZR-75 and T47D. This regulation is dependent on the progesterone receptor (PR) but does not require PR phosphorylation at serine 294 or the PR proline-rich region mPRO. The increase in PAR1 mRNA was transient, being present at 3 h and returning to basal levels at 18 h. The addition of a PAR1-activating peptide (aPAR1) to cells treated with progesterone resulted in an increase in focal adhesion (FA) formation as measured by the cellular levels of phosphorylated FA kinase. The combined but not individual treatment of progesterone and aPAR1 also markedly increased stress fiber formation and the migratory capacity of breast cancer cells. In agreement with in vitro findings, data mining from the Oncomine platform revealed that PAR1 expression was significantly upregulated in PR-positive breast tumors. Our observation that PAR1 expression and signal transduction are modulated by progesterone provides new insight into how the progestin component in hormone therapies increases the risk of breast cancer in postmenopausal women. Journal of Endocrinology (2012) 214, 165-175
- ItemProgesterone Utilizes Distinct Membrane Pools of Tissue Factor to Increase Coagulation and Invasion and These Effects are Inhibited by TFPI(WILEY, 2011) Henriquez, Soledad; Calderon, Claudia; Quezada, Marisol; Oliva, Barbara; Loreto Bravo, Maria; Aranda, Evelyn; Kato, Sumie; Cuello, Mauricio A.; Gutierrez, Jorge; Quest, Andrew F. G.; Owen, Gareth I.Tissue factor (TF) serving as the receptor for coagulation factor VII (FVII) initiates the extrinsic coagulation pathway. We previously demonstrated that progesterone increases TF, coagulation and invasion in breast cancer cell lines. Herein, we investigated if tissue factor pathway inhibitor (TFPI) could down-regulate progesterone-increased TF activity in these cells. Classically, TFPI redistributes TF-FVII-FX-TFPI in an inactive quaternary complex to membrane associated lipid raft regions. Herein, we demonstrate that TF increased by progesterone is localized to the heavy membrane fraction, despite progesterone-increased coagulation originating almost exclusively from lipid raft domains, where TF levels are extremely low. The progesterone increase in coagulation is not a rapid effect, but is progesterone receptor (PR) dependent and requires protein synthesis. Although a partial relocalization of TF occurs, TFPI does not require the redistribution to lipid rafts to inhibit coagulation or invasion. Inhibition by TFPI and anti-TF antibodies in lipid raft membrane fractions confirmed the dependence on TF for progesterone-mediated coagulation. Through the use of pathway inhibitors, we further demonstrate that the TF up-regulated by progesterone is not coupled to the progesterone increase in TF-mediated coagulation. However, the progesterone up-regulated TF protein may be involved in progesterone-mediated breast cancer cell invasion, which TFPI also inhibits. J. Cell. Physiol. 226: 3278-3285, 2011. (C) 2011 Wiley Periodicals, Inc.
- ItemRegulation of GLUT3 and glucose uptake by the cAMP signalling pathway in the breast cancer cell line ZR-75(2008) Meneses, Ana Maria; Medina, Rodolfo A.; Kato, Sumie; Pinto, Mauricio; Jaque, Maria Paz; Lizama, Isabel; Garcia, Maria De Los Angeles; Nualart, Francisco; Owen, Gareth I.Increased glucose uptake as a principal energy source is a requirement for the continued survival of tumour cells. Facilitative glucose transporter-1 (GLUT 1) and -3(GLUTS) have been previously shown to be present and regulated in breast cancer cells and are associated with poor patient prognosis. In cancer cells, the cAMP secondary messenger pathway is known to potentiate described glucose transporter activators and regulate cell fate. However, no regulation of the glucose transporters in breast cancer cells by cAMP has previously been examined. Herein, we determined in the well-characterized breast cancer cell line ZR-75, if the cAMP analogue 8-br-cAMP was capable of regulating GLUT I and GLUTS expression and thus glucose uptake. We demonstrated that 8-br-cAMP transiently up-regulates GLUTS mRNA levels. The use of actinomycin-D and the cloning of 1,200 by upstream of the human GLUTS promoter demonstrated that this regulation was transcriptional. Immunocytochemistry and Western blotting confirmed that the increase in mRNA was reflected by an increase in protein levels. No notable regulation of GLUT I in the presence of 8-br-cAMP was detected. Finally, we determined using the non-metabolizable glucose analogue 2-DOG if this up-regulation in GLUTS increased glucose uptake. We observed the presence of two uptake components, one corresponding to the Km of GLUT 1/4 and the other to GLUTS. A doubling in the uptake velocity was observed only at the Km corresponding to GLUTS. In conclusion, we demonstrate and characterize for the first time, an upregulation of GLUTS mRNA, protein and glucose uptake by the cAMP pathway in breast cancer cells.
- ItemThe 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, MauricioCancers 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.
- ItemTRAIL mediates apoptosis in cancerous but not normal primary cultured cells of the human reproductive tract (vol 12, pg 73, 2007)(SPRINGER, 2007) Sadarangani, Anil; Kato, Sumie; Espinoza, Natalia; Lange, Soledad; Llados, Carmen; Espinosa, Marisol; Villalon, Manuel; Lipkowitz, Stanley; Cuello, Mauricio; Owen, Gareth I.