Malignant ascites constitute a unique tumor microenvironment providing a physical structure for the accumulation of cellular and acellular components. Ascites is initiated and maintained by physical ...and biological factors resulting from underlying disease and forms an ecosystem that contributes to disease progression. It has been demonstrated that the cellular contents and the molecular signatures of ascites change continuously during the course of a disease. Over the past decade, increasing attention has been given to the characterization of components of ascites and their role in the progression of ovarian cancer, the most malignant gynecologic cancer in women. This review will discuss the role of ascites in disease progression, in terms of modulating cancer cell behavior and contributing to tumor heterogeneity.
The ascites of cancer provide a physical structure for the accumulation of cellular and acellular components. The resulting tumor microenvironment contributes to the disease progression and tumor heterogeneity, as well as poor prognosis in ovarian cancer.
Mitochondria as crucial organelles regulate cellular energy generation, calcium and redox homeostasis, and apoptosis. To perform the cellular functions effectively, mitochondria continuously change ...their structure and morphology through protein machineries controlling fission and fusion process (mitochondrial dynamics). Traditionally, many researches had focused on the interaction of mitochondrial dynamics and apoptosis. However, recent studies are reporting the alteration of mitochondrial dynamics in human diseases including many types of cancers. Considering that cancers maintain a high level of reactive oxygen species (ROS), mitochondrial dynamics can be influenced by oxidative stress. In this review, we will discuss the alteration of mitochondrial dynamics by ROS and its effect on metastasis and chemoresistance in cancers.
Abstract
While the precise diagnosis of early stage epiretinal membrane (ERM) at the time of cataract surgery and evaluation of risk factors for development or progression of ERM after cataract ...surgery is increasingly important, there is only limited information. In the present study, we evaluated the risk factors for onset or progression of ERM on spectral domain optical coherence tomography (SD-OCT) after cataract surgery. The univariate analysis showed that eyes with partial posterior vitreous detachment (PVD;
p
< 0.001), hyper-reflective foci (HF) on the inner retinal surface (
p
< 0.001), vitreoschisis (
p
= 0.014), and discrete margin of different retinal reflectivity (DMDRR;
p
= 0.007) on ultra-widefield fundus photography (UWF-FP) had significant risk for the onset or progression of ERM after cataract surgery. The multivariate analysis showed that partial PVD (HR, 3.743; 95% confidence interval CI, 1.956–7.162;
p
< 0.001), HF (HR, 2.330; 95% CI, 1.281–4.239;
p
= 0.006), and DMDRR on UWF-FP (HR, 3.392; 95% CI, 1.522–7.558;
p
= 0.003) were the independent risk factors for the onset or progression of ERM after cataract surgery after adjustment for other confounding factors. Our study shows that the onset or progression of ERM after cataract surgery depends on an abnormal vitreoretinal interface (VRI) represented by partial PVD, HF on SD-OCT, and DMDRR on UWF-FP, not on age, axial length, or presence of ERM at the time of surgery. A meticulous funduscopic evaluation of the VRI would help to predict the ERM risk before cataract surgery.
Zinc oxide nanoparticles (ZnO NPs) are widely used in versatile applications, from high technology to household products. While numerous studies have examined the toxic gene profile of ZnO NPs across ...various tissues, the specific lipid species associated with adverse effects and potential biomarkers remain elusive. In this study, we conducted a liquid chromatography-mass spectrometry based lipidomics analysis to uncover potential lipid biomarkers in human kidney cells following treatment with ZnO NPs. Furthermore, we employed lipid pathway enrichment analysis (LIPEA) to elucidate altered lipid-related signaling pathways. Our results demonstrate that ZnO NPs induce cytotoxicity in renal epithelial cells and modulate lipid species; we identified 64 lipids with a fold change (FC) > 2 and
< 0.01 with corrected
< 0.05 in HK2 cells post-treatment with ZnO NPs. Notably, the altered lipids between control HK2 cells and those treated with ZnO NPs were associated with the sphingolipid, autophagy, and glycerophospholipid pathways. This study unveils novel potential lipid biomarkers of ZnO NP nanotoxicity, representing the first lipidomic profiling of ZnO NPs in human renal epithelial cells.
The prevalence of epiretinal membrane (ERM) and associated factors in the phakic eyes have not been fully elucidated yet. This cross-sectional study included 2,354 phakic eyes without retinal ...diseases or surgical history. Ocular parameters, such as uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), spherical equivalent (SE), intraocular pressure (IOP), white-to-white corneal diameter (WTW), mean keratometric value (Km) of total corneal refractive power at 4-mm diameter (TCRP4), astigmatism of TCRP4, total corneal irregular astigmatism (TCIA), pupil diameter, axial length (AXL), anterior chamber depth (ACD), lens thickness (LT), and posterior vitreous detachment (PVD) were compared between ERM group and control group. Additionally, an age-matched control group was selected by individual matching and compared with the ERM group to eliminate the confounders. Multiple logistic regression analysis was performed to evaluate the factors associated with the presence of ERM. Among 2,354 eyes, 429 eyes (18.2%) had ERM based on spectral-domain optical coherence tomography. The ERM group showed higher prevalence of PVD, worse CDVA, higher astigmatism of TCRP4, higher TCIA, smaller pupil size, longer AXL, and thicker LT than control group (P < 0.001, P < 0.001, P = 0.011, P < 0.001, P = 0.023, P < 0.001, and P < 0.001, respectively). Only PVD, CDVA, SE, astigmatism of TCRP4, TCIA, and AXL maintained the significance when compared with the age-matched control group (P < 0.001, P = 0.026, P < 0.001, P = 0.001, P = 0.003, and P < 0.001, respectively). Multivariate logistic regression analysis showed that age, PVD, CDVA, and TCIA were independently associated with the presence of ERM (P < 0.001, P < 0.001, P = 0.011, and P = 0.002). The prevalence of ERM detected using SD-OCT was 18.2% in the middle aged phakic population. Eyes with TCIA, in addition to older age and PVD, were more likely to have ERM.
Pancreatic cancer is characterized by its high mortality rate and limited treatment options, often driven by oncogenic RAS mutations. In this study, we investigated the metabolomic profiles of ...pancreatic cancer cells based on their KRAS genetic status. Utilizing both KRAS-wildtype BxPC3 and KRAS-mutant PANC1 cell lines, we identified 195 metabolites differentially altered by KRAS status through untargeted metabolomics. Principal component analysis and hierarchical condition trees revealed distinct separation between KRAS-wildtype and KRAS-mutant cells. Metabolite set enrichment analysis highlighted significant pathways such as homocysteine degradation and taurine and hypotaurine metabolism. Additionally, lipid enrichment analysis identified pathways including fatty acyl glycosides and sphingoid bases. Mapping of identified metabolites to KEGG pathways identified nine significant metabolic pathways associated with KRAS status, indicating diverse metabolic alterations in pancreatic cancer cells. Furthermore, we explored the impact of TRPML1 inhibition on the metabolomic profile of KRAS-mutant pancreatic cancer cells. TRPML1 inhibition using ML-SI1 significantly altered the metabolomic profile, leading to distinct separation between vehicle-treated and ML-SI1-treated PANC1 cells. Metabolite set enrichment analysis revealed enriched pathways such as arginine and proline metabolism, and mapping to KEGG pathways identified 17 significant metabolic pathways associated with TRPML1 inhibition. Interestingly, some metabolites identified in PANC1 compared to BxPC3 were oppositely regulated by TRPML1 inhibition, suggesting their potential as biomarkers for KRAS-mutant cancer cells. Overall, our findings shed light on the distinct metabolite changes induced by both KRAS status and TRPML1 inhibition in pancreatic cancer cells, providing insights into potential therapeutic targets and biomarkers for this deadly disease.
Obesity is recognized as a significant risk factor for ovarian cancer, with accumulating evidence highlighting its impact on disease progression and chemoresistance. This review synthesizes current ...research elucidating the link between obesity-induced lysosomal dysfunction and ovarian cancer chemoresistance. Epidemiological studies consistently demonstrate a positive correlation between body mass index (BMI) and ovarian cancer risk, attributed in part to the predilection of epithelial ovarian cancer cells for adipose tissue, particularly the omentum. Adipokines released from the omentum contribute to cancer-associated characteristics, including energy supply to cancer cells. Moreover, obesity-induced alterations in lysosomal function have been implicated in systemic inflammation and lipid metabolism dysregulation, further exacerbating cancer progression. Lysosomes play a crucial role in drug resistance, as evidenced by studies demonstrating their involvement in mediating resistance to chemotherapy in ovarian cancer cells. Recent findings suggest that pharmacological inhibition of lysosomal calcium channels sensitizes drug-resistant ovarian cancer cells to cisplatin treatment, highlighting the therapeutic potential of targeting lysosomal dysfunction in obesity-related chemoresistance. This review underscores the importance of understanding the multifaceted roles of lysosomes in obesity-related drug resistance and their implications for the development of targeted therapeutic interventions in ovarian cancer management.
The central hypothesis of cancer metabolism evolved from the cell-centric Warburg and reverse Warburg effects to the microenvironment-centric dynamic interplays between a variety of tumor stromal ...components and cancer cells.
Our group reported a significant association between hexokinase II overexpression and chemoresistance in ovarian cancer, suggesting that aerobic glycolysis in the so-called Warburg effect might contribute to cancer progression. However, a growing body of evidence indicates contradictory findings with regard to the Warburg effect, such as high mitochondrial activity in highly invasive tumors and low ATP contribution of glycolysis in ovarian cancer. As a solution for the dilemma of the Warburg effect, the “reverse Warburg effect” was proposed in which aerobic glycolysis might occur in the stromal compartment of the tumor rather than in the cancer cells, indicating that the glycolytic tumor stroma feed the cancer cells through a type of symbiotic relationship. The reverse Warburg effect acting on the relationship between cancer cells and cancer-associated fibroblasts has evolved into dynamic interplay between cancer cells and multiple tumor stromal compartments, including cancer-associated fibroblasts, the extracellular matrix, endothelial cells, mesenchymal stem cells, adipocytes, and tumor-associated macrophages. Peritoneal cavities including ascites and the omentum also form a unique environment that is highly receptive for carcinomatosis in the advanced stages of ovarian cancer. The complicated but ingeniously orchestrated stroma-mediated cancer metabolism in ovarian cancer provides great heterogeneity in tumors with chemoresistance, which makes the disease thus far difficult to cure by single stromal-targeting agents. This review will discuss the experimental and clinical evidence of the cross-talk between cancer cells and various components of tumor stroma in terms of heterogeneous chemoresistance with focal points for therapeutic intervention in ovarian cancer.
Epithelial ovarian cancer (EOC) is a silent but mostly lethal gynecologic malignancy. Most patients present with malignant ascites and peritoneal seeding at diagnosis. In the present study, we used a ...laser-aided isolation technique to investigate the clonal relationship between the primary tumor and tumor spheroids found in the malignant ascites of an EOC patient. Somatic alteration profiles of ovarian cancer-related genes were determined for eight spatially separated samples from primary ovarian tumor tissues and ten tumor spheroids from the malignant ascites using next-generation sequencing. We observed high levels of intra-tumor heterogeneity (ITH) in copy number alterations (CNAs) and single-nucleotide variants (SNVs) in the primary tumor and the tumor spheroids. As a result, we discovered that tumor cells in the primary tissues and the ascites were genetically different lineages. We categorized the CNAs and SNVs into clonal and subclonal alterations according to their distribution among the samples. Also, we identified focal amplifications and deletions in the analyzed samples. For SNVs, a total of 171 somatic mutations were observed, among which 66 were clonal mutations present in both the primary tumor and the ascites, and 61 and 44 of the SNVs were subclonal mutations present in only the primary tumor or the ascites, respectively. Based on the somatic alteration profiles, we constructed phylogenetic trees and inferred the evolutionary history of tumor cells in the patient. The phylogenetic trees constructed using the CNAs and SNVs showed that two branches of the tumor cells diverged early from an ancestral tumor clone during an early metastasis step in the peritoneal cavity. Our data support the monophyletic spread of tumor spheroids in malignant ascites.
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