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Ovarian cancer (OVCA) arises from three cellular origins, namely surface epithelial cells, germ cells, and stromal cells. More than 85% of OVCAs are EOCs (epithelial ovarian carcinomas), which are the most lethal gynecological malignancies. Cancer stem/progenitor cells (CSPCs) are considered to be cancer promoters due to their capacity for unlimited self-renewal and drug resistance. Androgen receptor (AR) belongs to the nuclear receptor superfamily and can be activated through binding to its ligand androgens. Studies have reported an association between AR expression and EOC carcinogenesis, and AR is suggested to be involved in proliferation, migration/invasion, and stemness. In addition, alternative AR activating signals, including both ligand-dependent and ligand-independent, are involved in OVCA progression. Although some clinical trials have previously been conducted to evaluate the effects of anti-androgens in EOC, no significant results have been reported. In contrast, experimental studies evaluating the effects of anti-androgen or anti-AR reagents in AR-expressing EOC models have demonstrated positive results for suppressing disease progression. Since AR is involved in complex signaling pathways and may be expressed at various levels in OVCA, the aim of this article was to provide an overview of current studies and perspectives regarding the relevance of androgen/AR roles in OVCA.

Background While the Warburg effect links glycolysis to de novo lipid synthesis in carcinogenesis, the roles of lipids in cancer prognosis remain elusive. Here, a multi-omics approach was conducted in a cohort of hepatocellular carcinoma (HCC) to elucidate the role of lipid metabolites as prognostic markers. Methods Ninety-eight HCC patients were recruited between 2011 and 2013. Their specimens were subjected to transcriptomic and lipidomic profiling. The resulting data were then analyzed using strategic bioinformatics approaches to identify associations with HCC prognosis. Subsequently, lipid-related pathways implicated in these analyses were verified using cellular and molecular approaches. Results Our findings indicate that lipidomic profiling is a potential prognostic marker for HCC. Specifically, higher levels of ether-lipids were significantly associated with poor survival and adverse clinical features, such as advanced TNM stage and metastasis. Analysis of transcriptomic patterns within patient groups defined by lipidomic profiles revealed that ether-lipid abundance inversely correlated with PPAR signaling but positively correlated with the expression of metastasis-associated gene clusters (e.g., genes involved in ECM remodeling, adhesion, and migration). Functional studies verified that ether-lipids enhance cell mobility. Consistent with the proposed mechanism, treatment with a PPARα agonist reduced ether-lipid accumulation and cell mobility. Therefore, we delineated an axis whereby PPARα downregulation leads to ether-lipid accumulation, subsequently promoting cell mobility. Mechanistically, we propose that deficient PPARα-mediated lipophagy results in cellular ether-lipid accumulation. These lipids, in turn, promote cell mobility via Transient Receptor Potential Vanilloid 2 (TRPV2)-mediated cytoskeletal rearrangement. conclusion This study identifies lipidome patterns as a risk factor for patient prognosis. Mechanistically, deficient PPARα-mediated lipophagy leads to the accumulation of ether-lipids within cancer cells, which in turn promotes cell mobility via calcium-dependent, TRPV2 channel-mediated cytoskeletal rearrangement.

Introduction Gastric cancer (GCa) is a malignancy with few effective treatments. Ursolic acid (UA), a bioactive triterpenoid enriched in Hedyotis diffusa Willd, known to suppress GCa without identified target. CYP19A1 (cytochrome P450 family 19A1; also known as aromatase, Ar) was correlated to GCa prognosis. Relatedly, Ar silencers, which halt the expression of Ar exhibited anti‐GCa effects in experimental models, are currently being investigated. Method The docking simulation score of UA was compared with Ar inhibitors, e.g., letrozole, exemestane, in Ar protein crystallization. Hedyotis diffusa Willd ethanol extract, UA, or 5‐fluracil were applied onto AGS, SC‐M1, MKN45 GCa cells for cancer inhibition tests. Immunoblot for measuring gene expressions upon drug treatments, or gene knockdown/overexpression. Treatments were also applied in a MKN45 implantation tumor model. A web‐based GCa cohort for Ar expression association with prognosis was performed. Result The ethanol extracts of Hedyotis diffusa Willd, enrich with UA, exhibited cytotoxic activity against GCa cells. Molecular docking simulations with the 3D Ar structure revealed an excellent fitting score for UA. UA increase cytotoxic, and suppressed colony, in addition to its Ar silencing capacity. Moreover, UA synergistically facilitated 5‐FU, (a standard GCa treatment) regimen in vitro. Consistent with those results, adding estradiol did not reverse the cancer‐suppressing effects of UA, which confirmed UA acts as an Ar silencer. Furthermore, UA exhibited tumor‐suppressing index (TSI) score of 90% over a 6‐week treatment term when used for single dosing in xenograft tumor model. In the clinical setting, Ar expression was found to be higher in GCa tumors than normal parental tissue from the TCGA (The Cancer Genome Atlas) cohort, while high Ar expression associated with poor prognosis. Together, the results indicate UA could be used to treat GCa by silencing Ar expression in GCa. Hedyotis diffusa Willd ethanol extract could be an functional food supplements. Ursolic acid (UA) has been discovered to inhibit gastric cancer without identified target. This article defined UA as is aromatase silencer, of which turn off aromatase expression rather than suppressing enzymatic activity.

Current knowledge regarding mechanisms of carcinogenesis in human beings centres around the accumulation of genetic instability, amplified cellular signalling, disturbed cellular energy metabolism and microenvironmental regulation governed by complicated cell–cell interactions. In this article, we provide an alternative view of cancer biology. We propose that cancer behaves as a systemic dictator that interacts with tissues throughout the body to control their metabolism and eventually homeostasis. The mechanism of development of this endocrine organ–like tumour (EOLT) tissue might be the driving force for cancer progression. Here, we review the literature that led to the development of this hypothesis. The EOLT phenotype can be defined as a tumour that alters systemic homeostasis. The literature indicates that the EOLT phenotype is present throughout cancer progression. The feedback mechanism that governs the interaction between tumours and various organs is unknown. We believe that investigating the mechanism of EOLT development may advance the current knowledge of regulation within the tumour macroenvironment and consequently lead to new diagnostic methods and therapy.

Multicellular tumor spheroids and tumoroids are considered ideal in vitro models that reflect the features of the tumor microenvironment. Biomimetic components resembling the extracellular matrix form scaffolds to provide structure to 3-dimensional (3D) culture systems, supporting the growth of both spheroids and tumoroids. Although Matrigel has long been used to support 3D culture systems, batch variations, component complexity, and the use of components derived from tumors are complicating factors. To address these issues, we developed the ACD 3D culture system to provide better control and consistency. We evaluated spheroid and tumoroid formation using the ACD 3D culture system, including the assessment of cell viability and cancer marker expression. Under ACD 3D culture conditions, spheroids derived from cancer cell lines exhibited cancer stem cell characteristics, including a sphere-forming size and the expression of stem cell marker genes. The ACD 3D culture system was also able to support patient-derived primary cells and organoid cell cultures, displaying adequate cell growth, appropriate morphology, and resistance to oxaliplatin treatment. These spheroids could also be used for drug screening purposes. In conclusion, the ACD 3D culture system represents an efficient tool for basic cancer research and therapeutic development.

CYP19A1/aromatase (Ar) is a prognostic biomarker of gastric cancer (GCa). Ar is a critical enzyme for converting androstenedione to oestradiol in the steroidogenesis cascade. For decades, Ar has been targeted with Ar inhibitors (ARIs) in gynaecologic malignancies; however, it is unexplored in GCa. A single‐cohort tissue microarray examination was conducted to study the association between Ar expression and disease outcome in Asian patients with GCa. The results revealed that Ar was a prognostic promoter. Bioinformatics analyses conducted on a Caucasian‐based cDNA microarray databank showed Ar to be positively associated with GCa prognosis for multiple clinical modalities, including surgery, 5‐Fluorouracil (5‐FU) for adjuvant chemotherapy, or HER2 positivity. These findings imply that targeting Ar expression exhibits a potential for fulfilling unmet medical needs. Hence, Ar‐targeting compounds were tested, and the results showed that exemestane exhibited superior cancer‐suppressing efficacy to other ARIs. In addition, exemestane down‐regulated Ar expression. Ablating Ar abundance with short hairpin (sh)Ar could also suppress GCa cell growth, and adding 5‐FU could facilitate this effect. Notably, adding oestradiol could not prevent exemestane or shAr effects, implicating a nonenzymatic mechanism of Ar in cancer growth. Regarding translational research, treatment with exemestane alone exhibited tumour suppression efficacy in a dose‐dependent manner. Combining subminimal doses of 5‐FU and exemestane exerted an excellent tumour suppression effect without influencing bodyweight. This study validated the therapeutic potentials of exemestane in GCa. Combination of metronomic 5‐FU and exemestane for GCa therapy is recommended.

Small molecule compounds targeting multiple kinases involved in neoangiogenesis have shown survival benefits in patients with unresectable hepatocellular carcinoma (HCC). Nonetheless, despite the beneficial effects of multikinase inhibitors (MKIs), a lack of boosting adjuvant limits their objective response rate. Lipid conjugates have been used to improve delivery efficacy or pharmaceutical benefits for decades. However, the feasibility of utilizing lipid-drug conjugates (LDCs) in HCC regimens remains untested. In this study, oral feeding of linoleate-fluorescein isothiocyanate conjugates showed that the compound was well distributed in a spontaneous HCC mouse model. Therefore, a rationale design was developed for chemically synthesizing a linoleate-pazopanib conjugate (LAPC). The LAPC showed a significantly improved cytotoxicity compared to the parental drug pazopanib. Pazopanib’s angiogenic suppressing signals were not observed in LAPC-treated HCC cells, potentially suggesting an altered mechanism of action (MOA). In an efficacy trial comparing placebo, oral pazopanib, and LAPC treatments in the hepatitis B virus transgene-related spontaneous HCC mouse model (HBVtg-HCC), the LAPC treatment demonstrated superior tumor ablating capacity in comparison to both placebo and pazopanib treatments, without any discernible systemic toxicity. The LAPC exposure is associated with an apoptosis marker (Terminal deoxynucleotidyl transferase dUTP nick end labeling [TUNEL]) and an enhanced ferroptosis (glutathione peroxidase 4 [GPX4]) potential in HBVtg-HCC tumors. Therefore, the LAPC showed excellent HCC ablative efficacy with altered MOA. The molecular mechanisms of the LAPC and LDCs for HCC therapeutics are of great academic interest. Further comprehensive preclinical trials (e.g., chemical-manufacture-control, toxicity, distribution, and pharmacokinetics/pharmacodynamics) are expected.

Methadone maintenance treatment (MMT) is the major tapering therapy for morphine addictive patients. There have gender differences reported in response to MMT. This study discovered that the estrogen‐response element single nucleotide polymorphism (ERE‐SNP; rs16974799, C/T) of cytochrome 2B6 gene (cyp2b6; methadone catabolic enzyme) responded differently to MMT dosing. Oestradiol was associated with high MMT dosing, high enantiomer (R‐ or S‐) of 2‐ethylidene‐1,5‐dimethyl‐3,3‐dipheny‐pyrrolidine (EDDP; methadone metabolite) to methadone ratio and increased drug‐seeking behaviour, implicating oestradiol‐CYP‐EDDP/methadone axis decreasing MMT efficacy. In mouse model, oestrogen mitigates methadone antinociceptive response, facilitates methadone catabolism and up‐regulates methadone‐associated metabolizing enzymes. Oestrogen also ablates chronic methadone administration‐induced rewarding response. Mechanism dissection revealed the CC genotype of CYP2B6‐ERE‐SNP exerts higher ERE sequence alignment score, higher estrogenic response as compared to TT genotype. At last, preclinical study via targeting estrogen signal that tamoxifen (TMX; selective estrogen receptor modulator, SERM) could facilitate the tolerance phase rewarding response of methadone. Strikingly, TMX also reduces tapering/abstinence phases methadone liability in mice. In conclusion, this study demonstrates altering methadone metabolism through targeting estrogen signals might be able to free morphine addictive patients from the addiction of opioid replacement therapy. Therefore, the add‐on therapy clinical trial introducing SERM in MMT regimen is suggested.

Although the heterogeneity of high-density lipoprotein-cholesterol (HDL-c) composition is associated with atherosclerotic cardiovascular risk, the link between electronegative subfractions of HDL-c and atherosclerosis in rheumatoid arthritis (RA) remains unknown. We examined the association of the percentage of the most electronegative subfraction of HDL-c (H5%) and RA-related atherosclerosis. Using anion-exchange purification/fast-protein liquid chromatography, we demonstrated significantly higher H5% in patients (median, 7.2%) than HC (2.8%, p < 0.005). Multivariable regression analysis revealed H5% as a significant predictor for subclinical atherosclerosis. We subsequently explored atherogenic role of H5 using cell-based assay. The results showed significantly higher levels of IL-1β and IL-8 mRNA in H5-treated (mean ± SD, 4.45 ± 1.22 folds, 6.02 ± 1.43-folds, respectively) than H1-treated monocytes (0.89 ± 0.18-folds, 1.03 ± 0.26-folds, respectively, both p < 0.001). In macrophages, H5 upregulated the mRNA and protein expression of IL-1β and IL-8 in a dose-dependent manner, and their expression levels were significantly higher than H1-treated macrophages (all p < 0.001). H5 induced more foam cell formation compared with H1-treated macrophages (p < 0.005). In addition, H5 has significantly lower cholesterol efflux capacity than H1 (p < 0.005). The results of nanoLC-MS/MS approach reveal that the best discriminator between high-H5% and normal-H5% is Apo(a), the main constituent of Lp(a). Moreover, Lp(a) level is a significant predictor for high-H5%. These observations suggest that H5 is involved in RA-related atherosclerosis.

Cholesterol affects cancer progression, and acetyl‐CoA is the primary cholesterogenesis substrate. The previous work has defined cholesterol bioflux via lipoprotein/receptor route is the gastric cancer (GCa) prognosis biosignature. The prognosis importance of acetyl‐CoA to cholesterogenesis (mevalonate pathway) in GCa is yet to be defined. Using Kaplan–Meier Plotter web‐based gene survival analyzer and The Cancer Genome Atlas (TCGA)‐database analyzed with DBdriver.v2 platform, we revealed acetyl‐CoA production and the mevalonate pathway are associated with GCa prognosis. We found mitochondrial‐derived acetyl‐CoA contributing enzymes (acyl‐coA synthetase super‐family 3; ACSS3) is the GCa progression confounder. Interestingly, it is not HMGCR (the committee enzyme of mevalonate pathway), but lower mevalonate pathway enzymes (e.g., MVK, LSS, DHCR14A1, SC4MOL, HSD17B7, SC5D) promote GCa patients 5‐years overall survival in a differential level. Advanced analyses found ACSS3 is prognosis biosignatures for multiple GCa disease conditions. This report uncovered a higher expression of ACSS3 in tumor comparing to normal parental lesions, which implicates a targeting value for GCa therapy. While knockdown ACSS3 could suppress growth and invasion of GCa cells, of which even more impactful under starvation condition. This is the first report, surprisingly, revealed ACSS3 as important cancer prognosis biomarker. Targeting ACSS3 could be a novel therapeutic strategy for cancer, in this case, GCa. The cholesterogenic committing step enzyme (HMGCR) is not important in GCa patients, which explain the failure of statins in GCa clinical trials. However, the mitochondrial acetyl‐CoA producer (ACSS3), and lower‐mevalonate lipidomes are biosignatures for GCa progression. Interfering ACSS3 expression could almost abolished GCa cell growth under starvation stress. This study suggesting a targeting value of ACSS3 for GCa therapy.