Cancer & Metabolism最新文献

{"title":"The relationship between Stroma AReactive Invasion Front Areas (SARIFA), Warburg-subtype and survival: results from a large prospective series of colorectal cancer patients.","authors":"Kelly Offermans, Nic G Reitsam, Colinda C J M Simons, Bianca Grosser, Jessica Zimmermann, Heike I Grabsch, Bruno Märkl, Piet A van den Brandt","doi":"10.1186/s40170-024-00349-z","DOIUrl":"10.1186/s40170-024-00349-z","url":null,"abstract":"<p><strong>Background: </strong>Stroma AReactive Invasion Front Areas (SARIFA) is a recently identified haematoxylin & eosin (H&E)based histopathologic biomarker in gastrointestinal cancers, including colorectal cancer (CRC), defined as direct contact between tumour cells and adipocytes at the tumour invasion front. The current study aimed at validating the prognostic relevance of SARIFA in a large population-based CRC series as well as at investigating the relationship between SARIFA-status and previously established Warburg-subtypes, both surrogates of the metabolic state of the tumour cells.</p><p><strong>Methods: </strong>SARIFA-status (positive versus negative) was determined on H&E slides of 1,727 CRC specimens. Warburg-subtype (high versus moderate versus low) data was available from our previous study. The associations between SARIFA-status, Warburg-subtype, clinicopathological characteristics and CRC-specific as well as overall survival were investigated.</p><p><strong>Results: </strong>28.7% (n=496) CRC were SARIFA-positive. SARIFA-positivity was associated with more advanced disease stage, higher pT category, and more frequent lymph node involvement (all p<0.001). SARIFA-positivity was more common in Warburg-high CRC. 44.2% (n=219) of SARIFA-positive CRCs were Warburg-high compared to 22.8% (n=113) being Warburg-low and 33.1% (n=164) being Warburg-moderate (p<0.001). In multivariable-adjusted analysis, patients with SARIFA-positive CRCs had significantly poorer CRC-specific (HR_CRC-specific 1.65; 95% CI 1.41-1.93) and overall survival (HR_{overall survival} 1.46; 95% CI 1.28-1.67) independent of clinically known risk factors and independent of Warburg-subtype. Combining the SARIFA-status and the Warburg-subtype to a combination score (SARIFA-negative/Warburg-high versus SARIFA-positive/Warburg-low versus SARIFA-positive/Warburg-high, and so on) did not improve the survival prediction compared to the use of SARIFA-status alone (SARIFA-negative + Warburg-high: HR_CRC-specific 1.08; 95% CI 0.84-1.38; SARIFA-positive + Warburg-low: HR_CRC-specific 1.79; 95% CI 1.32-2.41; SARIFA-positive + Warburg-high: HR_CRC-specific 1.58; 95% CI 1.23-2.04).</p><p><strong>Conclusions: </strong>Our current study is the by far largest external validation of SARIFA-positivity as a novel independent negative prognostic H&E-based biomarker in CRC. In addition, our study shows that SARIFA-positivity is associated with the Warburg-high subtype. Further research is warranted to provide a more mechanistic understanding of the underlying tumour biology. Based on our data, we conclude SARIFA-status should be implemented in pathologic routine practice to stratify CRC patients.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"12 1","pages":"21"},"PeriodicalIF":6.0,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11241902/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141589649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Subclinical dose irradiation triggers human breast cancer migration via mitochondrial reactive oxygen species.","authors":"Justin D Rondeau, Justine A Van de Velde, Yasmine Bouidida, Pierre Sonveaux","doi":"10.1186/s40170-024-00347-1","DOIUrl":"10.1186/s40170-024-00347-1","url":null,"abstract":"<p><strong>Background: </strong>Despite technological advances in radiotherapy, cancer cells at the tumor margin and in diffusive infiltrates can receive subcytotoxic doses of photons. Even if only a minority of cancer cells are concerned, phenotypic consequences could be important considering that mitochondrial DNA (mtDNA) is a primary target of radiation and that damage to mtDNA can persist. In turn, mitochondrial dysfunction associated with enhanced mitochondrial ROS (mtROS) production could promote cancer cell migration out of the irradiation field in a natural attempt to escape therapy. In this study, using MCF7 and MDA-MB-231 human breast cancer cells as models, we aimed to elucidate the molecular mechanisms supporting a mitochondrial contribution to cancer cell migration induced by subclinical doses of irradiation (< 2 Gy).</p><p><strong>Methods: </strong>Mitochondrial dysfunction was tested using mtDNA multiplex PCR, oximetry, and ROS-sensitive fluorescent reporters. Migration was tested in transwells 48 h after irradiation in the presence or absence of inhibitors targeting specific ROS or downstream effectors. Among tested inhibitors, we designed a mitochondria-targeted version of human catalase (mtCAT) to selectively inactivate mitochondrial H₂O₂.</p><p><strong>Results: </strong>Photon irradiation at subclinical doses (0.5 Gy for MCF7 and 0.125 Gy for MDA-MB-231 cells) sequentially affected mtDNA levels and/or integrity, increased mtROS production, increased MAP2K1/MEK1 gene expression, activated ROS-sensitive transcription factors NF-κB and AP1 and stimulated breast cancer cell migration. Targeting mtROS pharmacologically by MitoQ or genetically by mtCAT expression mitigated migration induced by a subclinical dose of irradiation.</p><p><strong>Conclusion: </strong>Subclinical doses of photon irradiation promote human breast cancer migration, which can be countered by selectively targeting mtROS.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"12 1","pages":"20"},"PeriodicalIF":6.0,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11229245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141558155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-acting Erwinia chrysanthemi, Pegcrisantaspase, induces alternate amino acid biosynthetic pathways in a preclinical model of pancreatic ductal adenocarcinoma.","authors":"Dominique Bollino, Kanwal Hameed, Anusha Bhat, Arveen Zarrabi, Andrea Casildo, Xinrong Ma, Kayla M Tighe, Brandon Carter-Cooper, Erin T Strovel, Rena G Lapidus, Ashkan Emadi","doi":"10.1186/s40170-024-00346-2","DOIUrl":"10.1186/s40170-024-00346-2","url":null,"abstract":"<p><strong>Background: </strong>Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease without meaningful therapeutic options beyond the first salvage therapy. Targeting PDAC metabolism through amino acid restriction has emerged as a promising new strategy, with asparaginases, enzymes that deplete plasma glutamine and asparagine, reaching clinical trials. In this study, we investigated the anti-PDAC activity of the asparaginase formulation Pegcrisantaspase (PegC) alone and in combination with standard-of-care chemotherapeutics.</p><p><strong>Methods: </strong>Using mouse and human PDAC cell lines, we assessed the impact of PegC on cell proliferation, cell death, and cell cycle progression. We further characterized the in vitro effect of PegC on protein synthesis as well as the generation of reactive oxygen species and levels of glutathione, a major cellular antioxidant. Additional cell line studies examined the effect of the combination of PegC with standard-of-care chemotherapeutics. In vivo, the tolerability and efficacy of PegC, as well as the impact on plasma amino acid levels, was assessed using the C57BL/6-derived KPC syngeneic mouse model.</p><p><strong>Results: </strong>Here we report that PegC demonstrated potent anti-proliferative activity in a panel of human and murine PDAC cell lines. This decrease in proliferation was accompanied by inhibited protein synthesis and decreased levels of glutathione. In vivo, PegC was tolerable and effectively reduced plasma levels of glutamine and asparagine, leading to a statistically significant inhibition of tumor growth in a syngeneic mouse model of PDAC. There was no observable in vitro or in vivo benefit to combining PegC with standard-of-care chemotherapeutics, including oxaliplatin, irinotecan, 5-fluorouracil, paclitaxel, and gemcitabine. Notably, PegC treatment increased tumor expression of asparagine and serine biosynthetic enzymes.</p><p><strong>Conclusions: </strong>Taken together, our results demonstrate the potential therapeutic use of PegC in PDAC and highlight the importance of identifying candidates for combination regimens that could improve cytotoxicity and/or reduce the induction of resistance pathways.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"12 1","pages":"19"},"PeriodicalIF":6.0,"publicationDate":"2024-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11218198/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141476008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sulfatide imaging identifies tumor cells in colorectal cancer peritoneal metastases.","authors":"G M Sarcinelli, L Varinelli, S Ghislanzoni, F Padelli, D Lorenzini, A Vingiani, M Milione, M Guaglio, S Kusamura, M Deraco, G Pruneri, M Gariboldi, D Baratti, I Bongarzone","doi":"10.1186/s40170-024-00345-3","DOIUrl":"10.1186/s40170-024-00345-3","url":null,"abstract":"<p><p>Even with systemic chemotherapy, cytoreductive surgery (CRS), and hyperthermic intraperitoneal chemotherapy (HIPEC), peritoneal metastases (PM) remain a common site of disease progression for colorectal cancer (CRC) and are frequently associated with a poor prognosis. The mass spectrometry (MS) method known as Matrix-Assisted Laser Desorption/Ionization - Time of Flight (MALDI-TOF) is frequently used in medicine to identify structural compounds and biomarkers. It has been demonstrated that lipids are crucial in mediating the aggressive growth of tumors. In order to investigate the lipid profiles, particularly with regard to histological distribution, we used MALDI-TOF MS (MALDI-MS) and MALDI-TOF imaging MS (MALDI-IMS) on patient-derived tumor organoids (PDOs) and PM clinical samples. According to the MALDI-IMS research shown here, the predominant lipid signature of PDOs in PM tissues, glycosphingolipid (GSL) sulfates or sulfatides, or STs, is unique to the areas containing tumor cells and absent from the surrounding stromal compartments. Bioactive lipids are derived from arachidonic acid (AA), and AA-containing phosphatidylinositol (PI), or PI (18:0-20:4), is shown to be highly expressed in the stromal components. On the other hand, the tumor components contained a higher abundance of PI species with shorter and more saturated acyl chains (C34 and C36 carbons). The cellular subversion of PI and ST species may alter in ways that promote the growth, aggressiveness, and metastasis of tumor cells. Together, these findings suggest that the GSL/ST metabolic programming of PM may contain novel therapeutic targets to impede or halt PM progression.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"12 1","pages":"18"},"PeriodicalIF":6.0,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11212237/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glycemic status, insulin resistance, and mortality from lung cancer among individuals with and without diabetes.","authors":"In Young Cho, Yoosoo Chang, Eunju Sung, Boyoung Park, Jae-Heon Kang, Hocheol Shin, Sarah H Wild, Christopher D Byrne, Seungho Ryu","doi":"10.1186/s40170-024-00344-4","DOIUrl":"10.1186/s40170-024-00344-4","url":null,"abstract":"<p><strong>Background: </strong>The effects of glycemic status and insulin resistance on lung cancer remain unclear. We investigated the associations between both glycemic status and insulin resistance, and lung cancer mortality, in a young and middle-aged population with and without diabetes.</p><p><strong>Methods: </strong>This cohort study involved individuals who participated in routine health examinations. Lung cancer mortality was identified using national death records. Cox proportional hazards models were used to calculate hazard ratios (HRs) with 95% CIs for lung cancer mortality risk.</p><p><strong>Results: </strong>Among 666,888 individuals (mean age 39.9 ± 10.9 years) followed for 8.3 years (interquartile range, 4.6-12.7), 602 lung cancer deaths occurred. Among individuals without diabetes, the multivariable-adjusted HRs (95% CI) for lung cancer mortality comparing hemoglobin A1c categories (5.7-5.9, 6.0-6.4, and ≥ 6.5% or 39-41, 42-46, and ≥ 48 mmol/mol, respectively) with the reference (< 5.7% or < 39 mmol/mol) were 1.39 (1.13-1.71), 1.72 (1.33-2.20), and 2.22 (1.56-3.17), respectively. Lung cancer mortality was associated with fasting blood glucose categories in a dose-response manner (P for trend = 0.001) and with previously diagnosed diabetes. Insulin resistance (HOMA-IR ≥ 2.5) in individuals without diabetes was also associated with lung cancer mortality (multivariable-adjusted HR, 1.41; 95% CI, 1.13-1.75). These associations remained after adjusting for changing status in glucose, hemoglobin A1c, insulin resistance, smoking status, and other confounders during follow-up as time-varying covariates.</p><p><strong>Conclusions: </strong>Glycemic status within both diabetes and prediabetes ranges and insulin resistance were independently associated with an increased risk of lung cancer mortality.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"12 1","pages":"17"},"PeriodicalIF":6.0,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11188269/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141431480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic alterations and cellular responses to β-Hydroxybutyrate treatment in breast cancer cells","authors":"Hadas Fulman-Levy, Raichel Cohen-Harazi, Bar Levi, Lital Argaev-Frenkel, Ifat Abramovich, Eyal Gottlieb, Sarah Hofmann, Igor Koman, Elimelech Nesher","doi":"10.1186/s40170-024-00339-1","DOIUrl":"https://doi.org/10.1186/s40170-024-00339-1","url":null,"abstract":"The ketogenic diet (KD), based on high fat (over 70% of daily calories), low carbohydrate, and adequate protein intake, has become popular due to its potential therapeutic benefits for several diseases including cancer. Under KD and starvation conditions, the lack of carbohydrates promotes the production of ketone bodies (KB) from fats by the liver as an alternative source of metabolic energy. KD and starvation may affect the metabolism in cancer cells, as well as tumor characteristics. The aim of this study is to evaluate the effect of KD conditions on a wide variety of aspects of breast cancer cells in vitro. Using two cancer and one non-cancer breast cell line, we evaluate the effect of β-hydroxybutyrate (βHb) treatment on cell growth, survival, proliferation, colony formation, and migration. We also assess the effect of KB on metabolic profile of the cells. Using RNAseq analysis, we elucidate the effect of βHb on the gene expression profile. Significant effects were observed following treatment by βHb which include effects on viability, proliferation, and colony formation of MCF7 cells, and different effects on colony formation of MDA-MB-231 cells, with no such effects on non-cancer HB2 cells. We found no changes in glucose intake or lactate output following βHb treatment as measured by LC-MS, but an increase in reactive oxygen species (ROS) level was detected. RNAseq analysis demonstrated significant changes in genes involved in lipid metabolism, cancer, and oxidative phosphorylation. Based on our results, we conclude that differential response of cancer cell lines to βHb treatment, as alternative energy source or signal to alter lipid metabolism and oncogenicity, supports the need for a personalized approach to breast cancer patient treatment.","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"102 1","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141171139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disrupting Na⁺ ion homeostasis and Na⁺/K⁺ ATPase activity in breast cancer cells directly modulates glycolysis in vitro and in vivo.","authors":"Aidan M Michaels, Anna Zoccarato, Zoe Hoare, George Firth, Yu Jin Chung, Philip W Kuchel, Ajay M Shah, Michael J Shattock, Richard Southworth, Thomas R Eykyn","doi":"10.1186/s40170-024-00343-5","DOIUrl":"10.1186/s40170-024-00343-5","url":null,"abstract":"<p><strong>Background: </strong>Glycolytic flux is regulated by the energy demands of the cell. Upregulated glycolysis in cancer cells may therefore result from increased demand for adenosine triphosphate (ATP), however it is unknown what this extra ATP turnover is used for. We hypothesise that an important contribution to the increased glycolytic flux in cancer cells results from the ATP demand of Na⁺/K⁺-ATPase (NKA) due to altered sodium ion homeostasis in cancer cells.</p><p><strong>Methods: </strong>Live whole-cell measurements of intracellular sodium [Na⁺]_i were performed in three human breast cancer cells (MDA-MB-231, HCC1954, MCF-7), in murine breast cancer cells (4T1), and control human epithelial cells MCF-10A using triple quantum filtered ²³Na nuclear magnetic resonance (NMR) spectroscopy. Glycolytic flux was measured by ²H NMR to monitor conversion of [6,6-²H₂]D-glucose to [²H]-labelled L-lactate at baseline and in response to NKA inhibition with ouabain. Intracellular [Na⁺]_i was titrated using isotonic buffers with varying [Na⁺] and [K⁺] and introducing an artificial Na⁺ plasma membrane leak using the ionophore gramicidin-A. Experiments were carried out in parallel with cell viability assays, ¹H NMR metabolomics of intracellular and extracellular metabolites, extracellular flux analyses and in vivo measurements in a MDA-MB-231 human-xenograft mouse model using 2-deoxy-2-[¹⁸F]fluoroglucose (¹⁸F-FDG) positron emission tomography (PET).</p><p><strong>Results: </strong>Intracellular [Na⁺]_i was elevated in human and murine breast cancer cells compared to control MCF-10A cells. Acute inhibition of NKA by ouabain resulted in elevated [Na⁺]_i and inhibition of glycolytic flux in all three human cancer cells which are ouabain sensitive, but not in the murine cells which are ouabain resistant. Permeabilization of cell membranes with gramicidin-A led to a titratable increase of [Na⁺]_i in MDA-MB-231 and 4T1 cells and a Na⁺-dependent increase in glycolytic flux. This was attenuated with ouabain in the human cells but not in the murine cells. ¹⁸FDG PET imaging in an MDA-MB-231 human-xenograft mouse model recorded lower ¹⁸FDG tumour uptake when treated with ouabain while murine tissue uptake was unaffected.</p><p><strong>Conclusions: </strong>Glycolytic flux correlates with Na⁺-driven NKA activity in breast cancer cells, providing evidence for the 'centrality of the [Na⁺]_i-NKA nexus' in the mechanistic basis of the Warburg effect.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"12 1","pages":"15"},"PeriodicalIF":5.9,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11119389/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141086864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxia-induced NOS1 as a therapeutic target in hypercholesterolemia-related colorectal cancer.","authors":"Weiqing Qiu, Li Zhao, Hua Liu, Ping Xu, Changlin Qian","doi":"10.1186/s40170-024-00338-2","DOIUrl":"https://doi.org/10.1186/s40170-024-00338-2","url":null,"abstract":"<p><strong>Background: </strong>It is well established that hypercholesterolemia increases the risk of atherosclerosis, especially because it reduces the availability of nitric oxide (NO). However, the relationship between hypercholesterolemia and NO in regulating colorectal cancer development and progression remains unknown.</p><p><strong>Methods: </strong>We conducted bioinformatics analysis, qRT-PCR, ChIP-qPCR assays, luciferase report assays, clonogenic survival assays, and multiple mouse models to investigate the function and mechanism of hypercholesterolemia in regulating NO signaling. Additionally, NOS inhibitors were used to evaluate the potential of therapeutic strategy in anti-tumor response.</p><p><strong>Results: </strong>Here, we show that oxidized low-density lipoprotein (oxLDL) cholesterol and its receptor LOX-1 are essential for hypercholesterolemia-induced colorectal tumorigenesis. Mechanically, the oxLDL promotes the oxidant stress-dependent induction of hypoxia signaling to transcriptionally up-regulate NO synthase (NOS) especially NOS1 expression in colorectal cancer (CRC) cells. More importantly, our results suggested that selective inhibition of NOS1 with its specific inhibitor Nω-Propyl-L-arginine is a suitable therapeutic strategy for hypercholesterolemia-related CRC with both efficacy and toxicity reduction.</p><p><strong>Conclusions: </strong>Our findings established that hypercholesterolemia induces the oxidant stress-dependent induction of hypoxia signaling to transcriptionally up-regulate NOS1 expression in CRC cells, and the clinically applicable NOS1 inhibitor Nω-Propyl-L-arginine represents an effective therapeutic strategy for hypercholesterolemia-related CRC.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"12 1","pages":"14"},"PeriodicalIF":5.9,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11100240/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140956464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterizing OXPHOS inhibitor-mediated alleviation of hypoxia using high-throughput live cell-imaging","authors":"Anne P. M. Beerkens, Daan F. Boreel, James A. Nathan, Jiri Neuzil, Gang Cheng, Balaraman Kalyanaraman, Micael Hardy, Gosse J. Adema, Sandra Heskamp, Paul N. Span, Johan Bussink","doi":"10.1186/s40170-024-00342-6","DOIUrl":"https://doi.org/10.1186/s40170-024-00342-6","url":null,"abstract":"Hypoxia is a common feature of many solid tumors and causes radiotherapy and immunotherapy resistance. Pharmacological inhibition of oxidative phosphorylation (OXPHOS) has emerged as a therapeutic strategy to reduce hypoxia. However, the OXPHOS inhibitors tested in clinical trials caused only moderate responses in hypoxia alleviation or trials were terminated due to dose-limiting toxicities. To improve the therapeutic benefit, FDA approved OXPHOS inhibitors (e.g. atovaquone) were conjugated to triphenylphosphonium (TPP+) to preferentially target cancer cell’s mitochondria. In this study, we evaluated the hypoxia reducing effects of several mitochondria-targeted OXPHOS inhibitors and compared them to non-mitochondria-targeted OXPHOS inhibitors using newly developed spheroid models for diffusion-limited hypoxia. B16OVA murine melanoma cells and MC38 murine colon cancer cells expressing a HIF-Responsive Element (HRE)-induced Green Fluorescent Protein (GFP) with an oxygen-dependent degradation domain (HRE-eGFP-ODD) were generated to assess diffusion-limited hypoxia dynamics in spheroids. Spheroids were treated with IACS-010759, atovaquone, metformin, tamoxifen or with mitochondria-targeted atovaquone (Mito-ATO), PEGylated mitochondria-targeted atovaquone (Mito-PEG-ATO) or mitochondria-targeted tamoxifen (MitoTam). Hypoxia dynamics were followed and quantified over time using the IncuCyte Zoom Live Cell-Imaging system. Hypoxic cores developed in B16OVA.HRE and MC38.HRE spheroids within 24 h hours after seeding. Treatment with IACS-010759, metformin, atovaquone, Mito-PEG-ATO and MitoTam showed a dose-dependent reduction of hypoxia in both B16OVA.HRE and MC38.HRE spheroids. Mito-ATO only alleviated hypoxia in MC38.HRE spheroids while tamoxifen was not able to reduce hypoxia in any of the spheroid models. The mitochondria-targeted OXPHOS inhibitors demonstrated stronger anti-hypoxic effects compared to the non-mito-targeted OXPHOS inhibitors. We successfully developed a high-throughput spheroid model in which hypoxia dynamics can be quantified over time. Using this model, we showed that the mitochondria-targeted OXPHOS inhibitors Mito-ATO, Mito-PEG-ATO and MitoTam reduce hypoxia in tumor cells in a dose-dependent manner, potentially sensitizing hypoxic tumor cells for radiotherapy.","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"14 1","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140839550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Statin use as a moderator on the association between metformin and breast cancer risk in women with type 2 diabetes mellitus","authors":"Fan Zhang, Geertruida H. de Bock, Gijs W. Landman, Qingying Zhang, Grigory Sidorenkov","doi":"10.1186/s40170-024-00340-8","DOIUrl":"https://doi.org/10.1186/s40170-024-00340-8","url":null,"abstract":"Metformin and statins are considered as potential agents for prevention of breast cancer, however, existing evidence does not uniformly substantiate this claim, and the data is scarce concerning their interaction in relation to breast cancer risk. This study aims to investigate whether the effect of metformin on breast cancer incidence varied by statin use among women with type 2 diabetes mellitus (T2DM). This study included women with T2DM, without a history of cancers, and followed up for more than one year from the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) for the period 1998–2014. The dataset was structured using a person-time approach, where the cumulative medication usage was annually updated for each person. The extended Cox proportional hazards models were employed, reporting adjusted hazard ratios (HR) with 95% confidence intervals (CI). During a median follow-up of 5 years, 515 of 29,498 women received a breast cancer diagnosis. Each additional year of metformin or statins use corresponded to a decrease in breast cancer incidence, while the magnitude attenuated over time. Noteworthily, statin use modified the effect of metformin on breast cancer incidence. For instance, after 5 years of follow-up, one-year increase of metformin use among women who used statins for 3 years was linked to a substantially reduced breast cancer risk (HR, 95% CI: 0.88, 0.84–0.93), however, there was no significant decrease in risk for those non-statins users (HR, 95% CI: 0.96, 0.89–1.04). Extending metformin or statin usage by one year conferred breast cancer protection in women with T2DM. Enhanced protective effect of metformin was observed among those who also use statins. These results suggest the potential of combined metformin and statin therapy as promising breast cancer prevention strategies.","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"232 1","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140574116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}