Ferroptosis is involved in trophoblast cells cytotoxicity induced by black phosphorus nanoparticles.

Black phosphorus (BP) is a new type of nanomaterial, which has been widely used in many biomedical fields due to its superior properties, but there are few studies on the toxicity of BP, especially in the reproductive system. To explore the effects of BP exposure on reproduction and reveal its molecular mechanism, we firstly investigated the potential toxicity of black phosphorus nanoparticles (BPNPs) in vivo. The results showed that BP exposure in pregnant mice can reduce the weight of fetal mice and placenta. H&E staining further indicated the changes of placental cross-section and vascular remodeling after BP treatment. Then, human exvillous trophoblast HTR8/SVneo was treated with different concentrations of BPNPs. We found that BPNPs induced significant cytotoxicity, including dose-dependent reduction of cell viability and proliferation. Trophoblast cell migration and invasion were also impaired by BPNPs exposure. Moreover, pretreatment with Cytochalasin D (Cyto-D), a classical phagocytic inhibitor, alleviated the decline of cell viability induced by BPNPs. Transcriptome sequencing showed that BPNPs exposure led to ferroptosis. Subsequently, the related indexes of ferroptosis were detected, including increase of iron ion concentration, decrease of the ferroptosis marker, GPX4 (Glutathione Peroxidase 4), increase of FTL (Ferritin Light Chain), and increase of lipid peroxidation indexes (MDA level and decrease of GSH level). In addition, ferroptosis inhibitors (Fer-1 and DFO) pretreatment can alleviate both the cytotoxic effects and functional impairment induced by BPNPs. In summary, our study confirmed the reproductive toxicity of BPNPs for the first time, and constructed BPNPs injury model in vitro using human villus trophoblast cells and revealed the role of ferroptosis in this process, which deepened our understanding of the biosafety of black phosphorus nanomaterials.

Combined exposure of beta-cypermethrin and emamectin benzoate interferes with the HPO axis through oxidative stress, causing an imbalance of hormone homeostasis in female rats.

The impact of pesticides on reproductive health has been increasingly recognized. ß-cypermethrin (ß-CYP) and emamectin benzoate (EMB) are commonly used with agricultural workers. There are few published studies on the effects of combined poisoning of these two pesticides on the reproductive system. This study investigated the toxic effects and mechanism of ß-CYP and EMB on the reproductive system of female rats based on the hypothalamic-pituitary-ovarian (HPO) axis. The hypothalamic GnRH content tended to decrease, and Kiss-1 and GPR-54 mRNA and protein expression tended to increase in exposed rats. FSH content was elevated for the pituitary gland, and Kiss-1 and GPR-54 mRNA and protein expression were enhanced in all experimental groups compared with the control group. E2 content in rat ovaries and ERα mRNA and protein expression were reduced by ß-CYP and EMB. Furthermore, there were interactive effects of ß-CYP and EMB on FSH and E2 release, pituitary GPR-54 mRNA and protein, and ovarian ERα mRNA expression. To investigate causes of damage, oxidative damage indicators were tested and showed that exposure to ß-CYP and EMB decreased GSH-Px and SOD activities in the HPO axis, increased MDA levels in the hypothalamus and ovary together with LDH activities in the HPO axis, with an interaction effect on GSH-Px and SOD activities in the hypothalamus and pituitary gland as well as on MDA in the ovary. The above results support the screening of sensitive molecular biomarkers and evaluation of the adverse effects of pesticide exposure in greenhouse operations on reproductive health.

Secreted insulin-like growth factor binding protein 5 functions as a tumor suppressor and chemosensitizer through inhibiting insulin-like growth factor 1 receptor/protein kinase B pathway in acute myeloid leukemia.

BACKGROUND: In addition to being secreted into the intercellular spaces by exocytosis, insulin-like growth factor binding protein 5 (IGFBP5) may also remain in the cytosol or be transported to the nucleus. Depending on the different cellular context and subcellular distribution, IGFBP5 can act as a tumor suppressor or promoter through insulin-like growth factor -dependent or -independent mechanisms. Yet, little is known about the impacts of IGFBP5 on acute myeloid leukemia (AML) and its underlying mechanism. METHODS: Here we investigated the roles of IGFBP5 in human AML by using recombinant human IGFBP5 (rhIGFBP5) protein and U937 and THP1 cell lines which stably and ectopically expressed IGFBP5 or mutant IGFBP5 (mtIGFBP5) with the lack of secretory signal peptide. Cell counting kit-8 and flow cytometry assay were conducted to assess the cell viability, cell apoptosis and cell cycle distribution. Cytotoxicity assay was used to detect the chemosensitivity. Leukemia xenograft model and hematoxylin-eosin staining were performed to evaluate AML progression and extramedullary infiltration in vivo. RESULTS: In silico analysis demonstrated a positive association between IGFBP5 expression and overall survival of the AML patients. Both IGFBP5 overexpression and extrinsic rhIGFBP5 suppressed the growth of THP1 and U937 cells by inducing cell apoptosis and arresting G1/S transition and promoted the chemosensitivity of U937 and THP1 cells to daunorubicin and cytarabine. However, overexpression of mtIGFBP5 failed to demonstrate these properties. An in vivo xenograft mouse model of U937 cells also indicated that overexpression of IGFBP5 rather than mtIGFBP5 alleviated AML progression and extramedullary infiltration. Mechanistically, these biological consequences depended on the inactivation of insulin-like growth factor 1 receptor -mediated phosphatidylinositol-3-kinase/protein kinase B pathway. CONCLUSIONS: Our findings revealed secreted rather than intracellular IGFBP5 as a tumor-suppressor and chemosensitizer in AML. Upregulation of serum IGFBP5 by overexpression or addition of extrinsic rhIGFBP5 may serve as a suitable therapeutic approach for AML.

HIF-1α is an important regulator of IL-8 expression in human bone marrow stromal cells under hypoxic microenvironment.

The secretion of IL-8 has been found increasing for different reasons in human bone marrow stromal cells (BMSCs), resulting in poor prognosis in patients with hematologic neoplasms. Hypoxia, a typical feature of numerous hematologic neoplasms microenvironment, often produces hypoxia inducible factor-1α (HIF-1α) which stabilizes and promotes tumor progression. Besides, hypoxic conditions also induce IL-8 production in BMSCs. However, very little is known about the mechanism of increased IL-8 expression in BMSCs caused by hypoxia. In the present study, HIF-1α and IL-8 were found highly expressed in BMSC lines under hypoxic conditions. In addition, the expression and secretion of IL-8 were significantly inhibited by the knockdown of HIF-1α under hypoxic conditions. Furthermore, HIF-1α was found to transcriptionally regulate IL-8 by binding to the region of IL-8 promoter at - 147 to - 140. Collectively, these results demonstrate that IL-8's increase is partly due to the hypoxic microenvironment in hematologic neoplasms, and activation of HIF-1α in BMSCs contributes to the induction and transcriptional regulation of IL-8 expression.

Deletion of Mettl3 in mesenchymal stem cells promotes acute myeloid leukemia resistance to chemotherapy.

Acute myeloid leukemia (AML) cell survival and chemoresistance are influenced by the existence of bone marrow mesenchymal stem cells (BMMSCs); however, the pathways by which BMMSCs contribute to these processes remain unclear. We earlier revealed that methyltransferase-like 3 (METTL3) expression is significantly reduced in AML BMMSCs and that METTL3 mediates BMMSC adipogenesis to promote chemoresistance in human AML cell lines in vitro. In this investigation, we evaluated the METTL3 function in vivo. Mice exhibiting a conditional removal of Mettl3 in BMMSCs were developed by mating Prrx1-CreERT2;Mettl3fl/+ mice with Mettl3fl/fl mice using the CRISPR-Cas9 system. The Mettl3 deletion increased bone marrow adiposity, enhanced disease progression in the transplantation-induced MLL-AF9 AML mouse model, and chemoresistance to cytarabine. The removal of Mettl3 in BMMSCs resulted in a significant increase in BMMSC adipogenesis. This effect was attributed to the downregulation of AKT1 expression, an AKT serine/threonine kinase 1, in an m6A-dependent manner. The development of chemoresistance in AML is linked to the promoted adipogenesis of BMMSCs. We conclude that METTL3 expression in BMMSCs has a critical function in limiting AML progression and chemoresistance, providing a basis for the progression of therapeutic approaches for AML.

Interleukin-6 Facilitates Acute Myeloid Leukemia Chemoresistance via Mitofusin 1-Mediated Mitochondrial Fusion.

Acute myeloid leukemia (AML), an aggressive hematopoietic malignancy, exhibits poor prognosis and a high recurrence rate largely because of primary and secondary drug resistance. Elevated serum IL6 levels have been observed in patients with AML and are associated with chemoresistance. Chemoresistant AML cells are highly dependent on oxidative phosphorylation (OXPHOS), and mitochondrial network remodeling is essential for mitochondrial function. However, IL6-mediated regulation of mitochondrial remodeling and its effectiveness as a therapeutic target remain unclear. We aimed to determine the mechanisms through which IL6 facilitates the development of chemoresistance in AML cells. IL6 upregulated mitofusin 1 (MFN1)-mediated mitochondrial fusion, promoted OXPHOS, and induced chemoresistance in AML cells. MFN1 knockdown impaired the effects of IL6 on mitochondrial function and chemoresistance in AML cells. In an MLL::AF9 fusion gene-induced AML mouse model, IL6 reduced chemosensitivity to cytarabine (Ara-C), a commonly used antileukemia drug, accompanied by increased MFN1 expression, mitochondrial fusion, and OXPHOS status. In contrast, anti-IL6 antibodies downregulated MFN1 expression, suppressed mitochondrial fusion and OXPHOS, enhanced the curative effects of Ara-C, and prolonged overall survival. In conclusion, IL6 upregulated MFN1-mediated mitochondrial fusion in AML, which facilitated mitochondrial respiration, in turn, inducing chemoresistance. Thus, targeting IL6 may have therapeutic implications in overcoming IL6-mediated chemoresistance in AML. IMPLICATIONS: IL6 treatment induces MFN1-mediated mitochondrial fusion, promotes OXPHOS, and confers chemoresistance in AML cells. Targeting IL6 regulation in mitochondria is a promising therapeutic strategy to enhance the chemosensitivity of AML.

Red Blood Cell Distribution Width as a Potential Valuable Survival Predictor in Hepatitis B Virus-related Hepatocellular Carcinoma.

Objectives: Red blood cell distribution width (RDW) is a widely used clinical parameter recently deployed in predicting various cancers. This study aimed to evaluate the prognostic value of RDW in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Methods: We conducted a retrospective study of 745 patients with HBV-related HCC, 253 patients with chronic hepatitis B (CHB), and 256 healthy individuals to compare their hematological parameters and analyze their RDW levels. Potential risk factors for long-term all-cause mortality in patients with HBV-related HCC were predicted using Multivariate Cox regression. A nomogram was generated, and its performance was evaluated. Results: The RDW of patients with HBV-related HCC was significantly higher than that of those with CHB and healthy controls. In the former, splenomegaly, liver cirrhosis, larger tumor diameter, multiple tumor number, portal vein tumor thrombus, and lymphatic or distant metastasis were significantly increased, and the later the Child-Pugh grade and Barcelona clinic liver cancer stage, the higher the RDW. Furthermore, multivariate Cox regression analysis identified RDW as an independent risk factor for predicting long-term all-cause mortality in patients with HBV-related HCC. Finally, we successfully generated a nomogram incorporating RDW and validated its predictive ability. Conclusions: RDW is a potentially valuable hematological marker for predicting the survival and prognosis of patients with HBV-related HCC. The nomogram incorporating RDW can be used as an effective tool to plan the individualized treatment of such patients.

Downregulation of ITGA5 inhibits lymphangiogenesis and cell migration and invasion in male laryngeal squamous cell carcinoma.

ITGA5, a fibronectin receptor was highly expressed in laryngeal squamous cell carcinoma (LSCC) samples and was related to poor survival. However, the potential mechanism remains unclear. To elucidate the regulatory role of ITGA5 in LSCC progression, we investigated the effect of ITGA5 expression on lymphangiogenesis, migration, and invasion of LSCC cells in vitro and in vivo using immunohistochemistry, siRNA transfection, qRT-PCR, western blotting, enzyme-linked immunosorbent assay, flow cytometry, transwell co-culture, tube formation, cell migration, and invasion assays, and a subcutaneous graft tumor model. The expression of ITGA5 was higher in the LSCC tissues and linked to lymph node metastasis and T staging. Moreover, ITGA5 expression was significantly positively correlated with VEGF-C expression, and the lymphatic vessel density of patients with high ITGA5 expression was noticeably higher than that of patients with low ITGA5 expression. Additionally, it was found in vitro that downregulation of ITGA5 expression not only inhibited the expression and secretion of VEGF-C, but also suppressed the tube-forming ability of human lymphatic endothelial cells (HLECs) and the migration and invasion ability of LSCC cells, while exogenous VEGF-C supplementation reversed these phenomena. Furthermore, a tumor xenograft assay showed that si-ITGA5 restrained the growth and metastasis of TU212-derived tumors in vivo. Our findings suggested that ITGA5 induces lymphangiogenesis and LSCC cell migration and invasion by enhancing VEGF-C expression and secretion.

The combined effect of titanium dioxide nanoparticles and cypermethrin on male reproductive toxicity in rats.

Titanium nanoparticles and pyrethroid pesticides are now being widely used in industrial, agriculture, and biomedical applications. In recent years, their health safety profiles have aroused concerns among health scientists. This study mainly explored the combined effects of titanium dioxide nanoparticles (TiO2NPs) and cypermethrin (CYP) on reproductive toxicity in male rats by gavage for 90 days. Thirty-two male Sprague-Dawley rats were assigned to four groups: the control group, the TiO2NPs group, the CYP group, and the combined titanium dioxide nanoparticles with cypermethrin (TiO2NPs + CYP) group. The results of biochemical analysis on testicular tissue homogenate showed that TiO2NPs and CYP mixtures decreased the activities of glutathione peroxidase (GSH-Px) and catalase (CAT) while increasing the activity of malondialdehyde (MDA) and lactate dehydrogenase (LDH). Meanwhile, the results of two-way factorial analysis of variance (ANOVA) showed a significant effect on GSH-Px, CAT, LDH, testicular cell apoptosis, and sperm quality in rats after exposure. Furthermore, the combined exposure group exhibited apoptosis of testicular cells and DNA damage. The results indicated that exposure to a mixture of TiO2NPs and CYP had adverse effects on the reproductive status of male rats.

m6A RNA methylation regulators predict prognosis and indicate characteristics of tumour microenvironment infiltration in acute myeloid leukaemia.

Patients with acute myeloid leukaemia (AML) have poor prognoses and low overall survival (OS) rates owing to its heterogeneity and the complexity of its tumour microenvironment (TME). N6-methyladenosine (m6A) modification plays a key role in the initiation and progression of haematopoietic malignancies. However, the underlying function of m6A regulators in AML remains elusive. This study thoroughly analysed the m6A modification features of 177 AML patients based on 22 m6A regulators. Utilizing unsupervised clustering, we determined three distinct m6A modification patterns related to different biological functions, TME cell-infiltrating characteristics and clinical outcomes. Additionally, a risk score was constructed based on six m6A regulators-associated prognostic signatures and was validated as an independent and valuable prognostic factor for AML. Patients with a low-risk score exhibited better survival than those with a high-risk score. Many m6A regulators were aberrantly expressed in AML, among which METTL14, YTHDC2, ZC3H13 and RBM15 were observed to be associated with the OS of AML. In addition, these four m6A regulators were found to be noticeably related to the immune checkpoint inhibitor (ICI) treatments. Finally, we verified the expression levels of these four m6A regulators in AML and healthy samples and three groups of AML patients with different risk categories. Collectively, our study indicates that the m6A modification pattern is involved in TME immune-infiltrating characteristics and prognosis in AML. A better understanding of the m6A modification pattern will help enhance our knowledge of the molecular mechanisms of AML and develop potential prognosis prediction indicators and more effective immunotherapeutic strategies.

Metformin sensitizes AML cells to chemotherapy through blocking mitochondrial transfer from stromal cells to AML cells.

Interaction between stromal cells and acute myeloid leukemia (AML) cells in bone marrow (BM) is known to contribute importantly to chemoresistance and disease recurrence. Therefore, disruption of a crosstalk between AML cells and BM microenvironment may offer a promising therapeutic strategy for AML treatment. Here, we demonstrate that in a niche-like co-culture system, AML cells took up functional mitochondria from bone marrow stromal cells (BMSCs) and inhibition of such mitochondrial transfer by metformin, the most commonly prescribed drug for type 2 diabetes mellitus, significantly enhanced the chemosensitivity of AML cells co-cultured with BMSCs. The chemo-sensitizing effect of metformin was acted through reducing the mitochondrial transfer and mitochondrial oxidative phosphorylation (OXPHOS) in the recipient AML cells. In addition, metformin potentiated the antitumor efficacy of cytarabine (Ara-C) in vivo in an NCG immunodeficient mouse xenograft model by inhibiting the mitochondrial transfer and OXPHOS activity in the engrafted human AML cells. Altogether, this study identifies a potential application of metformin in sensitizing AML cells to chemotherapy and unveils a novel mechanism by which metformin executes such effect via blocking the mitochondrial transfer from stromal cells to AML cells.

Bone marrow microenvironment drives AML cell OXPHOS addiction and AMPK inhibition to resist chemotherapy.

The stromal niche plays a pivotal role in AML chemoresistance and energy metabolism reprogramming is a hallmark of a tumor. 5'-Adenosine monophosphate-activated protein kinase (AMPK) is an important energy sensor suppressing mammalian target of rapamycin complex 1 (mTORC1) activity. However, the role of AMPK-mTORC1 pathway on connecting AML cell energy metabolism reprogramming and chemoresistance induced by the bone marrow microenvironment (BMM) is not defined. Here, with a co-culture system that simulates the interaction between BMM and AML cells, it is shown that stromal contact led to a decreased sensitivity to chemotherapy accompanied by an increase of oxidative phosphorylation (OXPHOS) activity and mitochondrial ATP synthesis in AML cells. The increased OXPHOS activity and excessive ATP production promoted chemoresistance of AML cells through inhibiting AMPK activity and in turn activating mTORC1 activity. In an in vivo AML mouse model, depletion of AMPK activity with genetic targeting promoted AML progression and reduced their sensitivity to chemotherapeutic drugs. Collectively, AML cells' acquired increased OXPHOS activity as well as AMPK inhibition could be therapeutically exploited in an effort to overcome BMM-mediated chemoresistance.

METTL3 mediates bone marrow mesenchymal stem cell adipogenesis to promote chemoresistance in acute myeloid leukaemia.

Adipogenesis of bone marrow mesenchymal stem cells (MSCs) promotes chemoresistance of acute myeloid leukaemia (AML) cells. MSCs from AML patients (AML-MSCs) display enhanced adipogenesis compared with bone marrow MSCs from healthy donors. However, the precise molecular mechanism by which adipogenesis of MSCs from AML marrow differs from normal counterparts remains obscure. We found that METTL3 significantly inhibits MSC adipogenesis. Here, we aimed to identify the molecular mechanism linking METTL3 and MSC adipogenesis. Analysis of m6 A epigenetic changes in MSCs determined via RIP-qPCR and MeRIP-qPCR indicated that METTL3 affects AKT protein expression in MSCs by mediating m6 A modification of AKT1-mRNA. Downregulated METTL3 expression in AML-MSCs induced an increase in AKT protein, resulting in enhanced MSC adipogenesis, thereby contributing to chemoresistance in AML cells. Therefore, targeting AKT regulation by mRNA modification in MSC adipogenesis might provide a novel therapeutic strategy to overcome AML chemoresistance.

Stromal cells promote chemoresistance of acute myeloid leukemia cells via activation of the IL-6/STAT3/OXPHOS axis.

BACKGROUND: Bone marrow stromal cells (BMSCs) are known to promote chemoresistance in acute myeloid leukemia (AML) cells. However, the molecular basis for BMSC-associated AML chemoresistance remains largely unexplored. METHODS: The mitochondrial oxidative phosphorylation (OXPHOS) levels of AML cells were measured by a Seahorse XFe24 cell metabolic analyzer. The activity of total or mitochondrial signal transducer and transcription activator 3 (STAT3) in AML cells was explored by flow cytometry and Western blotting. Real-time quantitative PCR, Western blotting and enzyme-linked immunosorbent assay (ELISA) were used to analyze expression of interleukin 6 (IL-6) in the human BMSC line HS-5, and IL-6 was knocked out in HS-5 cells by CRISPR/Cas9 system. RESULTS: In this study, we observed that co-culturing with BMSCs heightened OXPHOS levels in AML cells, thus promoting chemoresistance in these cells. HS-5 cell-induced upregulation of OXPHOS is dependent on the activation of STAT3, especially on that of mitochondrial serine phosphorylated STAT3 (pS-STAT3) in AML cells. The relationship among pS-STAT3, OXPHOS, and chemosensitivity of AML cells induced by BMSCs was demonstrated by the STAT3 activator and inhibitor, which upregulated and downregulated the levels of mitochondrial pS-STAT3 and OXPHOS, respectively. Intriguingly, AML cells remodeled HS-5 cells to secrete more IL-6, which augmented mitochondrial OXPHOS in AML cells and stimulated their chemoresistance. IL-6 knockout in HS-5 cells impaired the ability of these cells to activate STAT3, to increase OXPHOS, or to promote chemoresistance in AML cells. CONCLUSIONS: BMSCs promoted chemoresistance in AML cells via the activation of the IL-6/STAT3/OXPHOS pathway. These findings exhibit a novel mechanism of chemoresistance in AML cells in the bone marrow microenvironment from a metabolic perspective.

Melatonin inhibits lung metastasis of gastric cancer in vivo.

AIM: Melatonin shows therapeutic benefits in gastric cancer, but the mechanism underlying its anticancer effects remains elusive. The aim of this study was to determine whether melatonin inhibits lung metastasis in gastric cancer. MAIN METHODS: A lung metastasis model of gastric cancer was established in nude mice injected with human gastric adenocarcinoma MGC80-3 cells. Mice were divided into control, IL-1ß-treated, melatonin-treated, and IL-1ß plus melatonin-treated groups and analyzed for the formation of lung metastatic nodules by flow cytometry and hematoxylin and eosin staining. The mRNA expression of epithelial-mesenchymal transition (EMT) markers was assessed by RT-qPCR. The activities of matrix metalloproteinase (MMP)-2 and MMP-9 were determined by gelatin zymography and their protein expression by western blotting and immunohistochemistry. The levels of NF-κB p65 and phosphorylated (p)-p65 were detected by immunohistochemistry. KEY FINDINGS: The number of lung metastases in the IL-1ß plus melatonin group was significantly lower and the sizes of nodules were smaller than those in the IL-1ß group. Furthermore, melatonin reversed changes in the expression of EMT markers induced by IL-1ß by increasing mRNA levels of ß-catenin and E-cadherin and decreasing those of fibronectin, vimentin, and Snail compared to IL-1ß. Treatment with IL-1ß upregulated the expression and activities of MMP-2 and MMP-9 and expression of NF-κB p65 and phospho-p65 (p-p65), but melatonin alleviated these effects. SIGNIFICANCE: Melatonin inhibited IL-1ß-induced lung metastasis of gastric cancer through downregulation of MMP-2, MMP-9, and NF-κB p65 expression and activities. These findings provide a basis for potential use of melatonin as a supplementary therapy for patients with advanced gastric cancer.

Homoharringtonine potentiates the antileukemic activity of arsenic trioxide against acute myeloid leukemia cells.

Relapse of minimal residual disease (MRD) is a major problem after conventional chemotherapy in patients with acute myeloid leukemia (AML). The bone marrow stroma can protect AML cells from insults of chemotherapy, partly contributing to AML relapse. Arsenic trioxide (ATO) is the main component of arsenical traditional Chinese medicines and has been widely used for the treatment of hematologic malignancies particularly acute promyelocytic leukemia over the past three decades. ATO acts through a direct arsenic binding to cysteine residues in zinc fingers located in promyelocytic leukemia protein (PML), thus killing the leukemia stem cells (LSCs). Our prior study has demonstrated that adhesion to stroma cells could render AML cells resistant to ATO but the detailed mechanism remains to be explored. Here, we report that the adhesion-induced resistance to ATO is related to the up-regulation of myeloid cell leukemia-1 (Mcl-1). Homoharringtonine (HHT) can potentiate the anti-leukemia effects of ATO on adhered AML cells by suppressing Mcl-1 through glycogen synthase kinase-3ß (GSK3ß). Furthermore, a potentiating effect of HHT on ATO was also observed in primary AML cells and AML xenografted tumors. Thus, these data indicate that HHT could enhance ATO anti-leukemia activity both in vitro and in vivo.

Exosomes derived from acute myeloid leukemia cells promote chemoresistance by enhancing glycolysis-mediated vascular remodeling.

Acute myeloid leukemia (AML) is the most common type of leukemia in adults. AML cells secrete angiogenic factors to remodel vasculature and acquire chemoresistance; however, antiangiogenic drugs are often ineffective in AML treatment. Cancer cell-derived exosomes can induce angiogenesis, but their role in vascular remodeling during AML is unclear. Here, we found that exosomes secreted by AML cells promoted proliferation and migration and tube-forming activity of human umbilical vein endothelial cells (HUVECs), whereas HUVECs conferred chemoresistance to AML cells. AML cell-derived exosomes contained vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) messenger RNA and induced VEGFR expression in HUVECs. Furthermore, they enhanced glycolysis, which correlated with HUVEC proliferation, tube formation, and resistance to apoptosis. Thus, AML cells secrete VEGF/VEGFR-containing exosomes that induce glycolysis in HUVECs leading to vascular remodeling and acquisition of chemoresistance. These findings may contribute to the development of novel therapeutic strategies targeting exosomes in AML.