bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2025–04–20
fourteen papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Glucosamine induces hepatic FGF21 expression by activating the Akt/mTOR/p70S6K axis and driving PGC-1α activity.
  2. Saturated Phosphatidic Acids Induce mTORC1-Driven Integrated Stress Response Contributing to Glucolipotoxicity in Hepatocytes.
  3. The mitochondrial unfolded protein response: acting near and far.
  4. Integrative metabolic profiling of hypothalamus and skeletal muscle in a mouse model of cancer cachexia.
  5. INFLAMMATION IN CANCER CACHEXIA: STILL THE CENTRAL TENET OR JUST ANOTHER PLAYER?
  6. Housing Temperature Impacts the Systemic and Tissue-Specific Molecular Responses to Cancer in Mice.
  7. GDF15 links adipose tissue lipolysis with anxiety.
  8. Impact of SLC16A8 on tumor microenvironment and angiogenesis in colorectal cancer: New therapeutic target insights.
  9. Mutant CEBPA promotes tolerance to inflammatory stress through deficient AP-1 activation.
  10. Metabolic Dialogue Shapes Immune Response in the Tumor Microenvironment.
  11. Hypoxia LUAD H1975 cell-derived exosomal miR-671-3p promotes angiogenesis via regulating KLF2-VEGFR2 axis.
  12. Integrator loss leads to dsRNA formation that triggers the integrated stress response.
  13. Interactions between leukemia and feeders in co-cultivation under hypoxia.
  14. Blockade of Exosome Release Sensitizes Breast Cancer to Doxorubicin via Inhibiting Angiogenesis.
  1. Sci Rep. 2025 Apr 16. 15(1): 13096
    Glucosamine induces hepatic FGF21 expression by activating the Akt/mTOR/p70S6K axis and driving PGC-1α activity.
    Shui-Yu Liu, Luen-Kui Chen, Pin-Hsuan Li, Guan-Lin Wu, Tsung-Hui Wu, Yuan-Bin Yu, Heng-Fu Lin, Chi-Chang Juan.
      Glucosamine (GlcN) is a common supplement used to alleviate osteoarthritis, but it may dysregulate glucose tolerance and induce insulin resistance, thereby increasing metabolic burden. The liver is a vital organ that modulates the Akt/mTOR/p70S6K signaling pathway in response to growth and metabolism. Fibroblast growth factor 21 (FGF21) is a hepatokine involved in regulating glucose and lipid metabolism. Additionally, increased circulating FGF21 levels have been linked to the prediction of metabolic disorders and type 2 diabetes. However, the regulatory mechanism controlling FGF21 expression by GlcN remains unclear. In the present study, GlcN stimulation led to several outcomes, including an increase in cell content, secretion, and mRNA and protein levels of FGF21 in hepatocytes. Moreover, inhibition of the Akt/mTOR/p70S6K axis resulted in reduced FGF21 expression in response to GlcN. Importantly, GlcN-mediated expression of FGF21 relies on PGC-1α upregulation. These results suggest that GlcN increases FGF21 expression through the activation between Akt/mTOR/p70S6K pathway and PGC-1α dependent manner.
    Keywords:  Diabetes; FGF21; Glucosamine; Hepatocyte; PGC-1α
    DOI:  https://doi.org/10.1038/s41598-025-96249-3
  2. Am J Physiol Gastrointest Liver Physiol. 2025 Apr 17.
    Saturated Phosphatidic Acids Induce mTORC1-Driven Integrated Stress Response Contributing to Glucolipotoxicity in Hepatocytes.
    Rui Guo, Yanhui Li, Yuwei Jiang, Md Wasim Khan, Brian T Layden, Zhenyuan Song.
      Hepatic glucolipotoxicity, characterized by the synergistic detrimental effects of elevated glucose levels combined with excessive lipid accumulation in hepatocytes, plays a central role in the pathogenesis of various metabolic liver diseases. Despite recent advancements, the precise mechanisms underlying this process remain unclear. Employing cultured AML12 and HepG2 cells exposed to excess palmitate, with and without high glucose, as an in vitro model, we aimed to elucidate the cellular and molecular mechanisms underlying hepatic glucolipotoxicity. Our data showed that palmitate exposure induced the integrated stress response (ISR) in hepatocytes, evidenced by increased eIF2α phosphorylation (serine 51) and upregulated ATF4 expression. Moreover, we identified mTORC1 as a novel upstream kinase responsible for palmitate-triggered ISR induction. Furthermore, we showed that either mTORC1 inhibitors, ISRIB (an ISR inhibitor), or ATF4 knockdown abolished palmitate-induced cell death, indicating that the mTORC1-eIF2α- ATF4 pathway activation plays a mechanistic role in mediating palmitate-induced hepatocyte cell death. Our continuous investigations revealed that GPAT4-mediated metabolic flux of palmitate into the glycerolipid synthesis pathway is required for palmitate-induced mTORC1 activation and subsequent ISR induction. Specifically, we uncovered that saturated phosphatidic acid production contributes to palmitate-triggered mTORC1 activation. Our study provides the first evidence that high glucose enhances palmitate-induced activation of the mTORC1-eIF2α-ATF4 pathway, thereby exacerbating palmitate-induced hepatotoxicity. This effect is mediated by the increased availability of glycerol-3-phosphate, a substrate essential for phosphatidic acid synthesis. In conclusion, our study highlights that the activation of the mTORC1-eIF2α-ATF4 pathway, driven by saturated phosphatidic acid overproduction, plays a mechanistic role in hepatic glucolipotoxicity.
    Keywords:  ISR; Palmitate; glucolipotoxicity; mTORC1; phosphatidic acid
    DOI:  https://doi.org/10.1152/ajpgi.00027.2025
  3. Biol Chem. 2025 Apr 17.
    The mitochondrial unfolded protein response: acting near and far.
    Nikolaos Charmpilas, Qiaochu Li, Thorsten Hoppe.
      Mitochondria are central hubs of cellular metabolism and their dysfunction has been implicated in a variety of human pathologies and the onset of aging. To ensure proper mitochondrial function under misfolding stress, a retrograde mitochondrial signaling pathway known as UPRmt is activated. The UPRmt ensures that mitochondrial stress is communicated to the nucleus, where gene expression for several mitochondrial proteases and chaperones is induced, forming a protective mechanism to restore mitochondrial proteostasis and function. Importantly, the UPRmt not only acts within cells, but also exhibits a conserved cell-nonautonomous activation across species, where mitochondrial stress in a defined tissue triggers a systemic response that affects distant organs. Here, we summarize the molecular basis of the UPRmt in the invertebrate model organism Caenorhabditis elegans and in mammals. We also describe recent findings on cell-nonautonomous activation of the UPRmt in worms, flies and mice, and how UPRmt activation in specific tissues affects organismal metabolism and longevity.
    Keywords:  cell-nonautonomous regulation; integrated stress response; mitochondria; mitochondrial unfolded protein response; stress signaling
    DOI:  https://doi.org/10.1515/hsz-2025-0107
  4. Biochem Biophys Res Commun. 2025 Apr 05. pii: S0006-291X(25)00480-2. [Epub ahead of print]763 151766
    Integrative metabolic profiling of hypothalamus and skeletal muscle in a mouse model of cancer cachexia.
    Jae Yeon Choi, Ye Jin Kim, Jeong Seob Shin, EunBi Choi, Yuhyun Kim, Min Gwan Kim, Yang Tae Kim, Byong Seo Park, Jae Kwang Kim, Jae Geun Kim.
      Cancer cachexia is a multifactorial metabolic syndrome characterized by progressive weight loss, muscle wasting, and systemic inflammation. Despite its clinical significance, the underlying mechanisms linking central and peripheral metabolic changes remain incompletely understood. In this study, we employed a murine model of cancer cachexia induced by intraperitoneal injection of Lewis lung carcinoma (LLC1) cells to investigate tissue-specific metabolic adaptations. Cachectic mice exhibited reduced food intake, body weight loss, impaired thermoregulation, and decreased energy expenditure. Metabolomic profiling of serum, skeletal muscle, and hypothalamus revealed distinct metabolic shifts, with increased fatty acid and ketone body utilization and altered amino acid metabolism. Notably, hypothalamic metabolite changes diverged from peripheral tissues, showing decreased neurotransmitter-related metabolites and enhanced lipid-based energy signatures. Gene expression analysis further confirmed upregulation of glycolysis- and lipid oxidation-related genes in both hypothalamus and muscle. These findings highlight coordinated yet compartmentalized metabolic remodeling in cancer cachexia and suggest that hypothalamic adaptations may play a central role in the systemic energy imbalance associated with cachexia progression.
    Keywords:  Cancer cachexia; Energy metabolism; Hypothalamus; Metabolites; Muscle
    DOI:  https://doi.org/10.1016/j.bbrc.2025.151766
  5. Am J Physiol Cell Physiol. 2025 Apr 18.
    INFLAMMATION IN CANCER CACHEXIA: STILL THE CENTRAL TENET OR JUST ANOTHER PLAYER?
    Noemi Iaia, Chiara Noviello, Maurizio Muscaritoli, Paola Costelli.
      Cancer cachexia, a multifactorial syndrome characterised by body weight loss, muscle and adipose tissue wasting, affects cancer patients. Over time, the definition of cachexia has been modified, including inflammation as one of the main causal factors. Evidences have suggested that a range of pro-inflammatory mediators may be involved in the regulation of intracellular signalling, resulting in enhanced resting energy expenditure, metabolic changes, and muscle atrophy, all of which are typical features of cachexia. Physiologically speaking, however, inflammation is a response aimed at facing potentially damaging events. Along this line, its induction in the cancer hosts could be an attempt to restore the physiological homeostasis. Interesting observations have shown that cytokines such as interleukins 4 and 6 could improve muscle wasting, supporting the view that the same mediator may exert pro- or anti-inflammatory activity depending on the immune cells involved as well as on the tissue metabolic demand. In conclusion, whether inflammation is crucial to the occurrence of cachexia or just one contributor among others, is still unclear. Indeed, inflammation could trigger cachexia, but it could also be the response to alterations of energy and protein metabolism and hormonal homeostasis. Probably both aspects are true, supporting the view that inflammation could be a crucial issue or just another player. Whether the causative role prevails over the compensatory one likely depends on the tumour type and stage, on patient lifestyle, on the presence of comorbidities, on the response to anticancer treatments, paving the way to a holistic, personalized approach to cancer cachexia.
    Keywords:  Cachexia; Cancer; Cytokines; Inflammation; Skeletal muscle
    DOI:  https://doi.org/10.1152/ajpcell.00808.2024
  6. J Cachexia Sarcopenia Muscle. 2025 Apr;16(2): e13781
    Housing Temperature Impacts the Systemic and Tissue-Specific Molecular Responses to Cancer in Mice.
    Andrea Irazoki, Emma Frank, Tang Cam Phung Pham, Jessica L Braun, Amy M Ehrlich, Mark Haid, Fabien Riols, Camilla Hartmann Friis Hansen, Anne-Sofie Rydal Jørgensen, Nicoline Resen Andersen, Laura Hidalgo-Corbacho, Roberto Meneses-Valdes, Mona Sadek Ali, Steffen Henning Raun, Johanne Louise Modvig, Samantha Gallero, Steen Larsen, Zach Gerhart-Hines, Thomas Elbenhardt Jensen, Maria Rohm, Jonas T Treebak, Val Andrew Fajardo, Lykke Sylow.
       BACKGROUND: Cancer cachexia, affecting up to 80% of patients with cancer, is characterized by muscle and fat loss with functional decline. Preclinical research seeks to uncover the molecular mechanisms underlying cachexia to identify potential targets. Housing laboratory mice at ambient temperature induces cold stress, triggering thermogenic activity and metabolic adaptations. Yet, the impact of housing temperature on preclinical cachexia remains unknown.
    METHODS: Colon 26 carcinoma (C26)-bearing and PBS-inoculated (Ctrl) mice were housed at standard (ST; 20°C-22°C) or thermoneutral temperature (TN; 28°C-32°C). They were monitored for body weight, composition, food intake and systemic factors. Upon necropsy, tissues were weighed and used for evaluation of ex vivo force and respiration, or snap frozen for biochemical assays.
    RESULTS: C26 mice lost 7.5% body weight (p = 0.0001 vs. Ctrls), accounted by decreased fat mass (-35%, p < 0.0001 vs. Ctrls), showing mild cachexia irrespective of housing temperature. All C26 mice exhibited reduced force (-40%, p < 0.0001 vs. Ctrls) and increased atrogene expression (3-fold, p < 0.003 vs. Ctrls). Cancer altered white adipose tissue (WAT)'s functional gene signature (49%, p < 0.05 vs. Ctrls), whereas housing temperature reduced brown adipose tissue (BAT)'s (-78%, p < 0.05 vs. ST Ctrl). Thermogenic capacity measured by Ucp1 expression decreased upon cancer in both WAT and BAT (-93% and -63%, p < 0.0044 vs. Ctrls). Cancer-driven glucose intolerance was noted at ST (26%, p = 0.0192 vs. ST Ctrl), but restored at TN (-23%, p = 0.005 vs. ST C26). Circulating FGF21, GDF-15 and IL-6 increased in all C26 mice (4-fold, p < 0.009 vs. Ctrls), with a greater effect on IL-6 at TN (76%, p = 0.0018 vs. ST C26). Tumour and WAT Il6 mRNA levels remained unchanged, while cancer induced skeletal muscle (SkM) Il6 (2-fold, p = 0.0016 vs. Ctrls) at both temperatures. BAT Il6 was only induced in C26 mice at TN (116%, p = 0.0087 vs. ST C26). At the bioenergetics level, cancer increased SkM SERCA ATPase activity at ST (4-fold, p = 0.0108 vs. ST Ctrl) but not at TN. In BAT, O2 consumption enhanced in C26 mice at ST (119%, p < 0.03 vs. ST Ctrl) but was blunted at TN (-44%, p < 0.0001 vs. ST C26). Cancer increased BAT ATP levels regardless of temperature (2-fold, p = 0.0046 vs. Ctrls), while SERCA ATPase activity remained unchanged at ST and decreased at TN (-59%, p = 0.0213 vs. TN Ctrl).
    CONCLUSIONS: In mild cachexia, BAT and SkM bioenergetics are susceptible to different housing temperatures, which influences cancer-induced alterations in glucose metabolism and systemic responses.
    Keywords:  bioenergetics; cancer cachexia; cold‐induced stress; thermogenic tissues; thermoneutrality
    DOI:  https://doi.org/10.1002/jcsm.13781
  7. Nat Metab. 2025 Apr 15.
    GDF15 links adipose tissue lipolysis with anxiety.
    Logan K Townsend, Dongdong Wang, Carly M Knuth, Russta Fayyazi, Ahmad Mohammad, Léa J Becker, Evangelia E Tsakiridis, Eric M Desjardins, Zeel Patel, Celina M Valvano, Junfeng Lu, Alice E Payne, Ofure Itua, Kyle D Medak, Daniel M Marko, Jonathan D Schertzer, David C Wright, Shawn M Beaudette, Katherine M Morrison, André C Carpentier, Denis P Blondin, Rebecca E K MacPherson, Jordan G McCall, Marc G Jeschke, Gregory R Steinberg.
      Psychological stress changes both behaviour and metabolism to protect organisms. Adrenaline is an important driver of this response. Anxiety correlates with circulating free fatty acid levels and can be alleviated by a peripherally restricted β-blocker, suggesting a peripheral signal linking metabolism with behaviour. Here we show that adrenaline, the β3 agonist CL316,243 and acute restraint stress induce growth differentiation factor 15 (GDF15) secretion in white adipose tissue of mice. Genetic inhibition of adipose triglyceride lipase or genetic deletion of β-adrenergic receptors blocks β-adrenergic-induced increases in GDF15. Increases in circulating GDF15 require lipolysis-induced free fatty acid stimulation of M2-like macrophages within white adipose tissue. Anxiety-like behaviour elicited by adrenaline or restraint stress is eliminated in mice lacking the GDF15 receptor GFRAL. These data provide molecular insights into the mechanisms linking metabolism and behaviour and suggest that inhibition of GDF15-GFRAL signalling might reduce acute anxiety.
    DOI:  https://doi.org/10.1038/s42255-025-01264-3
  8. World J Gastrointest Oncol. 2025 Apr 15. 17(4): 99188
    Impact of SLC16A8 on tumor microenvironment and angiogenesis in colorectal cancer: New therapeutic target insights.
    Hong-Peng Tian, Zhong-Xiang Xiao, Bo-Wen Su, Yi-Xuan Li, Hong Peng, Chang-Yuan Meng.
       BACKGROUND: SLC16A8, a lactate efflux transporter, is upregulated in various cancers, but its effects on tumor microenvironments remain understudied. This research explores its role in colorectal cancer (CRC) and the impact on the associated microenvironment consisting of vascular endothelial cells.
    AIM: To explore the role in CRC and the impact on the associated microenvironment consisting of vascular endothelial cells.
    METHODS: Hypoxic conditions prompted examination of SLC16A8 expression, glycolysis, lactate efflux, and Warburg effect correlations in CRC cell lines. Co-culture with HUVEC allowed for endothelial-mesenchymal transition (EndMT) characterization, revealing lactate efflux's influence. Knockdown of SLC16A8 in CRC cells enabled relevant phenotype tests and tumorigenesis experiments, investigating tumor growth, blood vessel distribution, and signaling pathway alterations.
    RESULTS: SLC16A8 expression was significantly upregulated in CRC tissues compared to adjacent normal tissues and correlated with disease progression (P < 0.05). Under hypoxic conditions, HIF-1α induced SLC16A8 expression, leading to enhanced metabolic reprogramming and increased lactate production. siRNA-mediated SLC16A8 knockdown effectively reversed hypoxia-induced changes, including reduced glucose consumption and lactate production. Co-culture experiments revealed that SLC16A8 knockdown significantly inhibited hypoxia-induced EndMT in HUVEC cells. In vivo studies demonstrated that SLC16A8 knockdown suppressed tumor growth, reduced Ki67 expression, and decreased HIF-1α levels. Furthermore, SLC16A8 silencing led to decreased expression of key metabolic enzymes PKM2 and LDHA, indicating its role in glycolytic regulation.
    CONCLUSION: Our findings reveal that SLC16A8 functions as a critical mediator of hypoxia-induced metabolic reprogramming in CRC progression.
    Keywords:  Angiogenesis; Colorectal cancer; Glycolysis; Hypoxia; SLC16A8
    DOI:  https://doi.org/10.4251/wjgo.v17.i4.99188
  9. Nat Commun. 2025 Apr 12. 16(1): 3492
    Mutant CEBPA promotes tolerance to inflammatory stress through deficient AP-1 activation.
    Maria Cadefau-Fabregat, Gerard Martínez-Cebrián, Lucía Lorenzi, Felix D Weiss, Anne-Katrine Frank, José Manuel Castelló-García, Eric Julià-Vilella, Andrés Gámez-García, Laura Yera, Carini Picardi Morais de Castro, Yi-Fang Wang, Felix Meissner, Alejandro Vaquero, Matthias Merkenschlager, Bo T Porse, Sergi Cuartero.
      The CEBPA transcription factor is frequently mutated in acute myeloid leukemia (AML). Mutations in the CEBPA gene, which are typically biallelic, result in the production of a shorter isoform known as p30. Both the canonical 42-kDa isoform (p42) and the AML-associated p30 isoform bind chromatin and activate transcription, but the specific transcriptional programs controlled by each protein and how they are linked to a selective advantage in AML is not well understood. Here, we show that cells expressing the AML-associated p30 have reduced baseline inflammatory gene expression and display altered dynamics of transcriptional induction in response to LPS, consequently impacting cytokine secretion. This confers p30-expressing cells an increased resistance to the adverse effects of prolonged exposure to inflammatory signals. Mechanistically, we show that these differences primarily arise from the differential regulation of AP-1 family proteins. In addition, we find that the impaired function of the AP-1 member ATF4 in p30-expressing cells alters their response to ER stress. Collectively, these findings uncover a link between mutant CEBPA, inflammation and the stress response, potentially revealing a vulnerability in AML.
    DOI:  https://doi.org/10.1038/s41467-025-58712-7
  10. Eur J Immunol. 2025 Apr;55(4): e202451102
    Metabolic Dialogue Shapes Immune Response in the Tumor Microenvironment.
    Fengxia Gao, Rushil Shah, Gang Xin, Ruoning Wang.
      The fate of immune cells is fundamentally linked to their metabolic program, which is also influenced by the metabolic landscape of their environment. The tumor microenvironment represents a unique system for intercellular metabolic interactions, where tumor-derived metabolites suppress effector CD8+ T cells and promote tumor-promoting macrophages, reinforcing an immune-suppressive niche. This review will discuss recent advancements in metabolism research, exploring the interplay between various metabolites and their effects on immune cells within the tumor microenvironment.
    DOI:  https://doi.org/10.1002/eji.202451102
  11. Sci Rep. 2025 Apr 16. 15(1): 13148
    Hypoxia LUAD H1975 cell-derived exosomal miR-671-3p promotes angiogenesis via regulating KLF2-VEGFR2 axis.
    Kun Liu, Yi Wang, Qisen Li, Yujue Wang, Jinrui Liu, Jintao Zhou, Feiyu Song, Zhongyi Cong, Zhe Wang, Ning Kong.
      For solid tumors, hypoxia is associated with disease aggressiveness and poor outcomes. In addition to undergoing broad intracellular molecular and metabolic adaptations, hypoxic tumor cells extensively communicate with their microenvironments to facilitate conditions favorable for their survival, growth, and metastasis. This communication is mediated by diverse secretory factors, including exosomes (extracellular vesicles of endosomal origin). Exosomal cargo is altered considerably by hypoxia, with significant impacts on tumor-cell communication with both local and distant microenvironments. Exosomes released by cancer cells influence the tumor environment to accelerate metastasis. While tumor-derived exosomes have been identified as a major driver of premetastatic niche formation at distant sites, this mechanism in lung adenocarcinoma (LUAD) remains unclear. We found that miR-671-3p in exosomes derived from H1975 under hypoxic conditions target Krüppel-like factor 2 (KLF2) to regulate VEGFR2 expression in endothelial cells to promote angiogenesis. In addition, miR-671-3p is expressed at high levels in circulating exosomes isolated from patients with LUAD. Our study suggests that exosome miR-671-3p is involved in the formation of premetastatic niche and may serve as a blood-based biomarker for LUAD metastasis.
    Keywords:  Angiogenesis; Exosome; Hypoxia; LUAD; Premetastatic niche; miR-671-3p
    DOI:  https://doi.org/10.1038/s41598-025-97488-0
  12. Cell. 2025 Apr 10. pii: S0092-8674(25)00343-5. [Epub ahead of print]
    Integrator loss leads to dsRNA formation that triggers the integrated stress response.
    Apoorva Baluapuri, Nicole ChenCheng Zhao, Ryan J Marina, Kai-Lieh Huang, Anastasia Kuzkina, Maria E Amodeo, Chad B Stein, Lucie Y Ahn, Jordan S Farr, Ashleigh E Schaffer, Vikram Khurana, Eric J Wagner, Karen Adelman.
      Integrator (INT) is a metazoan-specific complex that targets promoter-proximally paused RNA polymerase II (RNAPII) for termination, preventing immature RNAPII from entering gene bodies and functionally attenuating transcription of stress-responsive genes. Mutations in INT subunits are associated with many human diseases, including cancer, ciliopathies, and neurodevelopmental disorders, but how reduced INT activity contributes to disease is unknown. Here, we demonstrate that the loss of INT-mediated termination in human cells triggers the integrated stress response (ISR). INT depletion causes upregulation of short genes such as the ISR transcription factor activating transcription factor 3 (ATF3). Further, immature RNAPII that escapes into genes upon INT depletion is prone to premature termination, generating incomplete pre-mRNAs with retained introns. Retroelements within retained introns form double-stranded RNA (dsRNA) that is recognized by protein kinase R (PKR), which drives ATF4 activation and prolonged ISR. Critically, patient cells with INT mutations exhibit dsRNA accumulation and ISR activation, thereby implicating chronic ISR in diseases caused by INT deficiency.
    Keywords:  IR-Alu; Integrator; RNA polymerase II pausing; double-stranded RNA; gene regulation; integrated stress response; premature cleavage and polyadenylation; premature termination; protein kinase R
    DOI:  https://doi.org/10.1016/j.cell.2025.03.025
  13. BMC Cancer. 2025 Apr 14. 25(1): 678
    Interactions between leukemia and feeders in co-cultivation under hypoxia.
    Miriama Sikorová, Pavel Klener, Pavla Tonarová, Marie Hubálek Kalbáčová.
       BACKGROUND: Leukemia is driven by complex interactions within the inherently hypoxic bone marrow microenvironment, impacting both disease progression and therapeutic resistance. Co-cultivation of leukemic cells with feeder cells has emerged as a valuable tool to mimic the bone marrow niche. This study explores the interplay between human commercial SD-1 and patient-derived UPF26K leukemic cell lines with feeders - human fibroblasts (NHDF) and mesenchymal stem cells (hMSCs) under normoxic and hypoxic conditions.
    RESULTS: Co-cultivation with feeders significantly enhances proliferation and glycolytic activity in the SD-1 cells, improving their viability, while this interaction inhibits the growth and glucose metabolism of the feeders, particularly NHDF. In contrast, UPF26K cells show reduced proliferation when co-cultivated with the feeders while this interaction stimulates NHDF and hMSCs proliferation and glycolysis but reduce their mitochondrial metabolism with hypoxia amplifying these effects.
    CONCLUSIONS: Cells that switch to glycolysis during co-cultivation, particularly under hypoxia, benefit most from these low oxygen conditions. Due to this leukemic cells' response heterogeneity, targeting microenvironmental interactions and oxygen levels is crucial for personalized leukemia therapy. Advancing co-cultivation models, particularly through innovations like spheroids, can further enhance in vitro studies of primary leukemic cells and support the testing of novel therapies.
    Keywords:  Co-cultivation; Feeders; Hypoxia; Leukemic cells; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12885-025-13988-2
  14. Cancer Med. 2025 Apr;14(8): e70785
    Blockade of Exosome Release Sensitizes Breast Cancer to Doxorubicin via Inhibiting Angiogenesis.
    Jindi He, Fengyi He, Qinlian Yang, Qiuyun Li.
       BACKGROUND: Chemotherapy combined with angiogenesis inhibition holds great promise in improving the therapeutic efficacy in cancer treatment. The aim of this study was to explore the effect of exosome blockade on tumor angiogenesis and chemotherapy efficacy.
    METHODS: Exosomes were extracted by ultracentrifugation, and the effect of exosomes on angiogenesis was evaluated by 4T1 mouse breast cancer cell line and the syngeneic mouse tumor model and immunofluorescence. The endocytosis of exosomes from vascular endothelial cells was evaluated in vitro by co-culture and immunofluorescence assays. Tube formation and CCK-8 assays were used to evaluate the effect of exosomes on angiogenesis in vitro. The effect of exosome blockade on the efficacy of doxorubicin was evaluated by 4T1 mouse breast cancer model, cancer cell-derived exosomes (Exo4T1), GW4869 and doxorubicin in vivo.
    RESULTS: Exo4T1 can be efficiently endocytosed by vascular endothelial cells both in vitro and in vivo. Within the recipient endothelial cells, Exo4T1 elicited angiogenesis at least partially via promoting cell proliferation, as the exosomes were carrying cargos with pro-proliferation capacity. Blockade of exosome release through GW4869 significantly inhibited angiogenesis, increased the concentration of doxorubicin within the tumor, and sensitized the tumor to doxorubicin in the murine 4T1 syngeneic model, whereas the therapeutic effects were abrogated when Exo4T1 was additionally treated. Moreover, we found there was no synergy between GW4869 and pazopanib (PP, a traditional angiogenesis inhibitor).
    CONCLUSIONS: Together, we here revealed that cancer-derived exosomes promote angiogenesis during cancer progression and GW4869 treatment would sensitize the cancer cells to doxorubicin at least partially via inhibiting angiogenesis.
    Keywords:  Adriamycin; GW4869; angiogenesis; breast cancer; exosome
    DOI:  https://doi.org/10.1002/cam4.70785
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