bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2023‒01‒08
eight papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge
  1. Small extracellular vesicles in metabolic remodeling of tumor cells: Cargos and translational application.
  2. Immunoediting instructs tumor metabolic reprogramming to support immune evasion.
  3. HIF-1α/YAP Signaling Rewrites Glucose/Iodine Metabolism Program to Promote Papillary Thyroid Cancer Progression.
  4. Tumor hypoxia: From basic knowledge to therapeutic implications.
  5. Hypoxia and TNF-α Synergistically Induce Expression of IL-6 and IL-8 in Human Fibroblast-like Synoviocytes via Enhancing TAK1/NF-κB/HIF-1α Signaling.
  6. Enhanced glutaminolysis drives hypoxia-induced chemoresistance in pancreatic cancer.
  7. IL-6 mediates suppression of T and NK cells function in EMT-associated TKI-resistant EGFR mutant NSCLC<.
  8. The role of unfolded protein response-associated miRNAs in immunogenic cell death amplification: A literature review and bioinformatics analysis.
  1. Front Pharmacol. 2022 ;13 1009952
    Small extracellular vesicles in metabolic remodeling of tumor cells: Cargos and translational application.
    Hao Yang, Jingyi Wang, Gang Huang.
      Warburg effect is characterized by excessive consumption of glucose by the tumor cells under both aerobic and hypoxic conditions. This metabolic reprogramming allows the tumor cells to adapt to the unique microenvironment and proliferate rapidly, and also promotes tumor metastasis and therapy resistance. Metabolic reprogramming of tumor cells is driven by the aberrant expression and activity of metabolic enzymes, which results in the accumulation of oncometabolites, and the hyperactivation of intracellular growth signals. Recent studies suggest that tumor-associated metabolic remodeling also depends on intercellular communication within the tumor microenvironment (TME). Small extracellular vesicles (sEVs), also known as exosomes, are smaller than 200 nm in diameter and are formed by the fusion of multivesicular bodies with the plasma membrane. The sEVs are instrumental in transporting cargoes such as proteins, nucleic acids or metabolites between the tumor, stromal and immune cells of the TME, and are thus involved in reprogramming the glucose metabolism of recipient cells. In this review, we have summarized the biogenesis and functions of sEVs and metabolic cargos, and the mechanisms through they drive the Warburg effect. Furthermore, the potential applications of targeting sEV-mediated metabolic pathways in tumor liquid biopsy, imaging diagnosis and drug development have also been discussed.
    Keywords:  drug development; exosomes; glycolysis; liquid biopsy; small extracellular vesicles; tumor metabolism; warburg effect
    DOI:  https://doi.org/10.3389/fphar.2022.1009952
  2. Cell Metab. 2023 Jan 03. pii: S1550-4131(22)00540-X. [Epub ahead of print]35(1): 118-133.e7
    Immunoediting instructs tumor metabolic reprogramming to support immune evasion.
    Chin-Hsien Tsai, Yu-Ming Chuang, Xiaoyun Li, Yi-Ru Yu, Sheue-Fen Tzeng, Shao Thing Teoh, Katherine E Lindblad, Mario Di Matteo, Wan-Chen Cheng, Pei-Chun Hsueh, Kung-Chi Kao, Hana Imrichova, Likun Duan, Hector Gallart-Ayala, Pei-Wen Hsiao, Massimiliano Mazzone, Julijana Ivanesevic, Xiaojing Liu, Karin E de Visser, Amaia Lujambio, Sophia Y Lunt, Susan M Kaech, Ping-Chih Ho.
      Immunoediting sculpts immunogenicity and thwarts host anti-tumor responses in tumor cells during tumorigenesis; however, it remains unknown whether metabolic programming of tumor cells can be guided by immunosurveillance. Here, we report that T cell-mediated immunosurveillance in early-stage tumorigenesis instructs c-Myc upregulation and metabolic reprogramming in tumor cells. This previously unexplored tumor-immune interaction is controlled by non-canonical interferon gamma (IFNγ)-STAT3 signaling and supports tumor immune evasion. Our findings uncover that immunoediting instructs deregulated bioenergetic programs in tumor cells to empower them to disarm the T cell-mediated immunosurveillance by imposing metabolic tug-of-war between tumor and infiltrating T cells and forming the suppressive tumor microenvironment.
    Keywords:  IFNγ; Myc; STAT3; immunoediting; immunosurveillance; tumor immunology
    DOI:  https://doi.org/10.1016/j.cmet.2022.12.003
  3. Int J Biol Sci. 2023 ;19(1): 225-241
    HIF-1α/YAP Signaling Rewrites Glucose/Iodine Metabolism Program to Promote Papillary Thyroid Cancer Progression.
    Hongjun Song, Zhongling Qiu, Yang Wang, Chuang Xi, Guoqiang Zhang, Zhenkui Sun, Quanyong Luo, Chentian Shen.
      Background: The management of aggressive and progressive metastatic papillary thyroid cancer (PTC) is very difficult. An inverse relationship between radioiodine and F-18 fluorodeoxyglucose (FDG) uptake (''flip-flop'' phenomenon) is described for invasive PTC during dedifferentiation. However, no satisfactory biologic explanation for this phenomenon. Hypoxia is an important microenvironmental factor that promotes cancer progression and glycolysis. The Hippo-YAP is a highly conserved tumor suppressor pathway and contributes to cancer metabolic reprogramming. Thus, we investigated the underlying molecular mechanisms of glucose/iodine metabolic reprogramming in PTC, focusing on the tumor hypoxia microenvironment and Hippo-YAP signaling. Methods: Immunohistochemistry staining was conducted to evaluate the expressions of hypoxia-inducible factor 1α (HIF-1α), yes-associated protein (YAP), glucose transporters 1 (GLUT1) and sodium iodine symporter (NIS) in matched PTC and the adjacent noncancerous tissues. PTC cell lines were cultured under normoxic (20% O2) and hypoxic (1% O2) conditions and the glycolysis level and NIS expression were measured. Further, we characterized the molecular mechanism of glucose/iodine metabolic reprogramming in PTC cell. Finally, we validated the results in vivo by establishing subcutaneous xenografts in nude mice. Results: The expression levels of HIF1-α, YAP and GLUT1 were upregulated in PTC tissues and YAP expression was positively associated with HIF-1α, GLUT1 and TNM stages. Meanwhile, the expression of NIS was negatively correlated with YAP. Further, in vitro studies indicated that hypoxia-induced YAP activation was critical for accelerating glycolysis and reducing NIS expression in PTC cells. Inhibition of YAP had the opposite effects in vitro and tumorigenicity in vivo. Hypoxia inhibited the Hippo signaling pathway resulting in the inactivation of YAP phosphorylation, further promoting the nuclear localization of YAP in PTC cells. The mechanism is that hypoxic stress promoted YAP binding to HIF-1α in the nucleus and maintained HIF-1α protein stability. The YAP/HIF-1α complex bound and directly activated the GLUT1 transcription to accelerate glycolysis. Meanwhile, HIF-1α/YAP signaling might indirectly reduce the expression of NIS by promoting the output of MAPK signaling. In vivo studies confirmed the YAP-mediated reprogramming of glucose/iodine metabolism promoted PTC progression. Conclusions: Collectively, our data revealed a novel regulatory mechanism of the glucose/iodine metabolic program rewritten by HIF-1α/YAP signaling in PTC. Inhibition of HIF-1α/YAP signaling alone or in combination with other potential markers may effectively combat aggressive PTC.
    Keywords:  Glucose/Iodine metabolism; HIF-1α; Papillary thyroid cancer; Progression.; YAP
    DOI:  https://doi.org/10.7150/ijbs.75459
  4. Semin Cancer Biol. 2023 Jan 02. pii: S1044-579X(22)00265-6. [Epub ahead of print]
    Tumor hypoxia: From basic knowledge to therapeutic implications.
    Chengheng Liao, Xijuan Liu, Cheng Zhang, Qing Zhang.
      Diminished oxygen availability, termed hypoxia, within solid tumors is one of the most common characteristics of cancer. Hypoxia shapes the landscape of the tumor microenvironment (TME) into a pro-tumorigenic and pro-metastatic niche through arrays of pathological alterations such as abnormal vasculature, altered metabolism, immune-suppressive phenotype, etc. In addition, emerging evidence suggests that limited efficacy or the development of resistance towards antitumor therapy may be largely due to the hypoxic TME. This review will focus on summarizing the knowledge about the molecular machinery that mediates the hypoxic cellular responses and adaptations, as well as highlighting the effects and consequences of hypoxia, especially for angiogenesis regulation, cellular metabolism alteration, and immunosuppressive response within the TME. We also outline the current advances in novel therapeutic implications through targeting hypoxia in TME. A deep understanding of the basics and the role of hypoxia in the tumor will help develop better therapeutic avenues in cancer treatment.
    Keywords:  Hypoxia; Hypoxia-inducible factors; Tumor microenvironment; angiogenesis; immunotherapy; metabolism
    DOI:  https://doi.org/10.1016/j.semcancer.2022.12.011
  5. Inflammation. 2023 Jan 06.
    Hypoxia and TNF-α Synergistically Induce Expression of IL-6 and IL-8 in Human Fibroblast-like Synoviocytes via Enhancing TAK1/NF-κB/HIF-1α Signaling.
    Guofen Wang, Junsong Wang, Xian Li, Qiyang Wu, Ruifeng Yao, Xinjing Luo.
      Hypoxia and increased levels of inflammatory cytokines in the joints are characteristics of rheumatoid arthritis (RA). However, the effects of hypoxia and tumor necrosis factor-α (TNF-α) on interleukin (IL)-6 and IL-8 production on fibroblast-like synoviocytes (FLSs) remain to be clarified. This study aimed to explore how hypoxia and TNF-α affect the expression of IL-6 and IL-8 in human FLSs isolated from RA patients. Hypoxia or TNF-α treatment alone significantly increased the expression and promoter activity of IL-6, IL-8, and hypoxia-inducible factor-1α (HIF-1α). Treatment of hypoxic FLSs with TNF-α further significantly elevated the expression of these cytokines and enhanced promoter activity of HIF-1α, which was abrogated by treatment with the HIF-1α inhibitor YC-1. Similarly, TNF-α alone elevated the phosphorylation and promoter activity of nuclear factor-κBp65 (NF-κBp65) in the FLSs. These effects were further enhanced by the combined treatment of hypoxia and TNFα but were attenuated by the NF-κB inhibitor BAY11-7082. NF-κB-p65 inhibition decreased the effect of TNF-α on HIF-1α upregulation in the FLSs in response to hypoxia. The combination of hypoxia and TNF-α also significantly upregulated transforming growth factor-β-activated kinase 1 (TAK1) expression, and silencing TAK1 dramatically decreased NF-κB-p65, HIF-1α, IL-6, and IL-8 expression under the same conditions. Our results indicate that hypoxia and TNF-α synergistically increase IL-6 and IL-8 expression in human FLSs via enhancing TAK1/NF-κB/HIF-1α signaling.
    Keywords:  cytokines; fibroblast-like synoviocytes; hypoxia; rheumatoid arthritis; signal pathways.
    DOI:  https://doi.org/10.1007/s10753-022-01779-x
  6. Cancer Res. 2023 Jan 03. pii: CAN-22-2045. [Epub ahead of print]
    Enhanced glutaminolysis drives hypoxia-induced chemoresistance in pancreatic cancer.
    Seung Joon Park, Hee Chan Yoo, Eunyong Ahn, Enzhi Luo, Yeabeen Kim, Yulseung Sung, Ya Chun Yu, Kibum Kim, Do Sik Min, Hee Seung Lee, Geum-Sook Hwang, TaeJin Ahn, Junjeong Choi, Seungmin Bang, Jung Min Han.
      Pancreatic ductal adenocarcinoma (PDAC) exhibits severe hypoxia, which is associated with chemoresistance and worse patient outcome. It has been reported that hypoxia induces metabolic reprogramming in cancer cells. However, it is not well known whether metabolic reprogramming contributes to hypoxia. Here, we established that increased glutamine catabolism is a fundamental mechanism inducing hypoxia, and thus chemoresistance, in PDAC cells. An extracellular matrix (ECM) component-based in vitro 3D cell printing model with patient-derived PDAC cells that recapitulates the hypoxic status in PDAC tumors showed that chemoresistant PDAC cells exhibit markedly enhanced glutamine catabolism compared to chemoresponsive PDAC cells. The augmented glutamine metabolic flux increased the oxygen consumption rate via mitochondrial oxidative phosphorylation (OXPHOS), promoting hypoxia and hypoxia-induced chemoresistance. Targeting glutaminolysis relieved hypoxia and improved chemotherapy efficacy in vitro and in vivo. This work suggests that targeting the glutaminolysis-OXPHOS-hypoxia axis is a novel therapeutic target for treating patients with chemoresistant PDAC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-2045
  7. Clin Cancer Res. 2023 Jan 03. pii: CCR-22-3379. [Epub ahead of print]
    IL-6 mediates suppression of T and NK cells function in EMT-associated TKI-resistant EGFR mutant NSCLC<.
    Sonia A Patel, Monique B Nilsson, Yan Yang, Xiuning Le, Hai Tran, Yasir Y Elamin, Xiaoxing Yu, Fahao Zhang, Alissa Poteete, Xiaoyang Ren, Li Shen, Jing Wang, Seyed Javad Moghaddam, Tina Cascone, Michael Curran, Don L Gibbons, John V Heymach.
      PURPOSE: Advanced non-small cell lung cancer (NSCLC) patients harboring activating epidermal growth factor receptor (EGFR) mutations are initially responsive to tyrosine kinase inhibitors (TKIs). However, therapeutic resistance eventually emerges, often via secondary EGFR mutations or EGFR-independent mechanisms such as EMT. Treatment options after EGFR-TKI resistance are limited as anti-PD-1/PD-L1 inhibitors typically display minimal benefit. Given that IL-6 is associated with worse outcomes in NSCLC patients, we investigate if IL-6 in part contributes to this immunosuppressed phenotype.EXPERIMENTAL DESIGN: We utilized a syngeneic genetically engineered mouse model (GEMM) of EGFR mutant NSCLC to investigate the effects of IL-6 on the tumor microenvironment and the combined efficacy of IL-6 inhibition and anti-PD1 therapy. Corresponding in vitro studies used EGFR mutant human cell lines and clinical specimens.
    RESULTS: We identified that EGFR mutant tumors which have oncogene-independent acquired resistance to EGFR-TKIs were more mesenchymal and had markedly enhanced IL-6 secretion. In EGFR mutant GEMMs, IL-6 depletion enhanced activation of infiltrating NK and T cell subpopulations and decreased immunosuppressive T-regulatory and Th17 cell populations. Inhibition of IL-6 increased NK and T cell -mediated killing of human osimertinib-resistant EGFR mutant NSCLC tumor cells in cell culture. IL-6 blockade sensitized EGFR mutant GEMM tumors to PD-1 inhibitors through an increase in tumor-infiltrating IFNγ+ CD8+ T cells.
    CONCLUSIONS: These data indicate that IL-6 is upregulated in EGFR mutant NSCLC tumors with acquired EGFR-TKI resistance and suppressed T and NK cell function. IL-6 blockade enhanced antitumor immunity and efficacy of anti-PD1 therapy warranting future clinical combinatorial investigations.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-3379
  8. Life Sci. 2022 Dec 29. pii: S0024-3205(22)01041-4. [Epub ahead of print]314 121341
    The role of unfolded protein response-associated miRNAs in immunogenic cell death amplification: A literature review and bioinformatics analysis.
    Mahdieh Azizi, Sadra Salehi-Mazandarani, Parvaneh Nikpour, Alireza Andalib, Marzieh Rezaei.
      Immunogenic cell death (ICD) is a type of cellular death that is elicited in response to the specific types of anti-cancer therapies and enhances the anti-tumor immune responses by the combination of antigenicity and adjuvanticity of dying tumor cells. There is a well-established interlink between endoplasmic reticulum stress (ERS) and ICD elicited by anti-cancer therapies. Most recent evidences support that unfolded protein response (UPR)-associated miRNAs can be key players in the ERS-induced ICD. Hence, in the present study, we conducted a literature review on the role of these miRNAs and associated molecular pathways that may regulate ICD. We first collected UPR-associated miRNAs that promote ERS-induced apoptosis and then focused on microRNAs (miRNAs) that promote ERS-induced apoptosis via PERK/eIF2α/ATF4/CHOP pathway activation, as the main core for ICD and release of damage-associated molecular patterns. To better identify PERK/eIF2α/ATF4/CHOP pathway-inducing miRNAs that can be used as potential therapeutic targets for improving ICD in cancer treatment, we did a comprehensive bioinformatics analysis and network construction. Our results showed that "pathways in cancer", "MAPK signaling pathway", "PI3K-Akt signaling pathway", and "Cellular senescence", which correlate with UPR components and ERS induction, were among the significant signaling pathways related to the target genes of these miRNAs. Furthermore, a protein-protein interaction (PPI) network was constructed, which revealed the involvement of the PPI-extracted hub genes in the regulation of proliferation and apoptosis. In conclusion, we propose that these types of miRNAs can be considered as the potential cancer therapy options for better induction of ICD in combination with other ICD inducers.
    Keywords:  Bioinformatics; Cancer therapy; Endoplasmic reticulum stress; Immunogenic cell death; Unfolded protein response; miRNAs
    DOI:  https://doi.org/10.1016/j.lfs.2022.121341
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