bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2024–06–16
nine papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Hypoxia-induced activation of HIF-1alpha/IL-1beta axis in microglia promotes glioma progression via NF-κB-mediated upregulation of heparanase expression.
  2. Serine Depletion Promotes Anti-Tumor Immunity by Activating Mitochondrial DNA-mediated cGAS-STING Signaling.
  3. Role of transforming growth factor-β1 pathway in angiogenesis induced by chronic stress in colorectal cancer.
  4. Targeting metabolic pathways to counter cancer immunotherapy resistance.
  5. Lactate-induced activation of tumor-associated fibroblasts and IL-8-mediated macrophage recruitment promote lung cancer progression.
  6. Role of HIF-1α in the Responses of Tumors to Radiotherapy and Chemotherapy.
  7. Glucose deprivation triggers DCAF1-mediated inactivation of Rheb-mTORC1 and promotes cancer cell survival.
  8. Tumor metabolic activity is associated with subcutaneous adipose tissue radiodensity and survival in non-small cell lung cancer.
  9. Loss of Lipocalin2 confers cisplatin vulnerability through modulating NF-ĸB mediated ferroptosis via ferroportin.
  1. Biol Direct. 2024 Jun 11. 19(1): 45
    Hypoxia-induced activation of HIF-1alpha/IL-1beta axis in microglia promotes glioma progression via NF-κB-mediated upregulation of heparanase expression.
    Jinchao Si, Jingya Guo, Xu Zhang, Wei Li, Shen Zhang, Shuyu Shang, Quanwu Zhang.
       BACKGROUND: Glioma is a common tumor that occurs in the brain and spinal cord. Hypoxia is a crucial feature of the tumor microenvironment. Tumor-associated macrophages/microglia play a crucial role in the advancement of glioma. This study aims to illuminate the detailed mechanisms by which hypoxia regulates microglia and, consequently, influences the progression of glioma.
    METHODS: The glioma cell viability and proliferation were analyzed by cell counting kit-8 assay and 5-ethynyl-2'-deoxyuridine assay. Wound healing assay and transwell assay were implemented to detect glioma cell migration and invasion, respectively. Enzyme-linked immunosorbent assay was conducted to detect protein levels in cell culture medium. The protein levels in glioma cells and tumor tissues were evaluated using western blot analysis. The histological morphology of tumor tissue was determined by hematoxylin-eosin staining. The protein expression in tumor tissues was determined using immunohistochemistry. Human glioma xenograft in nude mice was employed to test the influence of hypoxic microglia-derived interleukin-1beta (IL-1β) and heparanase (HPSE) on glioma growth in vivo.
    RESULTS: Hypoxic HMC3 cells promoted proliferation, migration, and invasion abilities of U251 and U87 cells by secreting IL-1β, which was upregulated by hypoxia-induced activation of hypoxia inducible factor-1alpha (HIF-1α). Besides, IL-1β from HMC3 cells promoted glioma progression and caused activation of nuclear factor-κB (NF-κB) and upregulation of HPSE in vivo. We also confirmed that IL-1β facilitated HPSE expression in U251 and U87 cells by activating NF-κB. Hypoxic HMC3 cells-secreted IL-1β facilitated the proliferation, migration, and invasion of U251 and U87 cells via NF-κB-mediated upregulation of HPSE expression. Finally, we revealed that silencing HPSE curbed the proliferation and metastasis of glioma in mice.
    CONCLUSION: Hypoxia-induced activation of HIF-1α/IL-1β axis in microglia promoted glioma progression via NF-κB-mediated upregulation of HPSE expression.
    Keywords:  Glioma; Heparanase; Hypoxia; Hypoxia inducible factor-1α; Interleukin-1β; Microglia
    DOI:  https://doi.org/10.1186/s13062-024-00487-w
  2. Cancer Res. 2024 Jun 11.
    Serine Depletion Promotes Anti-Tumor Immunity by Activating Mitochondrial DNA-mediated cGAS-STING Signaling.
    Suchandrima Saha, Monisankar Ghosh, Jinyu Li, Asher Wen, Lorenzo Galluzzi, Luis A Martinez, David C Montrose.
      Serine is critical for supporting cancer metabolism, and depriving malignant cells of this non-essential amino acid exerts anti-neoplastic effects, in large part, through disrupting metabolic pathways. Given the intricate relationship between cancer metabolism and the immune system, the metabolic defects imposed by serine deprivation might impact tumor-targeting immunity. Here, we demonstrated that restricting endogenous and exogenous sources of serine in colorectal cancer (CRC) cells results in mitochondrial dysfunction, leading to mitochondrial DNA (mtDNA) accumulation in the cytosol and consequent cGAS-STING1-driven type I interferon (IFN) secretion. Depleting mtDNA or blocking its release attenuated cGAS-STING1 activation during serine deprivation. In vivo studies revealed that serine deprivation limits tumor growth, accompanied by enhanced type I IFN signaling and intratumoral infiltration of immune effector cells. Notably, the tumor-suppressive and immune-enhancing effects of serine restriction were impaired by T cell depletion and IFN receptor blockade. Moreover, disrupting cGAS-STING1 signaling in CRC cells limited the immunostimulatory and tumor-suppressive effects of serine deprivation. Lastly, serine depletion increased the sensitivity of tumors to an immune checkpoint inhibitor targeting PD-1. Taken together, these findings reveal a role for serine as a suppressor of anti-tumor immunity, suggesting that serine deprivation may be employed to enhance tumor immunogenicity and improve responsiveness to immune checkpoint inhibitors.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-1788
  3. Cancer Biol Ther. 2024 Dec 31. 25(1): 2366451
    Role of transforming growth factor-β1 pathway in angiogenesis induced by chronic stress in colorectal cancer.
    Jie Zhang, Yao-Tiao Deng, Jie Liu, Lu Gan, Yu Jiang.
       BACKGROUND: Chronic stress can induce stress-related hormones; norepinephrine (NE) is considered to have the highest potential in cancer. NE can stimulate the expression of hypoxia-inducible factor-1α (HIF-1α), which is associated with vascular endothelial growth factor (VEGF) secretion and tumor angiogenesis. However, the underlying mechanisms are poorly understood.
    METHODS: Tumor-bearing mice were subjected to chronic restraint stress and treated with normal saline, human monoclonal VEGF-A neutralizing antibody bevacizumab, or β-adrenergic receptor (β-AR) antagonist (propranolol). Tumor growth and vessel density were also evaluated. Human colorectal adenocarcinoma cells were treated with NE, propranolol, or the inhibitor of transforming growth factor-β (TGF-β) receptor Type I kinase (Ly2157299) in vitro. TGF-β1 in mouse serum and cell culture supernatants was quantified using ELISA. The expression of HIF-1α was measured using Real time-PCR and western blotting. Cell migration and invasion were tested.
    RESULTS: Chronic restraint stress attenuated the efficacy of bevacizumab and promoted tumor growth and angiogenesis in a colorectal tumor model. Propranolol blocked this effect and inhibited TGF-β1 elevation caused by chronic restraint stress or NE. NE upregulated HIF-1α expression, which was reversed by propranolol or Ly2157299. Propranolol and Ly2157199 blocked NE-stimulated cancer cell migration and invasion.
    CONCLUSIONS: Our results demonstrate the effect of NE on tumor angiogenesis and the critical role of TGF-β1 signaling during this process. In addition, β-AR/TGF-β1 signaling/HIF-1α/VEGF is a potential signaling pathway. This study also indicates that psychosocial stress might be a risk factor which weakens the efficacy of anti-angiogenic therapy.
    Keywords:  Chronic stress; angiogenesis; hypoxia inducible factor-1α; norepinephrine; transforming growth factor-β1
    DOI:  https://doi.org/10.1080/15384047.2024.2366451
  4. Trends Immunol. 2024 Jun 13. pii: S1471-4906(24)00120-0. [Epub ahead of print]
    Targeting metabolic pathways to counter cancer immunotherapy resistance.
    Yuki Agarwala, Timothy A Brauns, Ann E Sluder, Mark C Poznansky, Yohannes Gemechu.
      Immunotherapies have revolutionized the treatment of certain cancers, but challenges remain in overcoming immunotherapy resistance. Research shows that metabolic modulation of the tumor microenvironment can enhance antitumor immunity. Here, we discuss recent preclinical and clinical evidence for the efficacy of combining metabolic modifiers with immunotherapies. While this combination holds great promise, a few key areas must be addressed, which include identifying the effects of metabolic modifiers on immune cell metabolism, the putative biomarkers of therapeutic efficacy, the efficacy of modifiers on tumors harboring metabolic heterogeneity, and the potential development of resistance due to tumor reliance on alternative metabolic pathways. We propose solutions to these problems and posit that assessing these parameters is crucial for considering the potential of metabolic modifiers in sensitizing tumors to immunotherapies.
    Keywords:  immunotherapy; immunotherapy resistance; metabolic reprogramming
    DOI:  https://doi.org/10.1016/j.it.2024.05.006
  5. Redox Biol. 2024 May 25. pii: S2213-2317(24)00187-3. [Epub ahead of print]74 103209
    Lactate-induced activation of tumor-associated fibroblasts and IL-8-mediated macrophage recruitment promote lung cancer progression.
    Xuyu Gu, Yifei Zhu, Jincheng Su, Sheng Wang, Xiangyu Su, Xu Ding, Lei Jiang, Xiang Fei, Wentian Zhang.
      Alterations in the tumor microenvironment are closely associated with the metabolic phenotype of tumor cells. Cancer-associated fibroblasts (CAFs) play a pivotal role in tumor growth and metastasis. Existing studies have suggested that lactate produced by tumor cells can activate CAFs, yet the precise underlying mechanisms remain largely unexplored. In this study, we initially identified that lactate derived from lung cancer cells can promote nuclear translocation of NUSAP1, subsequently leading to the recruitment of the transcriptional complex JUNB-FRA1-FRA2 near the DESMIN promoter and facilitating DESMIN transcriptional activation, thereby promoting CAFs' activation. Moreover, DESMIN-positive CAFs, in turn, secrete IL-8, which recruits TAMs or promotes M2 polarization of macrophages, further contributing to the alterations in the tumor microenvironment and facilitating lung cancer progression. Furthermore, we observed that the use of IL-8 receptor antagonists, SB225002, or Navarixin, significantly reduced TAM infiltration and enhanced the therapeutic efficacy of anti-PD-1 or anti-PD-L1 treatment. This finding indicates that inhibiting IL-8R activity can attenuate the impact of CAFs on the tumor microenvironment, thus restraining the progression of lung cancer.
    Keywords:  Cancer-associated fibroblasts; Lung cancer; Tumor microenvironment; Tumor progression; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.redox.2024.103209
  6. Cancer Res Treat. 2024 Jun 05.
    Role of HIF-1α in the Responses of Tumors to Radiotherapy and Chemotherapy.
    Chang W Song, Hyunkyung Kim, Mi-Sook Kim, Heon J Park, Sun-Ha Paek, Stephanie Terezakis, L Chinsoo Cho.
      Tumor microenvironment is intrinsically hypoxic with abundant hypoxia-inducible factors-1α (HIF-1α), a primary regulator of the cellular response to hypoxia and various stresses imposed on the tumor cells. HIF-1α increases radioresistance and chemoresistance by reducing DNA damage, increasing repair of DNA damage, enhancing glycolysis that increases antioxidant capacity of tumors cells, and promoting angiogenesis. In addition, HIF-1α markedly enhances drug efflux, leading to multidrug resistance. Radiotherapy and certain chemotherapy drugs evoke profound anti-tumor immunity by inducing immunologic cell death that release tumor associated antigens together with numerous pro-immunological factors, leading to priming of cytotoxic CD8+ T cells and enhancing the cytotoxicity of macrophages and NK cells. Radiotherapy and chemotherapy of tumors significantly increase HIF-1α activity in tumor cells. Unfortunately, HIF-1α effectively promotes various immune suppressive pathways including secretion of immune suppressive cytokines, activation of myeloid-derived suppressor cells (MIDSCs), activation of regulatory T cells (Tregs), inhibition of T cells priming and activity, and upregulation of immune checkpoints. Consequently, the anti-tumor immunity elevated by radiotherapy and chemotherapy is counterbalanced or masked by the potent immune suppression promoted by HIF-1α. Effective inhibition of HIF-1α may significantly increase the efficacy of radiotherapy and chemotherapy by increasing radiosensitivity and chemosensitivity of tumor cells and also by upregulating anti-tumor immunity.
    Keywords:  Anti-tumor immunity; Chemosensitivity; Chemotherapy; HIF-1ɑ; Immunologic cell death; Radiosensitivity; Radiotherapy
    DOI:  https://doi.org/10.4143/crt.2024.255
  7. Cell Death Dis. 2024 Jun 11. 15(6): 409
    Glucose deprivation triggers DCAF1-mediated inactivation of Rheb-mTORC1 and promotes cancer cell survival.
    Miaomiao Li, Wenjing Huang, Yuan Zhang, Yue Du, Shan Zhao, Longhao Wang, Yaxin Sun, Beibei Sha, Jie Yan, Yangcheng Ma, Jinlu Tang, Jianxiang Shi, Pei Li, Lijun Jia, Tao Hu, Ping Chen.
      Low glucose is a common microenvironment for rapidly growing solid tumors, which has developed multiple approaches to survive under glucose deprivation. However, the specific regulatory mechanism remains largely elusive. In this study, we demonstrate that glucose deprivation, while not amino acid or serum starvation, transactivates the expression of DCAF1. This enhances the K48-linked polyubiquitination and proteasome-dependent degradation of Rheb, inhibits mTORC1 activity, induces autophagy, and facilitates cancer cell survival under glucose deprivation conditions. This study identified DCAF1 as a new cellular glucose sensor and uncovered new insights into mechanism of DCAF1-mediated inactivation of Rheb-mTORC1 pathway for promoting cancer cell survival in response to glucose deprivation.
    DOI:  https://doi.org/10.1038/s41419-024-06808-1
  8. Clin Nutr. 2024 May 28. pii: S0261-5614(24)00186-9. [Epub ahead of print]43(7): 1809-1815
    Tumor metabolic activity is associated with subcutaneous adipose tissue radiodensity and survival in non-small cell lung cancer.
    Yan Sun, Min Deng, Olivier Gevaert, Merel Aberle, Steven W Olde Damink, David van Dijk, Sander S Rensen.
       BACKGROUND: Cachexia-associated body composition alterations and tumor metabolic activity are both associated with survival of cancer patients. Recently, subcutaneous adipose tissue properties have emerged as particularly prognostic body composition features. We hypothesized that tumors with higher metabolic activity instigate cachexia related peripheral metabolic alterations, and investigated whether tumor metabolic activity is associated with body composition and survival in patients with non-small-cell lung cancer (NSCLC), focusing on subcutaneous adipose tissue.
    METHODS: A retrospective analysis was performed on a cohort of 173 patients with NSCLC. 18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) scans obtained before treatment were used to analyze tumor metabolic activity (standardized uptake value (SUV) and SUV normalized by lean body mass (SUL)) as well as body composition variables (subcutaneous and visceral adipose tissue radiodensity (SAT/VAT radiodensity) and area; skeletal muscle radiodensity (SM radiodensity) and area). Subjects were divided into groups with high or low SAT radiodensity based on Youden Index of Receiver Operator Characteristics (ROC). Associations between tumor metabolic activity, body composition variables, and survival were analyzed by Mann-Whitney tests, Cox regression, and Kaplan-Meier analysis.
    RESULTS: The overall prevalence of high SAT radiodensity was 50.9% (88/173). Patients with high SAT radiodensity had shorter survival compared with patients with low SAT radiodensity (mean: 45.3 vs. 50.5 months, p = 0.026). High SAT radiodensity was independently associated with shorter overall survival (multivariate Cox regression HR = 1.061, 95% CI: 1.022-1.101, p = 0.002). SAT radiodensity also correlated with tumor metabolic activity (SULpeak rs = 0.421, p = 0.029; SUVpeak rs = 0.370, p = 0.048). In contrast, the cross-sectional areas of SM, SAT, and VAT were not associated with tumor metabolic activity or survival.
    CONCLUSION: Higher SAT radiodensity is associated with higher tumor metabolic activity and shorter survival in patients with NSCLC. This may suggest that tumors with higher metabolic activity induce subcutaneous adipose tissue alterations such as decreased lipid density, increased fibrosis, or browning.
    Keywords:  Body composition measurement; Non-small-cell lung cancer; PET–CT; Subcutaneous adipose tissue radiodensity; Survival; Tumor metabolic activity
    DOI:  https://doi.org/10.1016/j.clnu.2024.05.040
  9. Am J Cancer Res. 2024 ;14(5): 2088-2102
    Loss of Lipocalin2 confers cisplatin vulnerability through modulating NF-ĸB mediated ferroptosis via ferroportin.
    Meibao Feng, Xuesong Wu, Jing Zhang, Pei Chen, Senmi Qian, Chengdong Chang.
      Cisplatin is a widely used anti-cancer drug. Unfortunately, many cancers often develop resistance, which contributes to tumor recurrence and poorly prognosis. Growing knowledge has suggested the therapeutic potential of ferroptosis in cancer. Lipocalin2 (LCN2) is demonstrated to be a critical iron metabolic factor and implies in ferroptosis. Here, we aim to explore its role in chemotherapy resistance. The influence of LCN2 on colorectal cancer (CRC) cell chemoresistance and ferroptosis were evaluated by in vitro and in vivo approaches. The interaction between LCN2, NF-ĸB and ferroportin (FPN) was assessed by western blots, immunohistochemistry and dual luciferase reporter assays. Results showed that LCN2 was highly expressed in tumor regression grade 1 (TRG1) cases than that in TRG3 specimens. Loss of LCN2 contributed to resistance to cisplatin-induced ferroptosis. Mechanistically, loss of LCN2 inhibited cisplatin sensitivity and cisplatin-induced ferroptosis through elevating FPN expression which was regulated by NF-ĸB, subsequently reducing Fe2+ mediated Fenton reaction. Furthermore, FPN expression rate was much lower in TRG1 cases, and negative correlation between LCN2 and FPN expression was observed in clinical specimens. Collectively, low LCN2 expression enhances insensitivity of cisplatin to CRC cells via Fenton reaction mediated ferroptosis. LCN2/NF-ĸB/FPN pathway might be potentially utilized for chemoresistance strategy. LCN2 and FPN expression might be a promising biomarker of chemotherapy effect for CRC patients.
    Keywords:  Chemoresistance; Lipocalin2; biomarkers; colorectal cancer; ferroptosis
    DOI:  https://doi.org/10.62347/MEYW3975
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