bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2023–04–09
nine papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Stress-inducible IL-6 is regulated by KLF7 in brown adipocytes.
  2. GDNF family receptor alpha-like antagonist antibody alleviates chemotherapy-induced cachexia in melanoma-bearing mice.
  3. Activating mutations in EGFR and PI3K promote ATF4 induction for NSCLC cell survival during amino acid deprivation.
  4. The fifth element: a novel eIF2α kinase in microglia.
  5. Lipocalin-2 and neutrophil activation in pancreatic cancer cachexia.
  6. Does burning fat make tumor immune hot? Discovery of CD47 overexpression by radiation induced fatty acid oxidation.
  7. A novel orthotopic mouse model replicates human lung cancer cachexia.
  8. IGFBP-3 promotes cachexia-associated lipid loss by suppressing insulin-like growth factor/insulin signaling.
  9. Normal tissue homeostasis and impairment of selective inflammatory responses in dendritic cells deficient for ATF6α.
  1. Heliyon. 2023 Apr;9(4): e14931
    Stress-inducible IL-6 is regulated by KLF7 in brown adipocytes.
    Yihan Tang, Dingling Ma, Maodi Liang, Yanting Hou, Meixiu Zhang, Jingzhou Wang, Chenggang Yuan, Menghuan Li, Chaoyue Sun, Jianxin Xie, Cuizhe Wang, Jun Zhang.
      Stress-inducible interleukin 6 (IL-6) is generated in brown adipocytes via beta-3 adrenergic receptor (ADRB3) signaling, which is necessary in stress hyperglycemia, the kind of metabolic adaptation enabling "fight or flight" response by means of liver gluconeogenesis. Nevertheless, the mechanism of ADRB3 signaling mediates IL-6 in brown adipocytes remains unclear. As a result, it is critical to understand how brown adipocytes produce IL-6 via ADRB3 signaling. We found that the ADRB3 agonist and cold stimulation promoted the expression of KLF7 and IL-6 in brown adipocytes of mice. In parallel to these results in vivo, treatment with ADRB3 agonist promoted the expression of KLF7 and the release of IL-6 in primary brown adipocytes of mice. Notably, we discovered that KLF7 positively controls the expression of IL-6 and downregulated KLF7 largely blunted ADRB3 agonist induced IL-6 expressions in brown adipocytes. Our findings suggest that KLF7 is required for the generation of IL-6 when ADRB3 signaling is activated in brown adipocytes.
    Keywords:  ADRB3; Brown adipocytes; IL-6; KLF7
    DOI:  https://doi.org/10.1016/j.heliyon.2023.e14931
  2. J Cachexia Sarcopenia Muscle. 2023 Apr 05.
    GDNF family receptor alpha-like antagonist antibody alleviates chemotherapy-induced cachexia in melanoma-bearing mice.
    Beom Yong Lee, Jongwon Jeong, Inseong Jung, Hanchae Cho, Dokyung Jung, Jiwon Shin, Jun-Kook Park, Eunju Park, Soojeong Noh, Sanghee Shin, Sungmin Kang, Jong-Ik Heo, Moon-Chang Baek, Kyungmoo Yea.
       BACKGROUND: Patients with cancer undergoing chemotherapy experience cachexia with anorexia, body weight loss, and the depletion of skeletal muscles and adipose tissues. Effective treatment strategies for chemotherapy-induced cachexia are scarce. The growth differentiation factor 15 (GDF15)/GDNF family receptor alpha-like (GFRAL)/rearranged during transfection (RET) axis is a critical signalling pathway in chemotherapy-induced cachexia. In this study, we developed a fully human GFRAL antagonist antibody and investigated whether it inhibits the GDF15/GFRAL/RET axis, thereby alleviating chemotherapy-induced cachexia in tumour-bearing mice.
    METHODS: Anti-GFRAL antibodies were selected via biopanning, using a human combinatorial antibody phage library. The potent GFRAL antagonist antibody A11 was selected via a reporter cell assay and its inhibitory activity of GDF15-induced signalling was evaluated using western blotting. To investigate the in vivo function of A11, a tumour-bearing mouse model was established by inoculating 8-week-old male C57BL/6 mice with B16F10 cells (n = 10-16 mice per group). A11 was administered subcutaneously (10 mg/kg) 1 day before intraperitoneal treatment with cisplatin (10 mg/kg). Animals were assessed for changes in food intake, body weight, and tumour volume. Plasma and key metabolic tissues such as skeletal muscles and adipose tissues were collected for protein and mRNA expression analysis.
    RESULTS: A11 reduced serum response element-luciferase reporter activity up to 74% (P < 0.005) in a dose-dependent manner and blocked RET phosphorylation up to 87% (P = 0.0593), AKT phosphorylation up to 28% (P = 0.0593) and extracellular signal regulatory kinase phosphorylation up to 75% (P = 0.0636). A11 inhibited the action of cisplatin-induced GDF15 on the brainstem and decreased GFRAL-positive neuron population expressing c-Fos in the area postrema and nucleus of the solitary tract by 62% in vivo (P < 0.05). In a melanoma mouse model treated with cisplatin, A11 recovered anorexia by 21% (P < 0.05) and tumour-free body weight loss by 13% (P < 0.05). A11 significantly improved the cisplatin-induced loss of skeletal muscles (quadriceps: 21%, gastrocnemius: 9%, soleus: 13%, P < 0.05) and adipose tissues (epididymal white adipose tissue: 37%, inguinal white adipose tissue: 51%, P < 0.05).
    CONCLUSIONS: Our study suggests that GFRAL antagonist antibody may alleviate chemotherapy-induced cachexia, providing a novel therapeutic approach for patients with cancer experiencing chemotherapy-induced cachexia.
    Keywords:  Cancer cachexia; Chemotherapy; Cisplatin; GDF15; GFRAL; GFRAL antagonist antibody
    DOI:  https://doi.org/10.1002/jcsm.13219
  3. Heliyon. 2023 Apr;9(4): e14799
    Activating mutations in EGFR and PI3K promote ATF4 induction for NSCLC cell survival during amino acid deprivation.
    Mizuki Takahashi, Yuka Okamoto, Yu Kato, Hitomi Shirahama, Satomi Tsukahara, Yoshikazu Sugimoto, Akihiro Tomida.
      Some oncoproteins along with stress kinase general control non-derepressible 2 (GCN2) can ensure the induction of activating transcription factor 4 (ATF4) to counteract amino acid deprivation; however, little is known regarding the role of the oncogenic EGFR-PI3K pathway. In this study, we demonstrate that both mutated EGFR and PIK3CA contribute to ATF4 induction following GCN2 activation in NSCLC cells. The inhibition of EGFR or PI3K mutant proteins, pharmacologically or through genetic knockdown, inhibited ATF4 induction without affecting GCN2 activation. A downstream analysis revealed that the oncogenic EGFR-PI3K pathway may utilize mTOR-mediated translation control mechanisms for ATF4 induction. Furthermore, in NSCLC cells harboring co-mutations in EGFR and PIK3CA, the combined inhibition of these oncoproteins markedly suppressed ATF4 induction and the subsequent gene expression program as well as cell viability during amino acid deprivation. Our findings establish a role for the oncogenic EGFR-PI3K pathway in the adaptive stress response and provide a strategy to improve EGFR-targeted NSCLC therapy.
    Keywords:  ATF4; EGFR; ISR; NSCLC; Oncogenic mutation; PI3K
    DOI:  https://doi.org/10.1016/j.heliyon.2023.e14799
  4. EMBO Rep. 2023 Apr 06. e57231
    The fifth element: a novel eIF2α kinase in microglia.
    Alessia Ruggieri.
      The cellular integrated stress response (ISR) is a central signaling pathway that tunes translation initiation in response to a wide range of cellular insults to promote cell survival. The critical node of this regulation involves the phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α) by stress kinases. In this issue of EMBO reports, Wu et al (2023) report FAM69C as a novel eIF2α kinase that promotes ISR activation and stress granule (SG) assembly in microglia in response to oxidative stress. This work proposes a protective role for FAM69C and SGs in limiting damaging inflammatory responses commonly associated with neurodegenerative diseases.
    DOI:  https://doi.org/10.15252/embr.202357231
  5. Front Immunol. 2023 ;14 1159411
    Lipocalin-2 and neutrophil activation in pancreatic cancer cachexia.
    Min Deng, Merel R Aberle, Annemarie A J H M van Bijnen, Gregory van der Kroft, Kaatje Lenaerts, Ulf P Neumann, Georg Wiltberger, Frank G Schaap, Steven W M Olde Damink, Sander S Rensen.
       Background: Cancer cachexia is a multifactorial syndrome characterized by body weight loss and systemic inflammation. The characterization of the inflammatory response in patients with cachexia is still limited. Lipocalin-2, a protein abundant in neutrophils, has recently been implicated in appetite suppression in preclinical models of pancreatic cancer cachexia. We hypothesized that lipocalin-2 levels could be associated with neutrophil activation and nutritional status of pancreatic ductal adenocarcinoma (PDAC) patients.
    Methods: Plasma levels of neutrophil activation markers calprotectin, myeloperoxidase, elastase, and bactericidal/permeability-increasing protein (BPI) were compared between non-cachectic PDAC patients (n=13) and cachectic PDAC patients with high (≥26.9 ng/mL, n=34) or low (<26.9 ng/mL, n=34) circulating lipocalin-2 levels. Patients' nutritional status was assessed by the patient-generated subjective global assessment (PG-SGA) and through body composition analysis using CT-scan slices at the L3 level.
    Results: Circulating lipocalin-2 levels did not differ between cachectic and non-cachectic PDAC patients (median 26.7 (IQR 19.7-34.8) vs. 24.8 (16.6-29.4) ng/mL, p=0.141). Cachectic patients with high systemic lipocalin-2 levels had higher concentrations of calprotectin, myeloperoxidase, and elastase than non-cachectic patients or cachectic patients with low lipocalin-2 levels (calprotectin: 542.3 (355.8-724.9) vs. 457.5 (213.3-606.9), p=0.448 vs. 366.5 (294.5-478.5) ng/mL, p=0.009; myeloperoxidase: 30.3 (22.1-37.9) vs. 16.3 (12.0-27.5), p=0.021 vs. 20.2 (15.0-29.2) ng/mL, p=0.011; elastase: 137.1 (90.8-253.2) vs. 97.2 (28.8-215.7), p=0.410 vs. 95.0 (72.2-113.6) ng/mL, p=0.006; respectively). The CRP/albumin ratio was also higher in cachectic patients with high lipocalin-2 levels (2.3 (1.3-6.0) as compared to non-cachectic patients (1.0 (0.7-4.2), p=0.041). Lipocalin-2 concentrations correlated with those of calprotectin (rs =0.36, p<0.001), myeloperoxidase (rs =0.48, p<0.001), elastase (rs =0.50, p<0.001), and BPI (rs =0.22, p=0.048). Whereas no significant correlations with weight loss, BMI, or L3 skeletal muscle index were observed, lipocalin-2 concentrations were associated with subcutaneous adipose tissue index (rs =-0.25, p=0.034). Moreover, lipocalin-2 tended to be elevated in severely malnourished patients compared with well-nourished patients (27.2 (20.3-37.2) vs. 19.9 (13.4-26.4) ng/mL, p=0.058).
    Conclusions: These data suggest that lipocalin-2 levels are associated with neutrophil activation in patients with pancreatic cancer cachexia and that it may contribute to their poor nutritional status.
    Keywords:  appetite; cancer cachexia; complement; innate immunity; lipocalin-2; neutrophil activation; nutritional status
    DOI:  https://doi.org/10.3389/fimmu.2023.1159411
  6. Genes Dis. 2023 Jan;10(1): 7-9
    Does burning fat make tumor immune hot? Discovery of CD47 overexpression by radiation induced fatty acid oxidation.
    Nian Jiang, Bowen Xie, Ming Fan, Jian Jian Li.
      Although extensively studied, it is unknown what is the major cellular energy driving tumor metastasis after anti-cancer radiotherapy. Metabolic reprogramming is one of the fundamental hallmarks in carcinogenesis and tumor progression featured with the increased glycolysis in solid tumors. However, accumulating evidence indicates that in addition to the rudimentary glycolytic pathway, tumor cells are capable of reactivating mitochondrial OXPHOS under genotoxic stress condition to meet the increasing cellular fuel demand for repairing and surviving anti-cancer radiation. Such dynamic metabolic rewiring may play a key role in cancer therapy resistance and metastasis. Interestingly, data from our group and others have demonstrated that cancer cells can re-activate mitochondrial oxidative respiration to boost an annexing energy to meet the increasing cellular fuel demand for tumor cells surviving genotoxic anti-cancer therapy with metastatic potential.
    Keywords:  CD47; Immune checkpoint; Immunotherapy; Metabolic rewiring; Radiation therapy; Tumor acquired resistance
    DOI:  https://doi.org/10.1016/j.gendis.2022.07.019
  7. J Cachexia Sarcopenia Muscle. 2023 Apr 06.
    A novel orthotopic mouse model replicates human lung cancer cachexia.
    Wouter R P H van de Worp, Jan Theys, Alba Sanz González, Brent van der Heyden, Frank Verhaegen, Duncan Hauser, Florian Caiment, Hubertus J M Smeets, Annemie M W J Schols, Ardy van Helvoort, Ramon C J Langen.
       INTRODUCTION: Cancer cachexia, highly prevalent in lung cancer, is a debilitating syndrome characterized by involuntary loss of skeletal muscle mass and is associated with poor clinical outcome, decreased survival and negative impact on tumour therapy. Various lung tumour-bearing animal models have been used to explore underlying mechanisms of cancer cachexia. However, these models do not simulate anatomical and immunological features key to lung cancer and associated muscle wasting. Overcoming these shortcomings is essential to translate experimental findings into the clinic. We therefore evaluated whether a syngeneic, orthotopic lung cancer mouse model replicates systemic and muscle-specific alterations associated with human lung cancer cachexia.
    METHODS: Immune competent, 11 weeks old male 129S2/Sv mice, were randomly allocated to either (1) sham control group or (2) tumour-bearing group. Syngeneic lung epithelium-derived adenocarcinoma cells (K-rasG12D ; p53R172HΔG ) were inoculated intrapulmonary into the left lung lobe of the mice. Body weight and food intake were measured daily. At baseline and weekly after surgery, grip strength was measured and tumour growth and muscle volume were assessed using micro cone beam CT imaging. After reaching predefined surrogate survival endpoint, animals were euthanized, and skeletal muscles of the lower hind limbs were collected for biochemical analysis.
    RESULTS: Two-third of the tumour-bearing mice developed cachexia based on predefined criteria. Final body weight (-13.7 ± 5.7%; P < 0.01), muscle mass (-13.8 ± 8.1%; P < 0.01) and muscle strength (-25.5 ± 10.5%; P < 0.001) were reduced in cachectic mice compared with sham controls and median survival time post-surgery was 33.5 days until humane endpoint. Markers for proteolysis, both ubiquitin proteasome system (Fbxo32 and Trim63) and autophagy-lysosomal pathway (Gabarapl1 and Bnip3), were significantly upregulated, whereas markers for protein synthesis (relative phosphorylation of Akt, S6 and 4E-BP1) were significantly decreased in the skeletal muscle of cachectic mice compared with control. The cachectic mice exhibited increased pentraxin-2 (P < 0.001) and CXCL1/KC (P < 0.01) expression levels in blood plasma and increased mRNA expression of IκBα (P < 0.05) in skeletal muscle, indicative for the presence of systemic inflammation. Strikingly, RNA sequencing, pathway enrichment and miRNA expression analyses of mouse skeletal muscle strongly mirrored alterations observed in muscle biopsies of patients with lung cancer cachexia.
    CONCLUSIONS: We developed an orthotopic model of lung cancer cachexia in immune competent mice. Because this model simulates key aspects specific to cachexia in lung cancer patients, it is highly suitable to further investigate the underlying mechanisms of lung cancer cachexia and to test the efficacy of novel intervention strategies.
    Keywords:  Cancer cachexia; Lung cancer; Mouse model; Muscle wasting; OLCC; Orthotopic mouse model
    DOI:  https://doi.org/10.1002/jcsm.13222
  8. Chin Med J (Engl). 2023 Apr 04.
    IGFBP-3 promotes cachexia-associated lipid loss by suppressing insulin-like growth factor/insulin signaling.
    Xiaohui Wang, Jia Li, Wei Zhang, Feng Wang, Yunzi Wu, Yulin Guo, Dong Wang, Xinfeng Yu, Ang Li, Fei Li, Yibin Xie.
       BACKGROUND: Progressive lipid loss of adipose tissue is a major feature of cancer-associated cachexia. In addition to systemic immune/inflammatory effects in response to tumor progression, tumor-secreted cachectic ligands also play essential roles in tumor-induced lipid loss. However, the mechanisms of tumor-adipose tissue interaction in lipid homeostasis are not fully understood.
    METHODS: The yki-gut tumors were induced in fruit flies. Lipid metabolic assays were performed to investigate the lipolysis level of different types of insulin-like growth factor binding protein-3 (IGFBP-3) treated cells. Immunoblotting was used to display phenotypes of tumor cells and adipocytes. Quantitative polymerase chain reaction (qPCR) analysis was carried out to examine the gene expression levels such as Acc1, Acly, and Fasn et al .
    RESULTS: In this study, we revealed that tumor-derived IGFBP-3 was an important ligand directly causing lipid loss in matured adipocytes. We uncovered that IGFBP-3, which is highly expressed in cachectic tumor cells, antagonized insulin/IGF-like signaling (IIS) and impaired the balance between lipolysis and lipogenesis in 3T3-L1 adipocytes. Conditioned medium from cachectic tumor cells, such as Capan-1 and C26 cells, contained excessive IGFBP-3 that potently induced lipolysis in adipocyted. Notably, neutralization of IGFBP-3 by neutralizing antibody in the conditioned medium of cachectic tumor cells significantly alleviated the lipolytic effect and restored lipid storage in adipocytes. Furthermore, cachectic tumor cells were resistant to IGFBP-3 inhibition of IIS, ensuring their escape from IGFBP-3-associated growth suppression. Finally, cachectic tumor-derived ImpL2, the IGFBP-3 homolog, also impaired lipid homeostasis of host cells in an established cancer-cachexia model in Drosophila. Most importantly, IGFBP-3 was highly expressed in cancer tissues in pancreatic and colorectal cancer patients, especially higher in the sera of cachectic cancer patients than non-cachexia cancer patients.
    CONCLUSION: Our study demonstrates that tumor-derived IGFBP-3 plays a critical role in cachexia-associated lipid loss and could be a biomarker for diagnosis of cachexia in cancer patients.
    DOI:  https://doi.org/10.1097/CM9.0000000000002628
  9. Front Cell Dev Biol. 2023 ;11 1089728
    Normal tissue homeostasis and impairment of selective inflammatory responses in dendritic cells deficient for ATF6α.
    Francisca Gutiérrez-Ballesteros, Jonathan Morales-Reyes, Dominique Fernández, Antonia Geisse, Amada Arcaya, Felipe Flores-Santibañez, María Rosa Bono, Fabiola Osorio.
      The initiation of adaptive immunity relies on the performance of dendritic cells (DCs), which are specialized leukocytes with professional antigen presenting capabilities. As such, the molecular mechanisms safeguarding DC homeostasis are matter of intense research. Sensors of the unfolded protein response (UPR) of the endoplasmic reticulum, a three-pronged signaling pathway that maintains the fidelity of the cellular proteome, have emerged as regulators of DC biology. The archetypical example is the IRE1/XBP1s axis, which supports DC development and survival of the conventional type 1 DC (cDC1) subtype. However, the role of additional UPR sensors in DC biology, such as the ATF6α branch, has not been clearly elucidated. Even though Xbp1 is transcriptionally induced by ATF6α under ER stress, it is unclear if cDCs also co-opt the ATF6α branch in tissues. Here, we examine the role of ATF6α in cDC homeostasis in vivo and upon innate stimulation in vitro. In steady state, animals lacking ATF6α in CD11c+ cells (Itgax Cre x Atf6 fl/fl mice) display normal cDC frequencies in spleen, intestine, liver, and lung. Also, ATF6α deficient cDCs express normal levels of Xbp1 mRNA and additional UPR components. However, a reduction of lung monocytes is observed in Itgax Cre x Atf6 fl/fl conditional deficient animals suggesting that ATF6α may play a role in the biology of monocyte subsets. Notably, in settings of DC activation, ATF6α contributes to the production of IL-12 and IL-6 to inflammatory stimuli. Thus, although ATF6α may be dispensable for tissue cDC homeostasis in steady state, the transcription factor plays a role in the acquisition of selective immunogenic features by activated DCs.
    Keywords:  ATF6; IL-12; IL-6; dendritic cells; immunity; proinflammatory cytokines; tissues; unfolded protein response
    DOI:  https://doi.org/10.3389/fcell.2023.1089728
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