bims-stacyt 2023-08-20 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2023–08–20
nine papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Cross-species comparison of pregnancy-induced GDF15.
HIF-1α inhibition in macrophages preserves acute liver failure by reducing IL-1β production.
Exosomes from hypoxia-conditioned apical papilla stem cells accelerate angiogenesis in vitro through Notch/JAG1/VEGF signaling.
SOCS3 deletion in effector T cells confers an anti-tumorigenic role of IL-6 to the pro-tumorigenic cytokine.
Interleukin-6 signaling in osteoblasts regulates bone remodeling during exercise.
Endothelial ERα promotes glucose tolerance by enhancing endothelial insulin transport to skeletal muscle.
IL-6 translation is a therapeutic target of human cytokine release syndrome.
Restoring adiponectin via rosiglitazone ameliorates tissue wasting in mice with lung cancer.
PPARδ dysregulation of CCL20/CCR6 axis promotes gastric adenocarcinoma carcinogenesis by remodeling gastric tumor microenvironment.

Am J Physiol Endocrinol Metab. 2023 Aug 16.

Cross-species comparison of pregnancy-induced GDF15.

Anders Bue Klein, Pablo Ranea-Robles, Trine Sand Nicolaisen, Claudia Gil, Kornelia Johann, Julia Prats Quesada, Nina Pistoljevic, Kathrine V R Hviid, Line F Olsen, Simone M Offersen, Jorn Wulff Helge, Henriette Svarre-Nielsen, Jaco Bakker, Maximilian Kleinert, Christoffer Clemmensen.

  Growth differentiation factor 15 (GDF15) is a stress-induced cytokine. Although the exact physiological function of GDF15 is not yet fully comprehended, the significant elevation of circulating GDF15 levels during gestation suggests a potential role for this hormone in pregnancy. This is corroborated by genetic association studies in which GDF15 and the GDF15 receptor, GDNF Family Receptor Alpha Like (GFRAL) have been linked to morning sickness and hyperemesis gravidarum (HG) in humans. Here, we studied GDF15 biology during pregnancy in mice, rats, macaques, and humans. In contrast to macaques and humans, mice and rats exhibited an underwhelming induction in plasma GDF15 levels in response to pregnancy (~75-fold increase in macaques vs. ~2-fold increase in rodents). The changes in circulating GDF15 levels were corroborated by the magnitude of Gdf15 mRNA and GDF15 protein expression in placentae from mice, rats, and macaques. These species-specific findings may help guide future studies focusing on GDF15 in pregnancy and on the evaluation of pharmacological strategies to interfere with GDF15-GFRAL signaling to treat severe nausea and HG.

Keywords:  GDF15; GFRAL; nausea; placenta; pregnancy

DOI:  https://doi.org/10.1152/ajpendo.00134.2023
FASEB J. 2023 09;37(9): e23140

HIF-1α inhibition in macrophages preserves acute liver failure by reducing IL-1β production.

Xiangrong Kong, Wei Liu, Xinwen Zhang, Chendong Zhou, Xinyu Sun, Long Cheng, Jinxia Lin, Zhifu Xie, Jingya Li.

  The development of acute liver failure (ALF) is dependent on its local inducer. Inflammation is a high-frequency and critical factor that accelerates hepatocyte death and liver failure. In response to injury stress, the expression of the transcription factor hypoxia-inducible factor-1α (HIF-1α) in macrophages is promoted by both oxygen-dependent and oxygen-independent mechanisms, thus promoting the expression and secretion of the cytokine interleukin-1β (IL-1β). IL-1β further induces hepatocyte apoptosis or necrosis by signaling through the receptor (IL-1R) on hepatocyte. HIF-1α knockout in macrophages or IL-1R knockout in hepatocytes protects against liver failure. However, whether HIF-1α inhibition in macrophages has a protective role in ALF is unclear. In this study, we revealed that the small molecule HIF-1α inhibitor PX-478 inhibits the expression and secretion of IL-1β, but not tumor necrosis factor α (TNFα), in bone marrow-derived macrophages (BMDMs). PX-478 pretreatment alleviates liver injury in LPS/D-GalN-induced ALF mice by decreasing the hepatic inflammatory response. In addition, preventive or therapeutic administration of PX-478 combined with TNFα neutralizing antibody markedly improved LPS/D-GalN-induced ALF. Taken together, our data suggest that PX-478 administration leads to HIF-1α inhibition and decreased IL-1β secretion in macrophages, which represents a promising therapeutic strategy for inflammation-induced ALF.

Keywords:  HIF-1α inhibitor; acute liver failure; cell death; interleukin-1β; macrophage

DOI:  https://doi.org/10.1096/fj.202300428RR
Tissue Cell. 2023 Aug 11. pii: S0040-8166(23)00185-4. [Epub ahead of print]84 102197

Exosomes from hypoxia-conditioned apical papilla stem cells accelerate angiogenesis in vitro through Notch/JAG1/VEGF signaling.

Di Liu, Binwei Shi, Wenting Zhou, Guannan Tao.

  Dental pulp angiogenesis is a committed step in pulp regeneration therapy, and exosomes provide a new cell-free choice for tissue regeneration. This study revealed the underlying regulatory mechanism of exosomes from stem cells of the apical papilla (SCAPs) under hypoxic state on angiogenesis of human umbilical vein endothelial cells (HUVECs) in vitro. Exosomes extracted from normoxia or hypoxia-pretreated SCAPs were co-cultured with HUVECs, and hypoxia pretreatment increased the release of exosomes and the internalization of exosomes by HUVECs. Compared to normoxic SCAPs-derived exosomes, exosomes from hypoxic SCAPs were found to promote cell proliferation and migration in HUVECs, as it was respectively determined by Cell Counting Kit-8, RT-qPCR and Transwell assay. Besides, hypoxia-educated SCAPs-exosomes especially enhanced the angiogenesis abilities of HUVECs in vitro, which were confirmed by tube formation assay and RT-qPCR detection of angiogenesis-related molecular markers. Interestingly, we found that the hypoxia inducible factor-1α (HIF-1α)/Notch1 signaling pathway was activated in hypoxic SCAPs, and protein jagged-1 (JAG1) was delivered by hypoxic SCAPs-derived exosomes to increase vascular endothelial growth factor (VEGF) production in HUVECs. Moreover, exogenous interference of JAG1 expression in HUVECs partially neutralized the activities of hypoxic SCAPs-exosomes in promoting cell proliferation, migration and tube formation of HUVECs. In summary, this study elucidates that exosomes from hypoxic SCAPs shows high potential to promote angiogenesis in vitro through the HIF-1α/JAG1/VEGF signaling cascade, which may provide a new perspective for the development of vascular reconstruction measures during dental regeneration engineering.

Keywords:  Angiogenesis; Dental regeneration engineering; Human umbilical vein endothelial cells; Jagged-1; Stem cells of the apical papilla

DOI:  https://doi.org/10.1016/j.tice.2023.102197
Cell Rep. 2023 Aug 08. pii: S2211-1247(23)00951-8. [Epub ahead of print] 112940

SOCS3 deletion in effector T cells confers an anti-tumorigenic role of IL-6 to the pro-tumorigenic cytokine.

Setsuko Mise-Omata, Makoto Ando, Tanakorn Srirat, Kensuke Nakagawara, Taeko Hayakawa, Mana Iizuka-Koga, Hiroshi Nishimasu, Osamu Nureki, Minako Ito, Akihiko Yoshimura.

  Interleukin (IL)-6 is abundantly expressed in the tumor microenvironment and is associated with poor patient outcomes. Here, we demonstrate that the deletion of the suppressor of cytokine signaling 3 (SOCS3) in T cells potentiates anti-tumor immune responses by conferring the anti-tumorigenic function of IL-6 in mouse and human models. In Socs3-deficient CD8+ T cells, IL-6 upregulates the expression of type I interferon (IFN)-regulated genes and enhances the anti-tumor effector function of T cells, while also modifying mitochondrial fitness to increase mitochondrial membrane potential and reactive oxygen species (ROS) levels and to promote metabolic glycolysis in the energy state. Furthermore, Socs3 deficiency reduces regulatory T cells and increases T helper 1 (Th1) cells. SOCS3 knockdown in human chimeric antigen receptor T (CAR-T) cells exhibits a strong anti-tumor response in humanized mice. Thus, genetic disruption of SOCS3 offers an avenue to improve the therapeutic efficacy of adoptive T cell therapy.

Keywords:  CAR-T therapy; CP: Cancer; IL-6; anti-tumor immunity; cytotoxic T cell; effector T cells; mitochondrial fitness; regulatory T cells; suppressor of cytokine signaling 3

DOI:  https://doi.org/10.1016/j.celrep.2023.112940
Bone. 2023 Aug 14. pii: S8756-3282(23)00203-X. [Epub ahead of print] 116870

Interleukin-6 signaling in osteoblasts regulates bone remodeling during exercise.

Biagio Palmisano, Mara Riminucci, Gerard Karsenty.

  Aerobic exercise has many beneficial effects on human health. One of them, is to influence positively bone remodeling through, however, incompletely understood mechanisms. Given its recently demonstrated role as a mediator of the bone to muscle to bone crosstalk during exercise, we hypothesized that interleukin-6 (IL-6) signaling in bone may contribute to the beneficial effect that exercise has on bone homeostasis. In this study, we first show that aerobic exercise increases the expression of Il6r in bones of WT mice. Then, we analyzed a mutant mouse strain that lacks the IL-6 receptor alpha specifically in osteoblasts (Il6rosb-/-). As it has been reported in the case of Il6-/- mice, in sedentary conditions, bone mass and remodeling were normal in adult Il6rosb-/- mice when compared to controls. In contrast, Il6rosb-/- mice that were subjected to aerobic exercise did not show the increase in bone mass and remodeling parameters that control littermates demonstrated. Moreover, Il6rosb-/- mice undergoing aerobic exercise showed a severe impairment in bone formation, indicating that activation of bone-forming cells is defective when IL-6 signaling in osteoblasts is disrupted. In sum, this study provides evidence that a function of IL-6 signaling in osteoblasts is to promote high bone turnover during aerobic exercise.

Keywords:  Bone formation; Bone remodeling; Bone turnover; Exercise; IL-6; IL-6R; Osteoblast; Treadmill

DOI:  https://doi.org/10.1016/j.bone.2023.116870
Nat Commun. 2023 Aug 17. 14(1): 4989

Endothelial ERα promotes glucose tolerance by enhancing endothelial insulin transport to skeletal muscle.

Anastasia Sacharidou, Ken Chambliss, Jun Peng, Jose Barrera, Keiji Tanigaki, Katherine Luby-Phelps, İpek Özdemir, Sohaib Khan, Shashank R Sirsi, Sung Hoon Kim, Benita S Katzenellenbogen, John A Katzenellenbogen, Mohammed Kanchwala, Adwait A Sathe, Andrew Lemoff, Chao Xing, Kenneth Hoyt, Chieko Mineo, Philip W Shaul.

The estrogen receptor (ER) designated ERα has actions in many cell and tissue types that impact glucose homeostasis. It is unknown if these include mechanisms in endothelial cells, which have the potential to influence relative obesity, and processes in adipose tissue and skeletal muscle that impact glucose control. Here we show that independent of impact on events in adipose tissue, endothelial ERα promotes glucose tolerance by enhancing endothelial insulin transport to skeletal muscle. Endothelial ERα-deficient male mice are glucose intolerant and insulin resistant, and in females the antidiabetogenic actions of estradiol (E2) are absent. The glucose dysregulation is due to impaired skeletal muscle glucose disposal that results from attenuated muscle insulin delivery. Endothelial ERα activation stimulates insulin transcytosis by skeletal muscle microvascular endothelial cells. Mechanistically this involves nuclear ERα-dependent upregulation of vesicular trafficking regulator sorting nexin 5 (SNX5) expression, and PI3 kinase activation that drives plasma membrane recruitment of SNX5. Thus, coupled nuclear and non-nuclear actions of ERα promote endothelial insulin transport to skeletal muscle to foster normal glucose homeostasis.

DOI: https://doi.org/10.1038/s41467-023-40562-w
J Exp Med. 2023 11 06. pii: e20230577. [Epub ahead of print]220(11):

IL-6 translation is a therapeutic target of human cytokine release syndrome.

Yuzhuo Yang, Yajing Zhang, Xiaoyan Xing, Gang Xu, Xin Lin, Yao Wang, Meixia Chen, Chunmeng Wang, Bin Zhang, Weidong Han, Xiaoyu Hu.

Chimeric antigen receptor (CAR) T therapies have achieved remarkable success for treating hematologic malignancies, yet are often accompanied by severe cytokine release syndrome (CRS). Here, an accidental clinical observation raised the possibility that metoprolol, an FDA-approved β1 adrenergic receptor blocker widely used for cardiovascular conditions, may alleviate CAR T-induced CRS. Metoprolol effectively blocked IL-6 production in human monocytes through unexpected mechanisms of action of targeting IL-6 protein translation but not IL6 mRNA expression. Mechanistically, metoprolol diminished IL-6 protein synthesis via attenuating eEF2K-eEF2 axis-regulated translation elongation. Furthermore, an investigator-initiated phase I/II clinical trial demonstrated a favorable safety profile of metoprolol in CRS management and showed that metoprolol significantly alleviated CAR T-induced CRS without compromising CAR T efficacy. These results repurposed metoprolol, a WHO essential drug, as a potential therapeutic for CRS and implicated IL-6 translation as a mechanistic target of metoprolol, opening venues for protein translation-oriented drug developments for human inflammatory diseases.

DOI: https://doi.org/10.1084/jem.20230577
bioRxiv. 2023 Aug 02. pii: 2023.07.31.551241. [Epub ahead of print]

Restoring adiponectin via rosiglitazone ameliorates tissue wasting in mice with lung cancer.

Henning Tim Langer, Shakti Ramsamooj, Ezequiel Dantas, Anirudh Murthy, Mujmmail Ahmed, Seo-Kyoung Hwang, Rahul Grover, Rita Pozovskiy, Roger J Liang, Andre Lima Queiroz, Justin C Brown, Eileen P White, Tobias Janowitz, Marcus D Goncalves.

The cancer associated cachexia syndrome (CACS) is a systemic metabolic disorder resulting in loss of body weight due to skeletal muscle and adipose tissues atrophy. CACS is particularly prominent in lung cancer patients, where it contributes to poor quality of life and excess mortality. Using the Kras/Lkb1 (KL) mouse model, we found that CACS is associated with white adipose tissue (WAT) dysfunction that directly affects skeletal muscle homeostasis. WAT transcriptomes showed evidence of reduced adipogenesis, and, in agreement, we found low levels of circulating adiponectin. To preserve adipogenesis and restore adiponectin levels, we treated mice with the PPAR-γ agonist, rosiglitazone. Rosiglitazone treatment increased serum adiponectin levels, delayed weight loss, and preserved skeletal muscle and adipose tissue mass, as compared to vehicle-treated mice. The preservation of muscle mass with rosiglitazone was associated with increases in AMPK and AKT activity. Similarly, activation of the adiponectin receptors in muscle cells increased AMPK activity, anabolic signaling, and protein synthesis. Our data suggest that PPAR-γ agonists may be a useful adjuvant therapy to preserve tissue mass in lung cancer.
Key points: - The PPAR-γ agonist, rosiglitazone, restores circulating adiponectin levels in mice with lung cancer.- Rosiglitazone preserves skeletal muscle and adipose tissue mass in mice with lung cancer.- The preservation of muscle mass with rosiglitazone is associated with increases in AMPK and AKT activity.- Stimulation of adiponectin signaling increases AMPK activity, anabolic signaling, and protein synthesis in muscle cell culture.

DOI: https://doi.org/10.1101/2023.07.31.551241
Gastric Cancer. 2023 Aug 12.

PPARδ dysregulation of CCL20/CCR6 axis promotes gastric adenocarcinoma carcinogenesis by remodeling gastric tumor microenvironment.

Yi Liu, Daoyan Wei, Yasunori Deguchi, Weiguo Xu, Rui Tian, Fuyao Liu, Min Xu, Fei Mao, Donghui Li, Weidong Chen, Lovie Ann Valentin, Eriko Deguchi, James C Yao, Imad Shureiqi, Xiangsheng Zuo.

   BACKGROUND: Peroxisome proliferator-activated receptor delta (PPARδ) promotes inflammation and carcinogenesis in many organs, but the underlying mechanisms remains elusive. In stomachs, PPARδ significantly increases chemokine Ccl20 expression in gastric epithelial cells while inducing gastric adenocarcinoma (GAC). CCR6 is the sole receptor of CCL20. Here, we examine the role of PPARδ-mediated Ccl20/Ccr6 signaling in GAC carcinogenesis and investigate the underlying mechanisms.
METHODS: The effects of PPARδ inhibition by its specific antagonist GSK3787 on GAC were examined in the mice with villin-promoter-driven PPARδ overexpression (PpardTG). RNAscope Duplex Assays were used to measure Ccl20 and Ccr6 levels in stomachs and spleens. Subsets of stomach-infiltrating immune cells were measured via flow cytometry or immunostaining in PpardTG mice fed GSK3787 or control diet. A panel of 13 optimized proinflammatory chemokines in mouse sera were quantified by an enzyme-linked immunosorbent assay.
RESULTS: GSK3787 significantly suppressed GAC carcinogenesis in PpardTG mice. PPARδ increased Ccl20 level to chemoattract Ccr6+ immunosuppressive cells, including tumor-associated macrophages, myeloid-derived suppressor cells and T regulatory cells, but decreased CD8+ T cells in gastric tissues. GSK3787 suppressed PPARδ-induced gastric immunosuppression by inhibiting Ccl20/Ccr6 axis. Furthermore, Ccl20 protein levels increased in sera of PpardTG mice starting at the age preceding gastric tumor development and further increased with GAC progression as the mice aged. GSK3787 decreased the PPARδ-upregulated Ccl20 levels in sera of the mice.
CONCLUSIONS: PPARδ dysregulation of Ccl20/Ccr6 axis promotes GAC carcinogenesis by remodeling gastric tumor microenvironment. CCL20 might be a potential biomarker for the early detection and progression of GAC.

Keywords:  Biomarkers; CCL20/CCR6; Immunosuppression; PPARdelta; Stomach neoplasms

DOI:  https://doi.org/10.1007/s10120-023-01418-w