bims-stacyt 2023-05-07 papers

J Immunother Cancer. 2023 May;pii: e005719. [Epub ahead of print]11(5):

Metformin improves cancer immunotherapy by directly rescuing tumor-infiltrating CD8 T lymphocytes from hypoxia-induced immunosuppression.

Veronica Finisguerra, Tereza Dvorakova, Matteo Formenti, Pierre Van Meerbeeck, Lionel Mignion, Bernard Gallez, Benoit J Van den Eynde.

BACKGROUND: Despite their revolutionary success in cancer treatment over the last decades, immunotherapies encounter limitations in certain tumor types and patients. The efficacy of immunotherapies depends on tumor antigen-specific CD8 T-cell viability and functionality within the immunosuppressive tumor microenvironment, where oxygen levels are often low. Hypoxia can reduce CD8 T-cell fitness in several ways and CD8 T cells are mostly excluded from hypoxic tumor regions. Given the challenges to achieve durable reduction of hypoxia in the clinic, ameliorating CD8 T-cell survival and effector function in hypoxic condition could improve tumor response to immunotherapies.METHODS: Activated CD8 T cells were exposed to hypoxia and metformin and analyzed by fluorescence-activated cell sorting for cell proliferation, apoptosis and phenotype. In vivo, metformin was administered to mice bearing hypoxic tumors and receiving either adoptive cell therapy with tumor-specific CD8 T cells, or immune checkpoint inhibitors; tumor growth was followed over time and CD8 T-cell infiltration, survival and localization in normoxic or hypoxic tumor regions were assessed by flow cytometry and immunofluorescence. Tumor oxygenation and hypoxia were measured by electron paramagnetic resonance and pimonidazole staining, respectively.
RESULTS: We found that the antidiabetic drug metformin directly improved CD8 T-cell fitness in hypoxia, both in vitro and in vivo. Metformin rescued murine and human CD8 T cells from hypoxia-induced apoptosis and increased their proliferation and cytokine production, while blunting the upregulation of programmed cell death protein 1 and lymphocyte-activation gene 3. This appeared to result from a reduced production of reactive oxygen species, due to the inhibition of mitochondrial complex I. Differently from what others reported, metformin did not reduce tumor hypoxia, but rather increased CD8 T-cell infiltration and survival in hypoxic tumor areas, and synergized with cyclophosphamide to enhance tumor response to adoptive cell therapy or immune checkpoint blockade in different tumor models.
CONCLUSIONS: This study describes a novel mechanism of action of metformin and presents a promising strategy to achieve immune rejection in hypoxic and immunosuppressive tumors, which would otherwise be resistant to immunotherapy.

Keywords: immunotherapy; lymphocytes, tumor-infiltrating; tumor microenvironment

DOI: https://doi.org/10.1136/jitc-2022-005719

Biomed Pharmacother. 2023 May 03. pii: S0753-3322(23)00592-9. [Epub ahead of print]163 114802

Understanding the relationship between cancer associated cachexia and hypoxia-inducible factor-1.

Subramanian Muthamil, Hyun Yong Kim, Hyun-Jun Jang, Ji-Hyo Lyu, Ung Cheol Shin, Younghoon Go, Seong-Hoon Park, Hee Gu Lee, Jun Hong Park.

Cancer-associated cachexia (CAC) is a multifactorial disorder characterized by an unrestricted loss of body weight as a result of muscle and adipose tissue atrophy. Cachexia is influenced by several factors, including decreased metabolic activity and food intake, an imbalance between energy uptake and expenditure, excessive catabolism, and inflammation. Cachexia is highly associated with all types of cancers responsible for more than half of cancer-related mortalities worldwide. In healthy individuals, adipose tissue significantly regulates energy balance and glucose homeostasis. However, in metastatic cancer patients, CAC occurs mainly because of an imbalance between muscle protein synthesis and degradation which are organized by certain extracellular ligands and associated signaling pathways. Under hypoxic conditions, hypoxia-inducible factor-1 (HIF-1α) accumulated and translocated to the nucleus and activate numerous genes involved in cell survival, invasion, angiogenesis, metastasis, metabolic reprogramming, and cancer stemness. On the other hand, the ubiquitination proteasome pathway is inhibited during low O2 levels which promote muscle wasting in cancer patients. Therefore, understanding the mechanism of the HIF-1 pathway and its metabolic adaptation to biomolecules is important for developing a novel therapeutic method for cancer and cachexia therapy. Even though many HIF inhibitors are already in a clinical trial, their mechanism of action remains unknown. With this background, this review summarizes the basic concepts of cachexia, the role of inflammatory cytokines, pathways connected with cachexia with special reference to the HIF-1 pathway and its regulation, metabolic changes, and inhibitors of HIFs.

Keywords: Adipogenesis; Cancer-associated cachexia; Hypoxia-inducible factor-1; Metabolism; Muscle wasting; Signaling pathways

DOI: https://doi.org/10.1016/j.biopha.2023.114802

Endocrine. 2023 May 02.

Growth differentiation factor 15 (GDF-15) in endocrinology.

Pedro Iglesias, Ramona A Silvestre, Juan J Díez.

Human growth differentiation factor 15 (GDF-15) is a widely distributed protein that has shown to play multiple roles in both physiological and pathological conditions. In healthy individuals, GDF-15 is mainly expressed in the placenta, followed by the prostate, although low levels of expression have also been detected in different organs. GDF-15 acts through a recently identified receptor called glial-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) which signals through the rearranged during transfection (RET) tyrosine kinase receptor. The effects of GDF-15 are pleiotropic and include appetite regulation, and actions on metabolism, pregnancy, cell survival, immune response, and inflammation. GDF-15 also plays different roles in the pathophysiology of cardiovascular disease, autoimmunity, cancer-associated anorexia/cachexia, and diabetes. In recent years, several studies have reported a link between GDF-15 and the endocrine system. In this review, we up-date and summarize the relevant investigations of the relationships between GDF-15 and different endocrine conditions. We also assess the potential pathogenic role and potential therapeutic applications of GDF-15 in the field of endocrinology.

Keywords: Adrenal; Diabetes; Growth differentiation factor 15 (GDF-15); Macrophage inhibitory cytokine-1 (MIC-1); Pituitary; Thyroid

DOI: https://doi.org/10.1007/s12020-023-03377-9

Environ Pollut. 2023 Apr 27. pii: S0269-7491(23)00717-0. [Epub ahead of print]329 121715

Mild exposure to fine particulate matter promotes angiogenesis in non-small cell lung carcinoma.

Su Min Ji, Jae-Sun Choi, Ji Young Lee, Sungyeon Kim, Woom-Yee Bae, Ye Won Jang, Ja-Eun Kim, Seung Hyeun Lee, Seungyoon Nam, Joo-Won Jeong.

Fine particulate matter (PM2.5) is associated with public health problems worldwide. Especially, PM2.5 induces epigenetic and microenvironmental changes in lung cancer. Angiogenesis is important for the development and growth of cancer and is mediated by angiogenic factors, including vascular endothelial growth factor. However, the effects of mild PM2.5 exposure on angiogenesis in lung cancer remain unclear. In this study, we examined angiogenic effects using relatively lower concentrations of PM2.5 than in other studies and found that PM2.5 increased angiogenic activities in both endothelial cells and non-small cell lung carcinoma cells. PM2.5 also promoted the growth and angiogenesis of lung cancer via the induction of hypoxia-inducible factor-1α (HIF-1α) in a xenograft mouse tumor model. Angiogenic factors, including vascular endothelial growth factor (VEGF), were highly expressed in lung cancer patients in countries with high PM2.5 levels in the atmosphere, and high expression of VEGF in lung cancer patients lowered the survival rate. Collectively, these results provide new insight into the mechanisms by which mild exposure to PM2.5 is involved in HIF-1α-mediated angiogenesis in lung cancer patients.

Keywords: Angiogenesis; Fine particulate matter; Hypoxia-inducible factor-1α; Lung cancer; Vascular endothelial growth factor

DOI: https://doi.org/10.1016/j.envpol.2023.121715

J Cachexia Sarcopenia Muscle. 2023 May 01.

Impairment of aryl hydrocarbon receptor signalling promotes hepatic disorders in cancer cachexia.

Adeline Dolly, Sarah A Pötgens, Morgane M Thibaut, Audrey M Neyrinck, Gabriela S de Castro, Chloé Galbert, Camille Lefevre, Elisabeth Wyart, Silvio P Gomes, Daniela C Gonçalves, Nicolas Lanthier, Pamela Baldin, Joshua R Huot, Andrea Bonetto, Marília Seelaender, Nathalie M Delzenne, Harry Sokol, Laure B Bindels.

BACKGROUND: The aryl hydrocarbon receptor (AHR) is expressed in the intestine and liver, where it has pleiotropic functions and target genes. This study aims to explore the potential implication of AHR in cancer cachexia, an inflammatory and metabolic syndrome contributing to cancer death. Specifically, we tested the hypothesis that targeting AHR can alleviate cachectic features, particularly through the gut-liver axis.METHODS: AHR pathways were explored in multiple tissues from four experimental mouse models of cancer cachexia (C26, BaF3, MC38 and APCMin/+ ) and from non-cachectic mice (sham-injected mice and non-cachexia-inducing [NC26] tumour-bearing mice), as well as in liver biopsies from cancer patients. Cachectic mice were treated with an AHR agonist (6-formylindolo(3,2-b)carbazole [FICZ]) or an antibody neutralizing interleukin-6 (IL-6). Key mechanisms were validated in vitro on HepG2 cells.
RESULTS: AHR activation, reflected by the expression of Cyp1a1 and Cyp1a2, two major AHR target genes, was deeply reduced in all models (C26 and BaF3, P < 0.001; MC38 and APCMin/+ , P < 0.05) independently of anorexia. This reduction occurred early in the liver (P < 0.001; before the onset of cachexia), compared to the ileum and skeletal muscle (P < 0.01; pre-cachexia stage), and was intrinsically related to cachexia (C26 vs. NC26, P < 0.001). We demonstrate a differential modulation of AHR activation in the liver (through the IL-6/hypoxia-inducing factor 1α pathway) compared to the ileum (attributed to the decreased levels of indolic AHR ligands, P < 0.001), and the muscle. In cachectic mice, FICZ treatment reduced hepatic inflammation: expression of cytokines (Ccl2, P = 0.005; Cxcl2, P = 0.018; Il1b, P = 0.088) with similar trends at the protein levels, expression of genes involved in the acute-phase response (Apcs, P = 0.040; Saa1, P = 0.002; Saa2, P = 0.039; Alb, P = 0.003), macrophage activation (Cd68, P = 0.038) and extracellular matrix remodelling (Fga, P = 0.008; Pcolce, P = 0.025; Timp1, P = 0.003). We observed a decrease in blood glucose in cachectic mice (P < 0.0001), which was also improved by FICZ treatment (P = 0.026) through hepatic transcriptional promotion of a key marker of gluconeogenesis, namely, G6pc (C26 vs. C26 + FICZ, P = 0.029). Strikingly, these benefits on glycaemic disorders occurred independently of an amelioration of the gut barrier dysfunction. In cancer patients, the hepatic expression of G6pc was correlated to Cyp1a1 (Spearman's ρ = 0.52, P = 0.089) and Cyp1a2 (Spearman's ρ = 0.67, P = 0.020).
CONCLUSIONS: With this set of studies, we demonstrate that impairment of AHR signalling contributes to hepatic inflammatory and metabolic disorders characterizing cancer cachexia, paving the way for innovative therapeutic strategies in this context.

Keywords: CYP1A1; CYP1A2; HIF1α; TIPARP; fibroblast growth factor 21

DOI: https://doi.org/10.1002/jcsm.13246

PLoS Biol. 2023 05;21(5): e3001746

Tumor-derived interleukin-1α and leukemia inhibitory factor promote extramedullary hematopoiesis.

Derek A G Barisas, Ashraf Ul Kabir, Jun Wu, Karen Krchma, Minseo Kim, Madhav Subramanian, Bernd H Zinselmeyer, Colin L Stewart, Kyunghee Choi.

Extramedullary hematopoiesis (EMH) expands hematopoietic capacity outside of the bone marrow in response to inflammatory conditions, including infections and cancer. Because of its inducible nature, EMH offers a unique opportunity to study the interaction between hematopoietic stem and progenitor cells (HSPCs) and their niche. In cancer patients, the spleen frequently serves as an EMH organ and provides myeloid cells that may worsen pathology. Here, we examined the relationship between HSPCs and their splenic niche in EMH in a mouse breast cancer model. We identify tumor produced IL-1α and leukemia inhibitory factor (LIF) acting on splenic HSPCs and splenic niche cells, respectively. IL-1α induced TNFα expression in splenic HSPCs, which then activated splenic niche activity, while LIF induced proliferation of splenic niche cells. IL-1α and LIF display cooperative effects in activating EMH and are both up-regulated in some human cancers. Together, these data expand avenues for developing niche-directed therapies and further exploring EMH accompanying inflammatory pathologies like cancer.

DOI: https://doi.org/10.1371/journal.pbio.3001746

Heliyon. 2023 Apr;9(4): e14952

FGF21/FGFR1-β-KL cascade in cardiomyocytes modulates angiogenesis and inflammation under metabolic stress.

Namrita Kaur, Sanskruti Ravindra Gare, Andrea Ruiz-Velasco, Jessica M Miller, Riham R E Abouleisa, Qinghui Ou, Jiahan Shen, Handrean Soran, Tamer M A Mohamed, Wei Liu.

Diabetes is a metabolic disorder with an increased risk of developing heart failure. Inflammation and damaged vasculature are the cardinal features of diabetes-induced cardiac damage. Moreover, systemic metabolic stress triggers discordant intercellular communication, thus culminating in cardiac dysfunction. Fibroblast growth factor 21 (FGF21) is a pleiotropic hormone transducing cellular signals via fibroblast growth factor receptor 1 (FGFR1) and its co-receptor beta-klotho (β-KL). This study first demonstrated a decreased expression or activity of FGFR1 and β-KL in both human and mouse diabetic hearts. Reinforcing cardiac FGFR1 and β-KL expression can alleviate pro-inflammatory response and endothelial dysfunction upon diabetic stress. Using proteomics, novel cardiomyocyte-derived anti-inflammatory and proangiogenic factors regulated by FGFR1-β-KL signaling were identified. Although not exhaustive, this study provides a unique insight into the protective topology of the cardiac FGFR1-β-KL signaling-mediated intercellular reactions in the heart in response to metabolic stress.

Keywords: Angiogenesis; Diabetic cardiomyopathy; Inflammation; Intercellular communication; Metabolic stress

DOI: https://doi.org/10.1016/j.heliyon.2023.e14952