bims-stacyt 2023-03-12 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2023–03–12
eight papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Lactate in the tumor microenvironment: A rising star for targeted tumor therapy.
Inflammatory Cytokine Interleukin-6 (IL-6) Promotes the Proangiogenic Ability of Adipose Stem Cells from Obese Subjects via the IL-6 Signaling Pathway.
The role of AMPK in cancer metabolism and its impact on the immunomodulation of the tumor microenvironment.
NF-κB mediated regulation of tumor cell proliferation in hypoxic microenvironment.
Adipocyte-derived exosomal miR-30c-5p promotes ovarian angiogenesis in polycystic ovary syndrome via the SOCS3/STAT3/VEGFA pathway.
Tumor-derived Immunoglobulin-like transcript 4 facilitates angiogenesis of colorectal cancer.
Enriched environment promotes post-stroke angiogenesis through astrocytic interleukin-17A.
Macrophage fumarate hydratase restrains mtRNA-mediated interferon production.

Front Nutr. 2023 ;10 1113739

Lactate in the tumor microenvironment: A rising star for targeted tumor therapy.

Zhangzuo Li, Qi Wang, Xufeng Huang, Mengting Yang, Shujing Zhou, Zhengrui Li, Zhengzou Fang, Yidan Tang, Qian Chen, Hanjin Hou, Li Li, Fei Fei, Qiaowei Wang, Yuqing Wu, Aihua Gong.

  Metabolic reprogramming is one of fourteen hallmarks of tumor cells, among which aerobic glycolysis, often known as the "Warburg effect," is essential to the fast proliferation and aggressive metastasis of tumor cells. Lactate, on the other hand, as a ubiquitous molecule in the tumor microenvironment (TME), is generated primarily by tumor cells undergoing glycolysis. To prevent intracellular acidification, malignant cells often remove lactate along with H+, yet the acidification of TME is inevitable. Not only does the highly concentrated lactate within the TME serve as a substrate to supply energy to the malignant cells, but it also works as a signal to activate multiple pathways that enhance tumor metastasis and invasion, intratumoral angiogenesis, as well as immune escape. In this review, we aim to discuss the latest findings on lactate metabolism in tumor cells, particularly the capacity of extracellular lactate to influence cells in the tumor microenvironment. In addition, we examine current treatment techniques employing existing medications that target and interfere with lactate generation and transport in cancer therapy. New research shows that targeting lactate metabolism, lactate-regulated cells, and lactate action pathways are viable cancer therapy strategies.

Keywords:  immune cells; immunity; lactate; metabolic; tumor microenvironment

DOI:  https://doi.org/10.3389/fnut.2023.1113739
Curr Stem Cell Res Ther. 2023 ;18(1): 93-104

Inflammatory Cytokine Interleukin-6 (IL-6) Promotes the Proangiogenic Ability of Adipose Stem Cells from Obese Subjects via the IL-6 Signaling Pathway.

Yuanyuan Zhang, Pengju Lv, Yalong Li, Yonghui Zhang, Chaofei Cheng, Hongbo Hao, Han Yue.

   BACKGROUND: The prevalence of obesity, as well as obesity-induced chronic inflammatory diseases, is increasing worldwide. Chronic inflammation is related to the complex process of angiogenesis, and we found that adipose-derived stem cells from obese subjects (obADSCs) had proangiogenic features, including higher expression levels of interleukin-6 (IL-6), Notch ligands and receptors, and proangiogenic cytokines, than those from control subjects. We hypothesized that IL-6 and Notch signaling pathways are essential for regulating the proangiogenic characteristics of obADSCs.
OBJECTIVE: This study aimed to investigate whether the inflammatory cytokine interleukin 6 (IL-6) promotes the proangiogenic capacity of adipose stem cells in obese subjects via the IL-6 signaling pathway.
METHODS: We compared the phenotype analysis as well as cell doubling time, proliferation, migration, differentiation, and proangiogenic properties of ADSCs in vitro. Moreover, we used small interfering RNAs to inhibit the gene and protein expression of IL-6.
RESULTS: We found that ADSCs isolated from control individuals (chADSCs) and obADSCs had similar phenotypes and growth characteristics, and chADSCs had a stronger differentiation ability than obADSCs. However, obADSCs were more potent in promoting EA.hy926 cell migration and tube formation than chADSCs in vitro. We confirmed that IL-6 siRNA significantly reduced the transcriptional level of IL-6 in obADSCs, thereby reducing the expression of vascular endothelial growth factor (VEGF)- A, VEGF receptor 2, transforming growth factor β, and Notch ligands and receptors in obADSCs.
CONCLUSION: The finding suggests that inflammatory cytokine interleukin-6 (IL-6) promotes the proangiogenic ability of obADSCs via the IL-6 signaling pathway.

Keywords:  Notch signaling; Obesity; adipose-derived stem cells (ADSCs); angiogenesis; inflammation; interleukin-6 (IL-6)

DOI:  https://doi.org/10.2174/1574888X17666220429103935
Front Immunol. 2023 ;14 1114582

The role of AMPK in cancer metabolism and its impact on the immunomodulation of the tumor microenvironment.

Chenicheri Kizhakkeveettil Keerthana, Tennyson Prakash Rayginia, Sadiq Chembothumparambil Shifana, Nikhil Ponnoor Anto, Kalishwaralal Kalimuthu, Noah Isakov, Ruby John Anto.

  Adenosine monophosphate-activated protein kinase (AMPK) is a key metabolic sensor that is pivotal for the maintenance of cellular energy homeostasis. AMPK contributes to diverse metabolic and physiological effects besides its fundamental role in glucose and lipid metabolism. Aberrancy in AMPK signaling is one of the determining factors which lead to the development of chronic diseases such as obesity, inflammation, diabetes, and cancer. The activation of AMPK and its downstream signaling cascades orchestrate dynamic changes in the tumor cellular bioenergetics. It is well documented that AMPK possesses a suppressor role in the context of tumor development and progression by modulating the inflammatory and metabolic pathways. In addition, AMPK plays a central role in potentiating the phenotypic and functional reprogramming of various classes of immune cells which reside in the tumor microenvironment (TME). Furthermore, AMPK-mediated inflammatory responses facilitate the recruitment of certain types of immune cells to the TME, which impedes the development, progression, and metastasis of cancer. Thus, AMPK appears to play an important role in the regulation of anti-tumor immune response by regulating the metabolic plasticity of various immune cells. AMPK effectuates the metabolic modulation of anti-tumor immunity via nutrient regulation in the TME and by virtue of its molecular crosstalk with major immune checkpoints. Several studies including that from our lab emphasize on the role of AMPK in regulating the anticancer effects of several phytochemicals, which are potential anticancer drug candidates. The scope of this review encompasses the significance of the AMPK signaling in cancer metabolism and its influence on the key drivers of immune responses within the TME, with a special emphasis on the potential use of phytochemicals to target AMPK and combat cancer by modulating the tumor metabolism.

Keywords:  AMPK signaling; T cells; cancer metabolism; immune checkpoints; immune response; macrophages; phytochemicals; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2023.1114582
Front Pharmacol. 2023 ;14 1108915

NF-κB mediated regulation of tumor cell proliferation in hypoxic microenvironment.

Shubham Rastogi, Sara Aldosary, Abdulaziz S Saeedan, Mohd Nazam Ansari, Manjari Singh, Gaurav Kaithwas.

  Hypoxia is caused by a cancer-promoting milieu characterized by persistent inflammation. NF-κB and HIF-1α are critical participants in this transition. Tumor development and maintenance are aided by NF-κB, while cellular proliferation and adaptability to angiogenic signals are aided by HIF-1α. Prolyl hydroxylase-2 (PHD-2) has been hypothesized to be the key oxygen-dependent regulator of HIF-1α and NF-transcriptional B's activity. Without low oxygen levels, HIF-1α is degraded by the proteasome in a process dependent on oxygen and 2-oxoglutarate. As opposed to the normal NF-κB activation route, where NF-κB is deactivated by PHD-2-mediated hydroxylation of IKK, this method actually activates NF-κB. HIF-1α is protected from degradation by proteasomes in hypoxic cells, where it then activates transcription factors involved in cellular metastasis and angiogenesis. The Pasteur phenomenon causes lactate to build up inside the hypoxic cells. As part of a process known as lactate shuttle, MCT-1 and MCT-4 cells help deliver lactate from the blood to neighboring, non-hypoxic tumour cells. Non-hypoxic tumour cells use lactate, which is converted to pyruvate, as fuel for oxidative phosphorylation. OXOPHOS cancer cells are characterized by a metabolic switch from glucose-facilitated oxidative phosphorylation to lactate-facilitated oxidative phosphorylation. Although PHD-2 was found in OXOPHOS cells. There is no clear explanation for the presence of NF-kappa B activity. The accumulation of the competitive inhibitor of 2-oxo-glutarate, pyruvate, in non-hypoxic tumour cells is well established. So, we conclude that PHD-2 is inactive in non-hypoxic tumour cells due to pyruvate-mediated competitive suppression of 2-oxo-glutarate. This results in canonical activation of NF-κB. In non-hypoxic tumour cells, 2-oxoglutarate serves as a limiting factor, rendering PHD-2 inactive. However, FIH prevents HIF-1α from engaging in its transcriptional actions. Using the existing scientific literature, we conclude in this study that NF-κB is the major regulator of tumour cell growth and proliferation via pyruvate-mediated competitive inhibition of PHD-2.

Keywords:  HIF-1α; NF-κB; PHD2; cancer; hypoxia; lactate shuttle

DOI:  https://doi.org/10.3389/fphar.2023.1108915
J Steroid Biochem Mol Biol. 2023 Mar 03. pii: S0960-0760(23)00033-X. [Epub ahead of print]230 106278

Adipocyte-derived exosomal miR-30c-5p promotes ovarian angiogenesis in polycystic ovary syndrome via the SOCS3/STAT3/VEGFA pathway.

Jian Hu, Fangyou Lin, Yuchen Yin, Yunjie Shang, Zhuoni Xiao, Wangming Xu.

  Polycystic ovary syndrome (PCOS) is a systemic endocrine disease affecting women's reproductive health. Ovarian angiogenesis in PCOS patients is abnormal, manifested by increased ovarian stromal vascularization and upregulated proangiogenic factors such as vascular endothelial growth factor (VEGF). However, the specific mechanisms underlying these changes in PCOS remain unknown. In this study, we induced the adipogenic differentiation in preadipocyte 3T3-L1 cells and found that adipocyte-derived exosomes promoted proliferation, migration, tube formation, and VEGFA expression in human ovarian microvascular endothelial cells (HOMECs) by delivering miR-30c-5p. Mechanistically, dual luciferase reporter assay demonstrated that miR-30c-5p directly targeted the 3'- untranslated region (UTR) of suppressor of cytokine signaling 3 (SOCS3) mRNA. In addition, adipocyte-derived exosomal miR-30c-5p activated signal transducer and activator of transcription 3 (STAT3)/VEGFA pathway in HOMECs via targeting SOCS3. In vivo experiments indicated that tail vein injection of adipocyte-derived exosomes exacerbated endocrine and metabolic disorders and ovarian angiogenesis in mice with PCOS via miR-30c-5p. Taken together, the study revealed that adipocyte-derived exosomal miR-30c-5p promotes ovarian angiogenesis via the SOCS3/STAT3/VEGFA pathway, thereby participating in the development of PCOS.

Keywords:  Angiogenesis; Exosomes; MiR-30c-5p; Polycystic ovary syndrome; SOCS3; STAT3/VEGFA pathway

DOI:  https://doi.org/10.1016/j.jsbmb.2023.106278
Am J Cancer Res. 2023 ;13(2): 419-435

Tumor-derived Immunoglobulin-like transcript 4 facilitates angiogenesis of colorectal cancer.

Jing Liu, Fang Zhang, Jie He, Shuyun Wang, Leirong Wang, Juan Li, Wenjing Shi, Yali Han, Aiqin Gao, Yuping Sun.

Current anti-angiogenic therapies have changed the paradigm of treating colorectal cancer (CRC) patients with advanced diseases. However, the clinical response rate is still low at less than 10% due largely to complex angiogenic factors released by tumor cells. Exploring novel mechanisms of tumor angiogenesis and identifying alternative targets for combination therapies are therefore essential to effective inhibition of tumor vascularization and CRC development. Immunoglobulin-like transcript 4 (ILT4), initially identified as a suppressor of myeloid cell activity, is enriched in solid tumor cells. ILT4 favors tumor progression by inducing tumor malignant biologies as well as an immunosuppressive microenvironment. However, whether and how tumor-derived ILT4 orchestrates tumor angiogenesis is still undetermined. Here we found that tumor-derived ILT4 was positively correlated with microvessel density in CRC tissues. ILT4 induced the migration and tube formation of HUVECs in vitro and angiogenesis in vivo. Mechanistically, the activation of MAPK/ERK signaling and subsequent up-regulation of vascular endothelial growth factor-A (VEGF-A) and fibroblast growth factor 1 (FGF-1) were responsible for ILT4-induced angiogenesis and tumor progression. Importantly, ILT4 inhibition suppressed tumor angiogenesis and enhanced the efficacy of Bevacizumab treatment in CRC. Our study has identified a novel mechanism for ILT4-mediated tumor progression, which signals a new therapeutic target and alternative combination strategies to combat CRC.

Keywords: FGF-1; ILT4; VEGF-A; angiogenesis; colorectal cancer; combination therapy
Front Behav Neurosci. 2023 ;17 1053877

Enriched environment promotes post-stroke angiogenesis through astrocytic interleukin-17A.

Xiuping Chen, Lingling Liu, Yingjun Zhong, Yang Liu.

   Objective: Our previous studies have revealed that the protective effect of an enriched environment (EE) may be linked with astrocyte proliferation and angiogenesis. However, the relationship between astrocytes and angiogenesis under EE conditions still requires further study. The current research examined the neuroprotective effects of EE on angiogenesis in an astrocytic interleukin-17A (IL-17A)-dependent manner following cerebral ischemia/reperfusion (I/R) injury.
Methods: A rat model of ischemic stroke based on middle cerebral artery occlusion (MCAO) for 120 min followed by reperfusion was established, after which rats were housed in either EE or standard conditions. A set of behavior tests were conducted, including the modified neurological severity scores (mNSS) and the rotarod test. The infarct volume was evaluated by means of 2,3,5-Triphenyl tetrazolium chloride (TTC) staining. To evaluate the levels of angiogenesis, the protein levels of CD34 were examined by means of immunofluorescence and western blotting, while the protein and mRNA levels of IL-17A, vascular endothelial growth factor (VEGF), and the angiogenesis-associated factors interleukin-6 (IL-6), JAK2, and STAT3 were detected by western blotting and real-time quantitative PCR (RT-qPCR).
Results: We found that EE promoted functional recovery, reduced infarct volume, and enhanced angiogenesis compared to rats in standard conditions. IL-17A expression in astrocytes was also increased in EE rats. EE treatment increased the levels of microvascular density (MVD) and promoted the expression of CD34, VEGF, IL-6, JAK2, and STAT3 in the penumbra, while the intracerebroventricular injection of the IL-17A-neutralizing antibody in EE rats attenuated EE-mediated functional recovery and angiogenesis.
Conclusion: Our findings revealed a possible neuroprotective mechanism of astrocytic IL-17A in EE-mediated angiogenesis and functional recovery after I/R injury, which might provide the theoretical basis for EE in clinical practise for stroke patients and open up new ideas for the research on the neural repair mechanism mediated by IL-17A in the recovery phase of stroke.

Keywords:  IL-17A; angiogenesis; astrocyte; cerebral ischemia/reperfusion; enriched environment

DOI:  https://doi.org/10.3389/fnbeh.2023.1053877
Nature. 2023 Mar 08.

Macrophage fumarate hydratase restrains mtRNA-mediated interferon production.

Alexander Hooftman, Christian G Peace, Dylan G Ryan, Emily A Day, Ming Yang, Anne F McGettrick, Maureen Yin, Erica N Montano, Lihong Huo, Juliana E Toller-Kawahisa, Vincent Zecchini, Tristram A J Ryan, Alfonso Bolado-Carrancio, Alva M Casey, Hiran A Prag, Ana S H Costa, Gabriela De Los Santos, Mariko Ishimori, Daniel J Wallace, Swamy Venuturupalli, Efterpi Nikitopoulou, Norma Frizzell, Cecilia Johansson, Alexander Von Kriegsheim, Michael P Murphy, Caroline Jefferies, Christian Frezza, Luke A J O'Neill.

Metabolic rewiring underlies the effector functions of macrophages1-3, but the mechanisms involved remain incompletely defined. Here, using unbiased metabolomics and stable isotope-assisted tracing, we show that an inflammatory aspartate-argininosuccinate shunt is induced following lipopolysaccharide stimulation. The shunt, supported by increased argininosuccinate synthase (ASS1) expression, also leads to increased cytosolic fumarate levels and fumarate-mediated protein succination. Pharmacological inhibition and genetic ablation of the tricarboxylic acid cycle enzyme fumarate hydratase (FH) further increases intracellular fumarate levels. Mitochondrial respiration is also suppressed and mitochondrial membrane potential increased. RNA sequencing and proteomics analyses demonstrate that there are strong inflammatory effects resulting from FH inhibition. Notably, acute FH inhibition suppresses interleukin-10 expression, which leads to increased tumour necrosis factor secretion, an effect recapitulated by fumarate esters. Moreover, FH inhibition, but not fumarate esters, increases interferon-β production through mechanisms that are driven by mitochondrial RNA (mtRNA) release and activation of the RNA sensors TLR7, RIG-I and MDA5. This effect is recapitulated endogenously when FH is suppressed following prolonged lipopolysaccharide stimulation. Furthermore, cells from patients with systemic lupus erythematosus also exhibit FH suppression, which indicates a potential pathogenic role for this process in human disease. We therefore identify a protective role for FH in maintaining appropriate macrophage cytokine and interferon responses.

DOI: https://doi.org/10.1038/s41586-023-05720-6