bims-stacyt 2023-10-01 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2023–10–01
ten papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Alpha-Ketoglutarate Regulates Tnfrsf12a/Fn14 Expression via Histone Modification and Prevents Cancer-Induced Cachexia.
Can Exercise Enhance the Efficacy of Checkpoint Inhibition by Modulating Anti-Tumor Immunity?
Exosomal EIF5A derived from Lewis lung carcinoma induced adipocyte wasting in cancer cachexia.
GDF15 deficiency hinders human trophoblast invasion to mediate pregnancy loss through downregulating Smad1/5 phosphorylation.
Abstract Proceedings of 7th Cancer Cachexia Conference, 28-30 September 2023, Edinburgh.
Communicator Extraordinaire: Extracellular Vesicles in the Tumor Microenvironment Are Essential Local and Long-Distance Mediators of Cancer Metastasis.
Oncometabolite D-2-hydroxyglutarate-dependent metabolic reprogramming induces skeletal muscle atrophy during cancer cachexia.
D-2-hydroxyglutarate regulates human brain vascular endothelial cell proliferation and barrier function.
Endothelial Notch1 signaling in white adipose tissue promotes cancer cachexia.
The immune checkpoint adenosine 2A receptor is associated with aggressive clinical outcomes and reflects an immunosuppressive tumor microenvironment in human breast cancer.

Genes (Basel). 2023 Sep 19. pii: 1818. [Epub ahead of print]14(9):

Alpha-Ketoglutarate Regulates Tnfrsf12a/Fn14 Expression via Histone Modification and Prevents Cancer-Induced Cachexia.

Bryan I Ruiz, Xazmin H Lowman, Ying Yang, Qi Fan, Tianhong Wang, Hongmei Wu, Eric A Hanse, Mei Kong.

  Previous studies have shown that inhibition of TNF family member FN14 (gene: TNFRSF12A) in colon tumors decreases inflammatory cytokine expression and mitigates cancer-induced cachexia. However, the molecular mechanisms underlying the regulation of FN14 expression remain unclear. Tumor microenvironments are often devoid of nutrients and oxygen, yet how the cachexic response relates to the tumor microenvironment and, importantly, nutrient stress is unknown. Here, we looked at the connections between metabolic stress and FN14 expression. We found that TNFRSF12A expression was transcriptionally induced during glutamine deprivation in cancer cell lines. We also show that the downstream glutaminolysis metabolite, alpha-ketoglutarate (aKG), is sufficient to rescue glutamine-deprivation-promoted TNFRSF12A induction. As aKG is a co-factor for histone de-methylase, we looked at histone methylation and found that histone H3K4me3 at the Tnfrsf12a promoter is increased under glutamine-deprived conditions and rescued via DM-aKG supplementation. Finally, expression of Tnfrsf12a and cachexia-induced weight loss can be inhibited in vivo by DM-aKG in a mouse cancer cachexia model. These findings highlight a connection between metabolic stress and cancer cachexia development.

Keywords:  FN14; TNFRSF12A; alpha-ketoglutarate; cachexia; cancer; colon cancer; histone

DOI:  https://doi.org/10.3390/genes14091818
Cancers (Basel). 2023 Sep 21. pii: 4668. [Epub ahead of print]15(18):

Can Exercise Enhance the Efficacy of Checkpoint Inhibition by Modulating Anti-Tumor Immunity?

Christina Brummer, Tobias Pukrop, Joachim Wiskemann, Christina Bruss, Ines Ugele, Kathrin Renner.

  Immune checkpoint inhibition (ICI) has revolutionized cancer therapy. However, response to ICI is often limited to selected subsets of patients or not durable. Tumors that are non-responsive to checkpoint inhibition are characterized by low anti-tumoral immune cell infiltration and a highly immunosuppressive tumor microenvironment. Exercise is known to promote immune cell circulation and improve immunosurveillance. Results of recent studies indicate that physical activity can induce mobilization and redistribution of immune cells towards the tumor microenvironment (TME) and therefore enhance anti-tumor immunity. This suggests a favorable impact of exercise on the efficacy of ICI. Our review delivers insight into possible molecular mechanisms of the crosstalk between muscle, tumor, and immune cells. It summarizes current data on exercise-induced effects on anti-tumor immunity and ICI in mice and men. We consider preclinical and clinical study design challenges and discuss the role of cancer type, exercise frequency, intensity, time, and type (FITT) and immune sensitivity as critical factors for exercise-induced impact on cancer immunosurveillance.

Keywords:  NK cells; PD-1; PD-L1; T cells; anti-tumor immunity; cancer; exercise; immune checkpoint inhibition (ICI); immunotherapy; physical activity (PA); tumor microenvironment (TME)

DOI:  https://doi.org/10.3390/cancers15184668
Cell Signal. 2023 Sep 22. pii: S0898-6568(23)00316-9. [Epub ahead of print] 110901

Exosomal EIF5A derived from Lewis lung carcinoma induced adipocyte wasting in cancer cachexia.

Hairong Xiong, Jiaxin Ye, Qianqian Luo, Wen Li, Ning Xu, Hongmei Yang.

  Cancer cachexia is a systemic inflammation-driven syndrome, characterized by muscle atrophy and adipose tissue wasting, with progressive weight loss leading to serious impairment of physiological function. Extracellular vesicles (EVs) derived from cancer cells play a significant role in adipocyte lipolysis, yet the mechanism remain uneclucidated. In this study, EVs derived from Lewis lung carcinoma (LLC) cells were extracted and characterized. 3 T3-L1 and HIB1B adipocytes were cultured with conditioned medium or EVs from LLC, and LLC cells were used to establish a cancer cachexia mouse model. EVs derived from LLC cells were taken up by 3 T3-L1 and HIB1B adipocytes, and derived exosomal EIF5A protein-induced lipolysis of adipocytes. High level of EIF5A was expressed in EVs from LLC cells, exosomal EIF5A is linked to lipid metabolism. Elevated expression of EIF5A is associated with shorter overall survival in lung cancer patients. Western blots, glycerol release and Oil red O staining assays were used to evaluate lipolysis of adipocytes. The reduction of lipolysis in 3 T3-L1 and HIB1B adipocytes is achieved through silencing EIF5A or treating with pharmacologic inhibitor GC7 in vitro, and suppressing the expression of EIF5A in LLC cells by infected with shRNA or GC7 treatment partly alleviated white and brown adipose tissue lipolysis in vivo. Mechanistically, EIF5A directly binds with G protein-coupled bile acid receptor 1 (GPBAR1) mRNA to promote its translation and then activates cAMP response element binding protein (CREB) signaling pathway to induce lipolysis. This study demonstrates that exosomal EIF5A from LLC cells, with hypusinated EIF5A, has a lipolytic effect on adipocyte and adipose tissues in cancer cachexia model. Exosomal EIF5A could be involved in lipolysis and these findings indicate that a novel regulator and potential target for cachexia treatment.

Keywords:  Adipocyte wasting; Cancer cachexia; Eukaryotic translation initiation factor 5 A; Extracellular vesicles

DOI:  https://doi.org/10.1016/j.cellsig.2023.110901
iScience. 2023 Oct 20. 26(10): 107902

GDF15 deficiency hinders human trophoblast invasion to mediate pregnancy loss through downregulating Smad1/5 phosphorylation.

Yu-Ting Zeng, Wen-Fang Liu, Peng-Sheng Zheng, Shan Li.

  Growth differentiation factor 15 (GDF15) belongs to the Transforming growth factor β(TGF-β) superfamily. The decrease of GDF15 in the serum of pregnant women was associated with miscarriage. Both IHC and ELISA assays showed that GDF15 in trophoblast tissue and serum of pregnant women who miscarried was significantly lower than in those who had a live birth. GDF15 deficiency was associated with embryo resorption in GDF15 knockout mice through CRIPSR editing. In addition, the migration and invasion ability of HTR-8/SVneo and JEG-3 cells were promoted by GDF15. Mechanistically, GDF15 increased Smad1/5 phosphorylation, resulting in upregulating SNAI1/2, VIMENTIN and downregulating E-CADHERIN. A dual-luciferase reporter assay confirmed that Smad-binding elements (SBE) and/or GC-rich motifs were activated and target genes such as SNAI1/2, SERPINE1, and TIMP3 were transcriptionally regulated by GDF15/Smad5 signaling. Therefore, our data revealed a crucial role of GDF15 on invasion of trophoblast by upregulating the activity of TGF-β/Smad1/5 pathway.

Keywords:  Developmental biology; Molecular physiology; Reproductive medicine

DOI:  https://doi.org/10.1016/j.isci.2023.107902
J Cachexia Sarcopenia Muscle. 2023 09;14 Suppl 1 3-59

Abstract Proceedings of 7th Cancer Cachexia Conference, 28-30 September 2023, Edinburgh.

DOI: https://doi.org/10.1002/jcsm.13325
Biomedicines. 2023 Sep 14. pii: 2534. [Epub ahead of print]11(9):

Communicator Extraordinaire: Extracellular Vesicles in the Tumor Microenvironment Are Essential Local and Long-Distance Mediators of Cancer Metastasis.

Megan I Mitchell, Olivier Loudig.

  Human tumors are increasingly being described as a complex "ecosystem", that includes many different cell types, secreted growth factors, extracellular matrix (ECM) components, and microvessels, that altogether create the tumor microenvironment (TME). Within the TME, epithelial cancer cells control the function of surrounding stromal cells and the non-cellular ECM components in an intricate orchestra of signaling networks specifically designed for cancer cells to exploit surrounding cells for their own benefit. Tumor-derived extracellular vesicles (EVs) released into the tumor microenvironment are essential mediators in the reprogramming of surrounding stromal cells, which include cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), tumor-infiltrating lymphocytes (TILs), and tumor endothelial cells (TECs), which are responsible for the promotion of neo-angiogenesis, immune cell evasion, and invasion which are essential for cancer progression. Perhaps most importantly, tumor-derived EVs play critical roles in the metastatic dissemination of tumor cells through their two-fold role in initiating cancer cell invasion and the establishment of the pre-metastatic niche, both of which are vital for tumor cell migration, homing, and colonization at secondary tumor sites. This review discusses extracellular vesicle trafficking within the tumor microenvironment and pre-metastatic niche formation, focusing on the complex role that EVs play in orchestrating cancer-to-stromal cell communication in order to promote the metastatic dissemination of cancer cells.

Keywords:  biomarkers; cancer; cell-to-cell communication; extracellular vesicles; metastasis

DOI:  https://doi.org/10.3390/biomedicines11092534
Commun Biol. 2023 Sep 23. 6(1): 977

Oncometabolite D-2-hydroxyglutarate-dependent metabolic reprogramming induces skeletal muscle atrophy during cancer cachexia.

Xinting Zhu, Juan Hao, Hong Zhang, Mengyi Chi, Yaxian Wang, Jinlu Huang, Rong Xu, Zhao Xincai, Bo Xin, Xipeng Sun, Jianping Zhang, Shumin Zhou, Dongdong Cheng, Ting Yuan, Jun Ding, Shuier Zheng, Cheng Guo, Quanjun Yang.

Cancer cachexia is characterized by weight loss and skeletal muscle wasting. Based on the up-regulation of catabolism and down-regulation of anabolism, here we showed genetic mutation-mediated metabolic reprogramming in the progression of cancer cachexia by screening for metabolites and investigating their direct effect on muscle atrophy. Treatment with 93 μM D-2-hydroxyglutarate (D2HG) resulted in reduced myotube width and increased expression of E3 ubiquitin ligases. Isocitrate Dehydrogenase 1 (IDH1) mutant patients had higher D2HG than non-mutant patients. In the in vivo murine cancer cachexia model, mutant IDH1 in CT26 cancer cells accelerated cachexia progression and worsened overall survival. Transcriptomics and metabolomics revealed a distinct D2HG-induced metabolic imbalance. Treatment with the IDH1 inhibitor ivosidenib delayed the progression of cancer cachexia in murine GL261 glioma model and CT26 colorectal carcinoma models. These data demonstrate the contribution of IDH1 mutation mediated D2HG accumulation to the progression of cancer cachexia and highlight the individualized treatment of IDH1 mutation associated cancer cachexia.

DOI: https://doi.org/10.1038/s42003-023-05366-0
J Neuropathol Exp Neurol. 2023 Sep 22. pii: nlad072. [Epub ahead of print]

D-2-hydroxyglutarate regulates human brain vascular endothelial cell proliferation and barrier function.

Chuan Cao, Lingjun Zhang, Mia D Sorensen, Guido Reifenberger, Bjarne W Kristensen, Thomas M McIntyre, Feng Lin.

  Gain-of-function mutations in isocitrate dehydrogenase (IDH) genes result in excessive production of (D)-2-hydroxyglutarate (D-2HG) which intrinsically modifies tumor cell epigenetics and impacts surrounding noncancerous cells through nonepigenetic pathways. However, whether D-2HG has a paracrine effect on endothelial cells in the tumor microenvironment needs further clarification. We quantified microvessel density by immunohistochemistry using tissue sections from 60 high-grade astrocytic gliomas with or without IDH mutation. Microvessel density was found to be reduced in tumors carrying an IDH mutation. Ex vivo experiments showed that D-2HG inhibited endothelial cell migration, wound healing, and tube formation by suppressing cell proliferation but not viability, possibly through reduced activation of the mTOR/STAT3 pathway. Further, D-2HG reduced fluorescent dextran permeability and decreased paracellular T-cell transendothelial migration by augmenting expression of junctional proteins thereby collectively increasing endothelial barrier function. These results indicate that D-2HG may influence the tumor vascular microenvironment by reducing the intratumoral vasculature density and by inhibiting the transport of metabolites and extravasation of circulating cells into the astrocytoma microenvironment. These observations provide a rationale for combining IDH inhibition with antitumor immunological/angiogenic approaches and suggest a molecular basis for resistance to antiangiogenic drugs in patients whose tumors express a mutant IDH allele.

Keywords:  (D)-2-hydroxyglutarate (D-2HG); Astrocytic glioma; Brain vascular endothelial cell; Glioblastoma; Isocitrate dehydrogenase (IDH); Microvascular proliferation

DOI:  https://doi.org/10.1093/jnen/nlad072
Nat Cancer. 2023 Sep 25.

Endothelial Notch1 signaling in white adipose tissue promotes cancer cachexia.

Jacqueline Taylor, Leonie Uhl, Iris Moll, Sana Safatul Hasan, Lena Wiedmann, Jakob Morgenstern, Benedetto Daniele Giaimo, Tobias Friedrich, Elisenda Alsina-Sanchis, Francesca De Angelis Rigotti, Ronja Mülfarth, Sarah Kaltenbach, Darius Schenk, Felix Nickel, Thomas Fleming, David Sprinzak, Carolin Mogler, Thomas Korff, Adrian T Billeter, Beat P Müller-Stich, Mauricio Berriel Diaz, Tilman Borggrefe, Stephan Herzig, Maria Rohm, Juan Rodriguez-Vita, Andreas Fischer.

Cachexia is a major cause of morbidity and mortality in individuals with cancer and is characterized by weight loss due to adipose and muscle tissue wasting. Hallmarks of white adipose tissue (WAT) remodeling, which often precedes weight loss, are impaired lipid storage, inflammation and eventually fibrosis. Tissue wasting occurs in response to tumor-secreted factors. Considering that the continuous endothelium in WAT is the first line of contact with circulating factors, we postulated whether the endothelium itself may orchestrate tissue remodeling. Here, we show using human and mouse cancer models that during precachexia, tumors overactivate Notch1 signaling in distant WAT endothelium. Sustained endothelial Notch1 signaling induces a WAT wasting phenotype in male mice through excessive retinoic acid production. Pharmacological blockade of retinoic acid signaling was sufficient to inhibit WAT wasting in a mouse cancer cachexia model. This demonstrates that cancer manipulates the endothelium at distant sites to mediate WAT wasting by altering angiocrine signals.

DOI: https://doi.org/10.1038/s43018-023-00622-y
Front Immunol. 2023 ;14 1201632

The immune checkpoint adenosine 2A receptor is associated with aggressive clinical outcomes and reflects an immunosuppressive tumor microenvironment in human breast cancer.

Basma Zohair, Dounia Chraa, Ibtissam Rezouki, Hamza Benthami, Ibtissam Razzouki, Mohamed Elkarroumi, Daniel Olive, Mehdi Karkouri, Abdallah Badou.

   Background: The crosstalk between the immune system and cancer cells has aroused considerable interest over the past decades. To escape immune surveillance cancer cells evolve various strategies orchestrating tumor microenvironment. The discovery of the inhibitory immune checkpoints was a major breakthrough due to their crucial contribution to immune evasion. The A2AR receptor represents one of the most essential pathways within the TME. It is involved in several processes such as hypoxia, tumor progression, and chemoresistance. However, its clinical and immunological significance in human breast cancer remains elusive.
Methods: The mRNA expression and protein analysis were performed by RT-qPCR and immunohistochemistry. The log-rank (Mantel-Cox) test was used to estimate Kaplan-Meier analysis for overall survival. Using large-scale microarray data (METABRIC), digital cytometry was conducted to estimate cell abundance. Analysis was performed using RStudio software (7.8 + 2023.03.0) with EPIC, CIBERSORT, and ImmuneCellAI algorithms. Tumor purity, stromal and immune scores were calculated using the ESTIMATE computational method. Finally, analysis of gene set enrichment (GSEA) and the TISCH2 scRNA-seq database were carried out.
Results: Gene and protein analysis showed that A2AR was overexpressed in breast tumors and was significantly associated with high grade, elevated Ki-67, aggressive molecular and histological subtypes, as well as poor survival. On tumor infiltrating immune cells, A2AR was found to correlate positively with PD-1 and negatively with CTLA-4. On the other hand, our findings disclosed more profuse infiltration of protumoral cells such as M0 and M2 macrophages, Tregs, endothelial and exhausted CD8+ T cells within A2ARhigh tumors. According to the Single-Cell database, A2AR is expressed in malignant, stromal and immune cells. Moreover, it is related to tumor purity, stromal and immune scores. Our results also revealed that CD8+T cells from A2ARhigh patients exhibited an exhausted functional profile. Finally, GSEA analysis highlighted the association of A2AR with biological mechanisms involved in tumor escape and progression.
Conclusion: The present study is the first to elucidate the clinical and immunological relevance of A2AR in breast cancer patients. In light of these findings, A2AR could be deemed a promising therapeutic target to overcome immune evasion prevailing within the TME of breast cancer patients.

Keywords:  A2AR; CTLA-4; PD-1; breast cancer prognosis; immune checkpoint; immunosuppression; immunotherapy; tumor and immune microenvironment

DOI:  https://doi.org/10.3389/fimmu.2023.1201632