bims-stacyt 2020-03-15 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2020–03–15
nine papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Altered nutrient status reprograms host inflammation and metabolic health via gut microbiota.
Lymphatic endothelial cells promote T lymphocyte migration into lymph nodes under hyperlipidemic conditions.
The immunological Warburg effect: Can a metabolic-tumor-stroma score (MeTS) guide cancer immunotherapy?
Metabolic adaptation orchestrates tissue context-dependent behavior in regulatory T cells.
Stromal-Mdm2 promotes lung cancer cell invasion through tumor-host feedback signaling.
Ionizing radiation regulates vascular endothelial growth factor-A transcription in cultured human vascular endothelial cells via the PERK/eIF2α/ATF4 pathway.
Gemcitabine Recruits M2-Type Tumor-Associated Macrophages into the Stroma of Pancreatic Cancer.
Immune Response Dysfunction in Chronic Lymphocytic Leukemia: Dissecting Molecular Mechanisms and Microenvironmental Conditions.
Insulin resistance and body composition in cancer patients.

J Nutr Biochem. 2020 Feb 22. pii: S0955-2863(19)31268-9. [Epub ahead of print]80 108360

Altered nutrient status reprograms host inflammation and metabolic health via gut microbiota.

Rachel M Golonka, Xia Xiao, Ahmed A Abokor, Bina Joe, Matam Vijay-Kumar.

  The metabolism of macro- and micronutrients is a complex and highly regulated biological process. An imbalance in the metabolites and their signaling networks can lead to nonresolving inflammation and consequently to the development of chronic inflammatory-associated diseases. Therefore, identifying the accumulated metabolites and altered pathways during inflammatory disorders would not only serve as "real-time" markers but also help in the development of nutritional therapeutics. In this review, we explore recent research that has delved into elucidating the effects of carbohydrate/calorie restriction, protein malnutrition, lipid emulsions and micronutrient deficiencies on metabolic health and inflammation. Moreover, we describe the integrated stress response in terms of amino acid starvation and lipemia and how this modulates new age diseases such as inflammatory bowel disease and atherosclerosis. Lastly, we explain the latest research on metaflammation and inflammaging. This review focuses on multiple signaling pathways, including, but not limited to, the FGF21-β-hydroxybutryate-NLRP3 axis, the GCN2-eIF2α-ATF4 pathway, the von Hippel-Lindau/hypoxia-inducible transcription factor pathway and the TMAO-PERK-FoxO1 axis. Additionally, throughout the review, we explain how the gut microbiota responds to altered nutrient status and also how antimicrobial peptides generated from nutrient-based signaling pathways can modulate the gut microbiota. Collectively, it must be emphasized that metabolic starvation and inflammation are strongly regulated by both environmental (i.e., nutrition, gut microbiome) and nonenvironmental (i.e., genetics) factors, which can influence the susceptibility to inflammatory disorders.

Keywords:  Inflammaging; Integrated stress response; Ketogenic diet; Lipid emulsions; Metaflammation; Micronutrient deficiency

DOI:  https://doi.org/10.1016/j.jnutbio.2020.108360
Biochem Biophys Res Commun. 2020 Mar 05. pii: S0006-291X(20)30445-9. [Epub ahead of print]

Lymphatic endothelial cells promote T lymphocyte migration into lymph nodes under hyperlipidemic conditions.

Minhwa Park, Kyung-Ah Cho, Yu-Hee Kim, Kyung Ho Lee, So-Youn Woo.

  Lymphatic vessels serve as conduits through which immune cells traffic. Because lymphatic vessels are also involved in lipid transport, their function is vulnerable to abnormal metabolic conditions such as obesity and hyperlipidemia. Exactly how these conditions impact immune cell trafficking, however, is not well understood. Here, we found higher numbers of LYVE-1-positive lymphatic endothelial cells and CD3-positive T cells in the lymph nodes of mice fed high-cholesterol or high-fat diets compared with those of mice fed a normal chow diet. To confirm the effect of fat content on immune cell trafficking, the lymphatic endothelial SVEC4-10 cell line was treated with palmitic acid at a 100 μM concentration. After 24 h, palmitic acid-treated cells exhibited increased expression of podoplanin and vascular growth-associated molecules (VEGFC, VEGFD, VEGFR3, and NRP2) and enhanced tube formation. Microarray analysis showed an increase in pro-inflammatory cytokine and chemokine transcription after palmitic acid treatment. Finally, transwell migration assay confirmed that T cell line moved toward medium previously cultured with palmitic acid-treated SVEC4-10 cells. Together, our results suggest that hyperlipidemia drives lymphatic vessel remodeling and T cell migration toward lymphatic endothelial cells.

Keywords:  Chemokine; Hyperlipidemia; Lymphatic endothelial cells; T cell migration

DOI:  https://doi.org/10.1016/j.bbrc.2020.02.154
Immunol Rev. 2020 Mar 10.

The immunological Warburg effect: Can a metabolic-tumor-stroma score (MeTS) guide cancer immunotherapy?

Peter J Siska, Katrin Singer, Katja Evert, Kathrin Renner, Marina Kreutz.

  The "glycolytic switch" also known as the "Warburg effect" is a key feature of tumor cells and leads to the accumulation of lactate and protons in the tumor environment. Intriguingly, non-malignant lymphocytes or stromal cells such as tumor-associated macrophages and cancer-associated fibroblasts contribute to the lactate accumulation in the tumor environment, a phenomenon described as the "Reverse Warburg effect." Localized lactic acidosis has a strong immunosuppressive effect and mediates an immune escape of tumors. However, some tumors do not display the Warburg phenotype and either rely on respiration or appear as a mosaic of cells with different metabolic properties. Based on these findings and on the knowledge that T cell infiltration is predictive for patient outcome, we suggest a metabolic-tumor-stroma score to determine the likelihood of a successful anti-tumor immune response: (a) a respiring tumor with high T cell infiltration ("hot"); (b) a reverse Warburg type with respiring tumor cells but glycolytic stromal cells; (c) a mixed type with glycolytic and respiring compartments; and (d) a glycolytic (Warburg) tumor with low T cell infiltration ("cold"). Here, we provide evidence that these types can be independent of the organ of origin, prognostically relevant and might help select the appropriate immunotherapy approach.

Keywords:  GLUT; T cell; Warburg; acidification; immunotherapies; lactate

DOI:  https://doi.org/10.1111/imr.12846
Immunol Rev. 2020 Mar 08.

Metabolic adaptation orchestrates tissue context-dependent behavior in regulatory T cells.

Haiping Wang, Chun-Hao Lu, Ping-Chih Ho.

  The diverse distribution and functions of regulatory T cells (Tregs) ensure tissue and immune homeostasis; however, it remains unclear which factors can guide distribution, local differentiation, and tissue context-specific behavior in Tregs. Although the emerging concept that Tregs could re-adjust their transcriptome based on their habitations is supported by recent findings, the underlying mechanisms that reprogram transcriptome in Tregs are unknown. In the past decade, metabolic machineries have been revealed as a new regulatory circuit, known as immunometabolic regulation, to orchestrate activation, differentiation, and functions in a variety of immune cells, including Tregs. Given that systemic and local alterations of nutrient availability and metabolite profile associate with perturbation of Treg abundance and functions, it highlights that immunometabolic regulation may be one of the mechanisms that orchestrate tissue context-specific regulation in Tregs. The understanding on how metabolic program instructs Tregs in peripheral tissues not only represents a critical opportunity to delineate a new avenue in Treg biology but also provides a unique window to harness Treg-targeting approaches for treating cancer and autoimmunity with minimizing side effects. This review will highlight the metabolic features on guiding Treg formation and function in a disease-oriented perspective and aim to pave the foundation for future studies.

Keywords:  autoimmunity; cancer; immunometabolism; inflammation; metabolic adaptation; regulatory T cell

DOI:  https://doi.org/10.1111/imr.12844
Mol Cancer Res. 2020 Mar 13. pii: molcanres.0395.2019. [Epub ahead of print]

Stromal-Mdm2 promotes lung cancer cell invasion through tumor-host feedback signaling.

Iris Kamer, Inbal Daniel-Meshulam, Oranit Zadok, Elizabeta Bab-Dinitz, Gili Perry, Rotem Feniger-Barish, Marina Perelman, Iris Barshack, Alon Ben-Nun, Amir Onn, Jair Bar.

Tumor-host interactions play a major role in malignancies' initiation and progression. We have reported in the past that tumor cells attenuate genotoxic stress-induced p53 activation in neighboring stromal cells. Herein we aim to further elucidate cancer cells' impact on signaling within lung cancer stroma. Primary cancer-associated fibroblasts were grown from resected human lung tumors. Lung cancer lines as well as fresh cultures of resected human lung cancers were used to produce conditioned medium (CM) or co-cultured with stromal cells. Invasiveness of cancer cells was evaluated by transwell assays, and in vivo tumor growth was tested in Athymic nude mice. We found CM of a large variety of cancer cell lines as well as ex-vivo cultured lung cancers to rapidly induce protein levels of stromal-MDM2. CM of non-trasnformed cells had no such effect. Mdm2 induction occurred through enhanced translation, was mTORC1-dependent, and correlated with activation of AKT and p70 S6 Kinase. AKT or MDM2 knockdown in fibroblasts reduced the invasion of neighboring cancer cells, independently of stromal-p53. MDM2 overexpression in fibroblasts enhanced cancer cells' invasion and growth of inoculated tumors in mice. Our results indicate that stromal-MDM2 participates in a p53-independent cancer-host feedback mechanism. Soluble cancer-originated signals induce enhanced translation of stromal-MDM2 through AKT/mTORC1 signaling, which in turn enhances the neighboring cancer cells' invasion ability. The role of these tumor-host interactions needs to be further explored. Implications: We uncovered a novel tumor-stroma signaling loop, which is a potentially new therapeutic target in lung cancer and possibly in additional types of cancer.

DOI: https://doi.org/10.1158/1541-7786.MCR-19-0395
Int J Radiat Oncol Biol Phys. 2020 Mar 10. pii: S0360-3016(20)30894-4. [Epub ahead of print]

Ionizing radiation regulates vascular endothelial growth factor-A transcription in cultured human vascular endothelial cells via the PERK/eIF2α/ATF4 pathway.

Eun Ju Kim, Hyounji Lee, Yoon-Jin Lee, Jong Kyung Sonn, Young-Bin Lim.

PURPOSE: The delivery of high-dose hypofractionated radiation to a tumor induces vascular damage, but little is known about the responses of vascular endothelial cells to high-dose radiation. We examined whether high-dose irradiation alters VEGF signaling, which is a critical regulator of the functional integrity and viability of vascular endothelial cells.
METHODS AND MATERIALS: Human umbilical vein endothelial cells (HUVECs) and human coronary artery endothelial cells (HCAECs) were treated with 5, 10, 20, or 30 Gy ionizing radiation (IR). Expression values of VEGFA mRNA were analyzed by real-time PCR at 4 hours after irradiation and normalized to the average value of mock-irradiated HUVEC or HCAEC controls.
RESULTS: Irradiation with doses higher than 10 Gy causes an acute increase in VEGFA transcript levels, which was accompanied by activation of the PERK/eIF2α/ATF4 pathway in the human vascular endothelial cells. ATF4 knockdown with siRNA completely prevented the IR-induced up-regulation of VEGFA transcripts, and chromatin immunoprecipitation assays demonstrated that ATF4 binding to the VEGFA locus was enriched in response to IR. Post-irradiation treatment with a intracellualr inhibitor of VEGF signaling significantly enhances high-dose IR-induced apoptosis in human vascular endothelial cells.
CONCLUSION: Human vascular endothelial cells activate PERK/eIF2α/ATF4/VEGF signaling in response to high-dose IR to mitigate the apoptotic response. Thus, for cancer treatment, intracellular inhibitors of VEGF signaling could be employed to enhance stereotactic body radiation therapy-induced damage to the tumor vascular, which would augment tumor cell death.

DOI: https://doi.org/10.1016/j.ijrobp.2020.03.003
Transl Oncol. 2020 Mar 03. pii: S1936-5233(19)30540-6. [Epub ahead of print]13(3): 100743

Gemcitabine Recruits M2-Type Tumor-Associated Macrophages into the Stroma of Pancreatic Cancer.

Ashenafi Bulle, Jeroen Dekervel, Lise Deschuttere, David Nittner, Louis Libbrecht, Rekin's Janky, Stéphane Plaisance, Baki Topal, An Coosemans, Diether Lambrechts, Eric Van Cutsem, Chris Verslype, Jos van Pelt.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a very lethal disease that can develop therapy resistance over time. The dense stroma in PDAC plays a critical role in tumor progression and resistance. How this stroma interacts with the tumor cells and how this is influenced by chemotherapy remain poorly understood.
METHODS: The backbone of this study is the parallel transcriptome analysis of human tumor and mouse stroma in two molecular and clinical representative patient-derived tumor xenografts models. Mice (8 animals per group) were treated for 4 weeks with gemcitabine or control. We studied tumor growth, RNA expression in the stroma, tumor-associated macrophages (TAMs) with immunofluorescence, and cytokines in the serum.
RESULTS: A method for parallel transcriptome analysis was optimized. We found that the tumor (differentiation, gene expression) determines the infiltration of macrophages into the stroma. In aggressive PDAC (epithelial-to-mesenchymal transition high), we find more M2 polarized TAMs and the activation of cytokines and growth factors (TNFα, TGFβ1, and IL6). There are increased stromal glycolysis, reduced fatty acid oxidation, and reduced mitochondrial oxidation (tricarboxylic acid cycle and oxidative phosphorylation). Treatment with gemcitabine results in a shift of innate immune cells, especially additional infiltration of protumoral M2 TAMs (P < .001) and metabolic reprogramming.
CONCLUSIONS: Gemcitabine treatment of PDAC xenografts stimulates a protumoral macrophage phenotype, and this, in combination with a shift of the tumor cells to a mesenchymal phenotype that we reported previously, contributes to tumor progression and therapeutic resistance. Targeting M2-polarized TAMs may benefit PDAC patients at risk to become refractory to current anticancer regimens.

DOI: https://doi.org/10.1016/j.tranon.2020.01.004
Int J Mol Sci. 2020 Mar 06. pii: E1825. [Epub ahead of print]21(5):

Immune Response Dysfunction in Chronic Lymphocytic Leukemia: Dissecting Molecular Mechanisms and Microenvironmental Conditions.

Francesca Arruga, Benjamin Baffour Gyau, Andrea Iannello, Nicoletta Vitale, Tiziana Vaisitti, Silvia Deaglio.

  Representing the major cause of morbidity and mortality for chronic lymphocytic leukemia (CLL) patients, immunosuppression is a common feature of the disease. Effectors of the innate and the adaptive immune response show marked dysfunction and skewing towards the generation of a tolerant environment that favors disease expansion. Major deregulations are found in the T lymphocyte compartment, with inhibition of CD8+ cytotoxic and CD4+ activated effector T cells, replaced by exhausted and more tolerogenic subsets. Likewise, differentiation of monocytes towards a suppressive M2-like phenotype is induced at the expense of pro-inflammatory sub-populations. Thanks to their B-regulatory phenotype, leukemic cells play a central role in driving immunosuppression, progressively inhibiting immune responses. A number of signaling cascades triggered by soluble mediators and cell-cell contacts contribute to immunomodulation in CLL, fostered also by local environmental conditions, such as hypoxia and derived metabolic acidosis. Specifically, molecular pathways modulating T-cell activity in CLL, spanning from the best known cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death 1 (PD-1) to the emerging T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT)/CD155 axes, are attracting increasing research interest and therapeutic relevance also in the CLL field. On the other hand, in the microenvironment, the B cell receptor (BCR), which is undoubtedly the master regulator of leukemic cell behavior, plays an important role in orchestrating immune responses, as well. Lastly, local conditions of hypoxia, typical of the lymphoid niche, have major effects both on CLL cells and on non-leukemic immune cells, partly mediated through adenosine signaling, for which novel specific inhibitors are currently under development. In summary, this review will provide an overview of the molecular and microenvironmental mechanisms that modify innate and adaptive immune responses of CLL patients, focusing attention on those that may have therapeutic implications.

Keywords:  hypoxia; immune checkpoints; immunosuppression; microenvironment; tolerance

DOI:  https://doi.org/10.3390/ijms21051825
Ann Oncol. 2018 Feb;pii: S0923-7534(19)31680-1. [Epub ahead of print]29 Suppl 2 ii18-ii26

Insulin resistance and body composition in cancer patients.

R Dev, E Bruera, S Dalal.

  Cancer cachexia, weight loss with altered body composition, is a multifactorial syndrome propagated by symptoms that impair caloric intake, tumor byproducts, chronic inflammation, altered metabolism, and hormonal abnormalities. Cachexia is associated with reduced performance status, decreased tolerance to chemotherapy, and increased mortality in cancer patients. Insulin resistance as a consequence of tumor byproducts, chronic inflammation, and endocrine dysfunction has been associated with weight loss in cancer patients. Insulin resistance in cancer patients is characterized by increased hepatic glucose production and gluconeogenesis, and unlike type 2 diabetes, normal fasting glucose with high, normal or low levels of insulin. Cancer cachexia results in altered body composition with the loss of lean muscle mass with or without the loss of adipose tissue. Alteration in visceral adiposity, accumulation of intramuscular adipose tissue, and secretion of adipocytokines from adipose cells may play a role in promoting the metabolic derangements associated with cachexia including a proinflammatory environment and insulin resistance. Increased production of ghrelin, testosterone deficiency, and low vitamin D levels may also contribute to altered metabolism of glucose. Cancer cachexia cannot be easily reversed by standard nutritional interventions and identifying and treating cachexia at the earliest stage of development is advocated. Experts advocate for multimodal therapy to address symptoms that impact caloric intake, reduce chronic inflammation, and treat metabolic and endocrine derangements, which propagate the loss of weight. Treatment of insulin resistance may be a critical component of multimodal therapy for cancer cachexia and more research is needed.

Keywords:  body composition; cancer cachexia; insulin resistance

DOI:  https://doi.org/10.1093/annonc/mdx815