bims-stacyt 2022-07-31 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2022–07–31
nine papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

The Role of Metabolic Plasticity of Tumor-Associated Macrophages in Shaping the Tumor Microenvironment Immunity.
Immunotherapy: Reshape the Tumor Immune Microenvironment.
Cancer-Associated Fibroblasts in the Hypoxic Tumor Microenvironment.
Reprogramming of glutamine metabolism and its impact on immune response in the tumor microenvironment.
Host-Related Factors as Targetable Drivers of Immunotherapy Response in Non-Small Cell Lung Cancer Patients.
Hypoxic lung cancer cell-derived exosomal miR-21 mediates macrophage M2 polarization and promotes cancer cell proliferation through targeting IRF1.
Neuropeptide Y, a paracrine factor secreted by cancer cells, is an independent regulator of angiogenesis in colon cancer.
The Role of Adipokines in Pancreatic Cancer.
Palmitate Potentiates Lipopolysaccharide-Induced IL-6 Production via Coordinated Acetylation of H3K9/H3K18, p300, and RNA Polymerase II.

Cancers (Basel). 2022 Jul 08. pii: 3331. [Epub ahead of print]14(14):

The Role of Metabolic Plasticity of Tumor-Associated Macrophages in Shaping the Tumor Microenvironment Immunity.

Md Nabiul Hasan, Okan Capuk, Shivani M Patel, Dandan Sun.

  Cancer cells possess a high metabolic demand for their rapid proliferation, survival, and progression and thus create an acidic and hypoxic tumor microenvironment (TME) deprived of nutrients. Moreover, acidity within the TME is the central regulator of tumor immunity that influences the metabolism of the immune cells and orchestrates the local and systemic immunity, thus, the TME has a major impact on tumor progression and resistance to anti-cancer therapy. Specifically, myeloid cells, which include myeloid-derived suppressor cells (MDSC), dendritic cells, and tumor-associated macrophages (TAMs), often reprogram their energy metabolism, resulting in stimulating the angiogenesis and immunosuppression of tumors. This review summarizes the recent findings of glucose, amino acids, and fatty acid metabolism changes of the tumor-associated macrophages (TAMs), and how the altered metabolism shapes the TME and anti-tumor immunity. Multiple proton pumps/transporters are involved in maintaining the alkaline intracellular pH which is necessary for the glycolytic metabolism of the myeloid cells and acidic TME. We highlighted the roles of these proteins in modulating the cellular metabolism of TAMs and their potential as therapeutic targets for improving immune checkpoint therapy.

Keywords:  TAM; immune cell; immune response; immunotherapy; macrophage; metabolism; myeloid cells; proton pumps

DOI:  https://doi.org/10.3390/cancers14143331
Front Immunol. 2022 ;13 844142

Immunotherapy: Reshape the Tumor Immune Microenvironment.

Bingzhe Lv, Yunpeng Wang, Dongjiang Ma, Wei Cheng, Jie Liu, Tao Yong, Hao Chen, Chen Wang.

  Tumor immune microenvironment (TIME) include tumor cells, immune cells, cytokines, etc. The interactions between these components, which are divided into anti-tumor and pro-tumor, determine the trend of anti-tumor immunity. Although the immune system can eliminate tumor through the cancer-immune cycle, tumors appear to eventually evade from immune surveillance by shaping an immunosuppressive microenvironment. Immunotherapy reshapes the TIME and restores the tumor killing ability of anti-tumor immune cells. Herein, we review the function of immune cells within the TIME and discuss the contribution of current mainstream immunotherapeutic approaches to remolding the TIME. Changes in the immune microenvironment in different forms under the intervention of immunotherapy can shed light on better combination treatment strategies.

Keywords:  antibody; immune cell; immunotherapy; small molecule inhibitor; tumor immune microenvironment

DOI:  https://doi.org/10.3389/fimmu.2022.844142
Cancers (Basel). 2022 Jul 07. pii: 3321. [Epub ahead of print]14(14):

Cancer-Associated Fibroblasts in the Hypoxic Tumor Microenvironment.

Iljin Kim, Sanga Choi, Seongkyeong Yoo, Mingyu Lee, In-San Kim.

  Solid cancers are composed of malignant cells and their surrounding matrix components. Hypoxia plays a critical role in shaping the tumor microenvironment that contributes to cancer progression and treatment failure. Cancer-associated fibroblasts (CAFs) are one of the most prominent components of the tumor microenvironment. CAFs are highly sensitive to hypoxia and participates in the crosstalk with cancer cells. Hypoxic CAFs modulate several mechanisms that induce cancer malignancy, such as extracellular matrix (ECM) remodeling, immune evasion, metabolic reprogramming, angiogenesis, metastasis, and drug resistance. Key signaling molecules regulating CAFs in hypoxia include transforming growth factor (TGF-β) and hypoxia-inducible factors (HIFs). In this article, we summarize the mechanisms underlying the hypoxic regulation of CAFs and how hypoxic CAFs affect cancer development and progression. We also discuss the potential therapeutic strategies focused on targeting CAFs in the hypoxic tumor microenvironment.

Keywords:  cancer; cancer-associated fibroblast; hypoxia; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers14143321
Cell Commun Signal. 2022 Jul 27. 20(1): 114

Reprogramming of glutamine metabolism and its impact on immune response in the tumor microenvironment.

Guofeng Ma, Zhilei Zhang, Peng Li, Zhao Zhang, Manqin Zeng, Zhijuan Liang, Dan Li, Liping Wang, Yuanbin Chen, Ye Liang, Haitao Niu.

  Metabolic reprogramming and immune escape play a major role in tumorigenesis. Increasing number of studies have shown that reprogramming of glutamine metabolism is a putative determinant of the anti-tumor immune response in the tumor microenvironment (TME). Usually, the predatory uptake of glutamine by tumor cells in the TME results in the limited utilization of glutamine by immune cells and affects the anti-tumor immune response. The cell-programmed glutamine partitioning also affects the anti-tumor immune response. However, the reprogramming of glutamine metabolism in tumors modulates immune escape by regulating tumor PD-L1 expression. Likewise, the reprogramming of glutamine metabolism in the immune cells also affects their immune function. Additionally, different types of glutamine metabolism inhibitors extensively regulate the immune cells in the TME while suppressing tumor cell proliferation. Herein, we discuss how metabolic reprogramming of tumor and immune cells regulates anti-tumor immune responses, as well as functional changes in different immune cells in the context of targeting tumor glutamine metabolism, which can better explain the potential of targeting glutamine metabolism in combination with immunotherapy for cancer. Video abstract.

Keywords:  Glutamine metabolism; Glutamine metabolism inhibitors; Immune response; Immunity; Reprogramming; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12964-022-00909-0
Front Immunol. 2022 ;13 914890

Host-Related Factors as Targetable Drivers of Immunotherapy Response in Non-Small Cell Lung Cancer Patients.

Denisa Baci, Elona Cekani, Andrea Imperatori, Domenico Ribatti, Lorenzo Mortara.

  Despite some significant therapeutic breakthroughs leading to immunotherapy, a high percentage of patients with non-small cell lung cancer (NSCLC) do not respond to treatment on relapse, thus experiencing poor prognosis and survival. The unsatisfying results could be related to the features of the tumor immune microenvironment and the dynamic interactions between a tumor and immune infiltrate. Host-tumor interactions strongly influence the course of disease and response to therapies. Thus, targeting host-associated factors by restoring their physiologic functions altered by the presence of a tumor represents a new therapeutic approach to control tumor development and progression. In NSCLC, the immunogenic tumor balance is shifted negatively toward immunosuppression due to the release of inhibitory factors as well as the presence of immunosuppressive cells. Among these cells, there are myeloid-derived suppressor cells, regulatory T cells that can generate a tumor-permissive milieu by reprogramming the cells of the hosts such as tumor-associated macrophages, tumor-associated neutrophils, natural killer cells, dendritic cells, and mast cells that acquire tumor-supporting phenotypes and functions. This review highlights the current knowledge of the involvement of host-related factors, including innate and adaptive immunity in orchestrating the tumor cell fate and the primary resistance mechanisms to immunotherapy in NSCLC. Finally, we discuss combinational therapeutic strategies targeting different aspects of the tumor immune microenvironment (TIME) to prime the host response. Further research dissecting the characteristics and dynamic interactions within the interface host-tumor is necessary to improve a patient fitness immune response and provide answers regarding the immunotherapy efficacy, with the aim to develop more successful treatments for NSCLC.

Keywords:  anti-angiogenic therapies; immune checkpoint inhibitors; immunotherapy; non-small cell lung cancer; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2022.914890
World J Surg Oncol. 2022 Jul 27. 20(1): 241

Hypoxic lung cancer cell-derived exosomal miR-21 mediates macrophage M2 polarization and promotes cancer cell proliferation through targeting IRF1.

Jianxu Jin, Guiping Yu.

   BACKGROUND: Hypoxia is the hallmark of the tumor microenvironment (TME) and plays a critical role during the progress of tumor development. A variety of microRNAs (miRNAs) transmitted by tumor-derived exosomes were involved in intercellular communication. We aimed to elucidate the precise mechanism by which tumor cell-derived exosomes promote lung cancer development by affecting macrophage polarization under hypoxic conditions.
METHODS: CD163 signal in tumor tissue from lung cancer patients was detected by immunohistochemical (IHC). The M2 polarization-related markers were assessed by flow cytometry and western blot. Exosomes were isolated from normoxic and hypoxic lung cancer cell culture and characterized by transmission electron microscope (TEM), dynamic light scattering (DLS), and western blot. RNA sequencing was performed to show the abnormally expressed miRNAs in exosomes from normoxic and hypoxic lung cancer cell culture. In addition, CCK-8 and clone formation assays were used to assess cell proliferation. Dual luciferase reporter assay was used to evaluate the relationship between miR-21 and IRF1. For in vivo experiment, the male nude mice were injected with H1299 cells with exosomes and miR-21 mimic treatment.
RESULTS: Firstly, we found a strong CD163 signal in tumor tissue from lung cancer patients by IHC. Subsequently, we co-cultured lung cancer cell line H1299 with M0 macrophage THP-1 and found that H1299 in a hypoxic environment promoted THP-1 M2 polarization. PKH67 fluorescence staining experiments confirmed that exosomes of H1299 origin were able to enter THP-1 and induced M2 polarization. RNA sequencing of exosomes showed that miR-21 level was significantly higher in the hypoxic culture group compared to the normoxic group. Subsequent cellular assays showed that miR-21 inhibited the expression of IRF1 by targeting it. In addition, the overexpression of IRF1 reversed the role of miR-21 on macrophage M2 polarization. Finally, we have confirmed through animal experiments that either hypoxic environment or high miR-21 level promoted tumor progression.
CONCLUSIONS: High miR-21 level in hypoxic environments promoted macrophage M2 polarization and induced lung cancer progression through targeting IRF1.

Keywords:  Exosome; Hypoxia; IRF1; Lung cancer; Macrophage M2 polarization; miR-21

DOI:  https://doi.org/10.1186/s12957-022-02706-y
Br J Cancer. 2022 Jul 28.

Neuropeptide Y, a paracrine factor secreted by cancer cells, is an independent regulator of angiogenesis in colon cancer.

Debanjan Chakroborty, Sandeep Goswami, Hao Fan, Wendy L Frankel, Sujit Basu, Chandrani Sarkar.

BACKGROUND: Resistance to anti-angiogenic therapies targeting vascular endothelial growth factor-A (VEGF-A) stems from VEGF-A independent angiogenesis mediated by other proangiogenic factors. Therefore identifying these factors in colon adenocarcinoma (CA) will reveal new therapeutic targets.
METHODS: Neuropeptide Y (NPY) and Y2 receptor (Y2R) expressions in CA were studied by immunohistochemical analysis. Orthotopic HT29 with intact VEGF-A gene and VEGF-A knockdown (by CRISPR/Cas9 gene-editing technique) HT29 colon cancer-bearing mice were treated with specific Y2R antagonists, and the effects on angiogenesis and tumour growth were studied. The direct effect of NPY on angiogenesis and the underlying molecular mechanism was elucidated by the modulation of Y2R receptors expressed on colonic endothelial cells (CEC).
RESULTS: The results demonstrated that NPY and Y2R are overexpressed in human CA, orthotopic HT29, and most interestingly in VEGF-A-depleted orthotopic HT29 tumours. Treatment with Y2R antagonists inhibited angiogenesis and thereby HT29 tumour growth. Blocking /silencing Y2R abrogated NPY-induced angiogenic potential of CEC. Mechanistically, NPY regulated the activation of the ERK/MAPK signalling pathway in CEC.
CONCLUSIONS: NPY derived from cancer cells independently regulates angiogenesis in CA by acting through Y2R present on CEC. Targeting NPY/Y2R thus emerges as a novel potential therapeutic strategy in CA.

DOI: https://doi.org/10.1038/s41416-022-01916-1
Front Oncol. 2022 ;12 926230

The Role of Adipokines in Pancreatic Cancer.

Qi Wang, Huizhi Wang, Yuntao Ding, Mengtian Wan, Min Xu.

  In modern society, inappropriate diets and other lifestyle habits have made obesity an increasingly prominent health problem. Pancreatic cancer (PC), a kind of highly aggressive malignant tumor, is known as a silent assassin and is the seventh leading cause of cancer death worldwide, pushing modern medicine beyond help. Adipokines are coming into notice because of the role of the intermediate regulatory junctions between obesity and malignancy. This review summarizes the current evidence for the relationship between highly concerning adipokines and the pathogenesis of PC. Not only are classical adipokines such as leptin and adiponectin included, but they also cover the recognized chemerin and osteopontin. Through a summary of the biological functions of these adipokines as well as their receptors, it was discovered that in addition to their basic function of stimulating the biological activity of tumors, more studies confirm that adipokines intervene in the progression of PC from the viewpoint of tumor metabolism, immune escape, and reprogramming of the tumor microenvironment (TME). Besides endocrine function, the impact of white adipose tissue (WAT)-induced chronic inflammation on PC is briefly discussed. Furthermore, the potential implication of the acknowledged endocrine behavior of brown adipose tissue (BAT) in relation to carcinogenesis is also explored. No matter the broad spectrum of obesity and the poor prognosis of PC, supplemental research is needed to unravel the detailed network of adipokines associated with PC. Exploiting profound therapeutic strategies that target adipokines and their receptors may go some way to improving the current worrying prognosis of PC patients.

Keywords:  adipokines; adiponectin; chemerin; leptin; obesity; pancreatic cancer; white adipose tissue

DOI:  https://doi.org/10.3389/fonc.2022.926230
J Immunol. 2022 Jul 27. pii: ji2100928. [Epub ahead of print]

Palmitate Potentiates Lipopolysaccharide-Induced IL-6 Production via Coordinated Acetylation of H3K9/H3K18, p300, and RNA Polymerase II.

Shihab Kochumon, Texy Jacob, Merin Koshy, Fatema Al-Rashed, Sardar Sindhu, Ebaa Al-Ozairi, Fahd Al-Mulla, Evan D Rosen, Rasheed Ahmad.

IL-6 is elevated in obese individuals and participates in the metabolic dysfunction associated with that condition. However, the mechanisms that promote IL-6 expression in obesity are incompletely understood. Because elevated levels of palmitate and LPS have been reported in obesity, we investigated whether these agents interact to potentiate IL-6 production. In this study, we report that LPS induces higher levels of IL-6 in human monocytes in the presence of palmitate. Notably, the priming effect of palmitate is associated with enhanced p300 binding and transcription factor recruitment to Il6 promoter regions. Gene silencing of p300 blocks this action of palmitate. RNA polymerase II recruitment was also enhanced at the Il6 promoter in palmitate/LPS-exposed cells. Acetylation levels of H3K9 and H3K18 were increased in monocytes treated with palmitate. Moreover, LPS stimulation of palmitate-treated cells led to increased levels of the transcriptionally permissive acetylation marks H3K9/H3K18 in the Il6 promoter compared with LPS alone. The effect of palmitate on LPS-induced IL-6 production was suppressed by the inhibition of histone acetyltransferases. Conversely, histone deacetylase inhibitors trichostatin A or sodium butyrate can substitute for palmitate in IL-6 production. Esterification of palmitate with CoA was involved, whereas β-oxidation and ceramide biosynthesis were not required, for the induction of IL-6 and H3K9/H3K18 acetylation. Monocytes of obese individuals showed significantly higher H3K9/H3K18 acetylation and Il6 expression. Overall, our findings support a model in which increased levels of palmitate in obesity create a setting for LPS to potentiate IL-6 production via chromatin remodeling, enabling palmitate to contribute to metabolic inflammation.

DOI: https://doi.org/10.4049/jimmunol.2100928