Inflammation and tumor progression: signaling pathways and targeted intervention

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: July 12, 2021

Abstract Cancer development and its response to therapy are regulated by inflammation, which either promotes or suppresses tumor progression, potentially displaying opposing effects on therapeutic outcomes. Chronic inflammation facilitates progression treatment resistance, whereas induction of acute inflammatory reactions often stimulates the maturation dendritic cells (DCs) antigen presentation, leading anti-tumor immune responses. In addition, multiple signaling pathways, such as nuclear factor kappa B (NF-kB), Janus kinase/signal transducers activators transcription (JAK-STAT), toll-like receptor (TLR) cGAS/STING, mitogen-activated protein kinase (MAPK); factors, including cytokines (e.g., interleukin (IL), interferon (IFN), necrosis (TNF)-α), chemokines C-C motif chemokine ligands (CCLs) C-X-C (CXCLs)), growth factors vascular endothelial (VEGF), transforming (TGF)-β), inflammasome; well metabolites prostaglandins, leukotrienes, thromboxane, specialized proresolving mediators (SPM), have been identified pivotal regulators initiation resolution inflammation. Nowadays, local irradiation, recombinant cytokines, neutralizing antibodies, small-molecule inhibitors, DC vaccines, oncolytic viruses, TLR agonists, SPM developed specifically modulate in cancer therapy, with some these already undergoing clinical trials. Herein, we discuss crosstalk between processes. We also highlight potential targets for harnessing cancer.

Language: Английский

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Macrophages in immunoregulation and therapeutics

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: May 22, 2023

Abstract Macrophages exist in various tissues, several body cavities, and around mucosal surfaces are a vital part of the innate immune system for host defense against many pathogens cancers. possess binary M1/M2 macrophage polarization settings, which perform central role an array tasks via intrinsic signal cascades and, therefore, must be precisely regulated. Many crucial questions about signaling modulation yet to uncovered. In addition, clinical importance tumor-associated macrophages is becoming more widely recognized as significant progress has been made understanding their biology. Moreover, they integral tumor microenvironment, playing regulation wide variety processes including angiogenesis, extracellular matrix transformation, cancer cell proliferation, metastasis, immunosuppression, resistance chemotherapeutic checkpoint blockade immunotherapies. Herein, we discuss signaling, mechanical stresses modulation, metabolic pathways, mitochondrial transcriptional, epigenetic regulation. Furthermore, have broadly extended traps essential roles autophagy aging regulating functions. discussed recent advances macrophages-mediated autoimmune diseases tumorigenesis. Lastly, targeted therapy portray prospective targets therapeutic strategies health diseases.

Language: Английский

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Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Oct. 2, 2023

The mammalian target of rapamycin (mTOR) is a protein kinase that controls cellular metabolism, catabolism, immune responses, autophagy, survival, proliferation, and migration, to maintain homeostasis. mTOR signaling cascade consists two distinct multi-subunit complexes named complex 1/2 (mTORC1/2). catalyzes the phosphorylation several critical proteins like AKT, C, insulin growth factor receptor (IGF-1R), 4E binding 1 (4E-BP1), ribosomal S6 (S6K), transcription EB (TFEB), sterol-responsive element-binding (SREBPs), Lipin-1, Unc-51-like autophagy-activating kinases. plays central role in regulating translation, lipid synthesis, nucleotide biogenesis lysosomes, nutrient sensing, signaling. emerging pieces evidence have revealed constitutive activation pathway due mutations/amplification/deletion either its (mTORC1 mTORC2) or upstream targets responsible for aging, neurological diseases, human malignancies. Here, we provide detailed structure mTOR, complexes, comprehensive regulators, as well downstream effectors cascades biomolecules, autophagy. Additionally, summarize potential long noncoding RNAs (lncRNAs) an important modulator Importantly, highlighted disorders, cancers, cancer stem cells, drug resistance. discuss developments therapeutic targeting with improved anticancer efficacy benefit patients clinics.

Language: Английский

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Immunosuppressive cells in cancer: mechanisms and potential therapeutic targets

Journal of Hematology & Oncology, Journal Year: 2022, Volume and Issue: 15(1)

Published: May 18, 2022

Abstract Immunotherapies like the adoptive transfer of gene-engineered T cells and immune checkpoint inhibitors are novel therapeutic modalities for advanced cancers. However, some patients refractory or resistant to these therapies, mechanisms underlying tumor resistance have not been fully elucidated. Immunosuppressive such as myeloid-derived suppressive cells, tumor-associated macrophages, neutrophils, regulatory (Tregs), dendritic critical factors correlated with resistance. In addition, cytokines secreted by immunosuppressive also mediate progression escape Thus, targeting related signals is promising therapy improve efficacy immunotherapies reverse even certain success in preclinical studies specific types cancer, large perspectives unknown therapies undesirable outcomes clinical patients. this review, we comprehensively summarized phenotype, function, potential targets microenvironment.

Language: Английский

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Tumor‐associated macrophages in liver cancer: From mechanisms to therapy

Cancer Communications, Journal Year: 2022, Volume and Issue: 42(11), P. 1112 - 1140

Published: Sept. 7, 2022

Abstract Multidimensional analyses have demonstrated the presence of a unique tumor microenvironment (TME) in liver cancer. Tumor‐associated macrophages (TAMs) are among most abundant immune cells infiltrating TME and present at all stages cancer progression, targeting TAMs has become one favored immunotherapy strategies. In addition, distinct origins. At early stage cancer, can provide niche for maintenance stem cells. contrast, (CSCs) or poorly differentiated key factors modulating macrophage activation. review, we first propose origin connection between precursor Macrophages undergo dynamic phenotypic transition during carcinogenesis. this course such transition, it is critical to determine appropriate timing therapy block specific markers suppress pro‐tumoral TAMs. The review provides more detailed discussion trends surface than previous reviews. Complex crosstalk occurs play indispensable roles angiogenesis, autophagy due their heterogeneity robust plasticity. interact with other by directing cell‐to‐cell contact secreting various effector molecules. Similarly, combined drive recruitment polarization. Despite latest achievements advancements treatment strategies following studies, comprehensive discussions on communication currently lacking. discussed interactions (from cell maturation), therapeutic (including chimeric antigen receptor macrophages), clinical trials hepatocellular carcinoma (HCC) intrahepatic cholangiocarcinoma (iCCA) rationale further investigation as potential target treating patients

Language: Английский

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The Impact of the Tumor Microenvironment on Macrophage Polarization in Cancer Metastatic Progression

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(12), P. 6560 - 6560

Published: June 18, 2021

Rather than primary solid tumors, metastasis is one of the hallmarks most cancer deaths. Metastasis a multistage event in which cells escape from tumor survive circulation and disseminate to distant sites. According Stephen Paget's "Seed Soil" hypothesis, metastatic capacity determined not only by internal oncogenic driving force but also external environment cells. Throughout body, macrophages are required for maintaining tissue homeostasis, even milieu. To fulfill these multiple functions, polarized inflammation status (M1-like) anti-inflammation (M2-like) maintain balance between regeneration. However, cell-enforced tumor-associated (TAMs) (a high M2/M1 ratio status) associated with poor prognosis such as ovarian cancer. In fact, clinical evidence has verified that TAMs, representing up 50% mass, exert both protumor immunosuppressive effects promoting through secretion interleukin 10 (IL10), transforming growth factor β (TGFβ), VEGF, expression PD-1 consumption arginine inhibit T cell anti-tumor function. underlying molecular mechanisms microenvironment favors reprogramming TAMs establish premetastatic niche remain controversial. this review, we examine latest investigations during development, microenvironmental factors involved macrophage polarization, TAM-mediated metastasis. We hope dissect critical roles metastasis, potential applications TAM-targeted therapeutic strategies treatment discussed.

Language: Английский

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Reversing T-cell Exhaustion in Cancer: Lessons Learned from PD-1/PD-L1 Immune Checkpoint Blockade

Cancer Immunology Research, Journal Year: 2021, Volume and Issue: 10(2), P. 146 - 153

Published: Dec. 22, 2021

Anti-PD-1/PD-L1 immune checkpoint blockade (ICB) therapy has revolutionized the treatment of many types cancer over past decade. The initial therapeutic hypothesis underlying mechanism anti-PD-1/PD-L1 ICB was built around premise that it acts locally in tumor, reversing exhaustion PD-1hiCD8+ T cells by "releasing brakes." However, recent studies have provided unprecedented insight into complexity within CD8+ T-cell pool tumor microenvironment (TME). Single-cell RNA sequencing and epigenetic profiling identified novel cell surface markers, revealing heterogeneity states classified as unique. Moreover, these highlighted following ICB, outside TME possess a differential capacity to respond, mobilize TME, seed an effective antitumor response. In aggregate, developments led reevaluation our understanding both mechanisms sites action therapy. Here, we discuss evidence for reversibility after its implication further development immunotherapy.

Language: Английский

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Major pathways involved in macrophage polarization in cancer

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: Oct. 17, 2022

Macrophages play an important role in tissue homeostasis, remodeling, immune response, and progression of cancer. Consequently, macrophages exhibit significant plasticity change their transcriptional profile function response to environmental, tissue, inflammatory stimuli resulting pro- anti-tumor effects. Furthermore, the categorization situations remains difficult; however, there is agreement that are predominantly polarized into two different subtypes with anti-inflammatory properties, so-called M1-like M2-like macrophages, respectively. These macrophage classes can be considered as extreme borders a continuum many intermediate subsets. On one end, M1 pro-inflammatory initiate immunological damage integrity, dampen tumor by fostering robust T natural killer (NK) cell anti-tumoral responses. other M2 involved remodeling growth, promote cancer proliferation, invasion, metastasis, angiogenesis participate suppression. decisive roles occur through secretion cytokines, chemokines, growth factors, matrix metalloproteases, well expression checkpoint receptors case macrophages. Moreover, supported from Tumor Microenvironment (TME) relayed nucleus membrane signaling pathways result gene reprogramming thus giving rise polarization outcomes. In this review, we will focus on main activated upon ligand-receptor recognition presence immunomodulatory molecules

Language: Английский

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CAFs Interacting With TAMs in Tumor Microenvironment to Enhance Tumorigenesis and Immune Evasion

Frontiers in Oncology, Journal Year: 2021, Volume and Issue: 11

Published: July 14, 2021

Cancer associated fibroblasts (CAFs) and tumor macrophages (TAMs) are among the most important abundant players of microenvironment. CAFs as well TAMs known to play pivotal supportive roles in growth progression. The number CAF or TAM cells is mostly correlated with poor prognosis. Both a reciprocal communication milieu . In addition such interactions, also involved dynamic interrelationship each other. capable altering other’s functions. Here, current understanding distinct mechanisms about complex interplay between summarized. addition, consequences mutual relationship especially for progression immune evasion highlighted, focusing on synergistic pleiotropic effects. crucial components microenvironment; thus, they may prove be potential therapeutic targets. A better tri-directional interactions CAFs, cancer terms will pave way identification novel theranostic cues order target carcinogenesis.

Language: Английский

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The Role of EREG/EGFR Pathway in Tumor Progression

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(23), P. 12828 - 12828

Published: Nov. 27, 2021

Aberrant activation of the epidermal growth factor receptor (EGFR/ERBB1) by erythroblastic leukemia viral oncogene homolog (ERBB) ligands contributes to various tumor malignancies, including lung cancer and colorectal (CRC). Epiregulin (EREG) is one EGFR low expressed in most normal tissues. Elevated EREG cancers mainly activates signaling pathways promotes progression. Notably, a higher expression level CRC with wild-type Kirsten rat sarcoma (KRAS) related better efficacy therapeutic treatment. By contrast, resistance anti-EGFR therapy was driven expression, aberrant genetic mutation signal pathway alterations. Additionally, overexpression non-small cell (NSCLC) anticipated be target for EGFR-tyrosine kinase inhibitor (EGFR-TKI). However, recent findings indicate that derived from macrophages NSCLC EGFR-TKI The emerging events EREG-mediated promotion signals are generated autocrine paracrine loops arise epithelial cells, fibroblasts, microenvironment (TME). TME crucial element development types drug resistance. regulation EREG/EGFR depends on distinct oncogenic driver mutations contexts allows specific pharmacological targeting alone or combinational treatment tailored therapy. Novel strategies EREG/EGFR, tumor-associated macrophages, alternative oncoproteins under undergoing clinical trials. In this review, we summarize outcomes interaction ligand TME. may potential combined other targets combat cancers.

Language: Английский

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