Role of Microbial Infection-Induced Inflammation in the Development of Gastrointestinal Cancers

There has been increasing evidence that a local inflammatory response stimulates tumor cells to acquire metastatic potential, and the concept of inflammatory oncotaxis has been spreading in recent years. However, the interaction between microbial inflammation and the development of gastrointestinal cancer is still unclear. This review summarizes the present knowledge on the role of microbial inflammation in the development of gastrointestinal cancers from the perspective of molecular biological findings. Chronic inflammation caused by bacterial infection is known to induce cancers as exemplified by Helicobacter pylori, which is associated with the development of gastric cancer via the activation of the TLR4 pathway by bacterial lipopolysaccharide followed by cancer growth through CagA-MET signaling. In addition, the development of inflammatory bowel diseases has been known to become a risk factor for colorectal cancers, where inflammation caused by certain bacterial infections plays a key role. It is also known that the cancer microenvironment is associated with cancer growth. Moreover, infectious complication after surgery for gastrointestinal cancers may promote tumor progression via the stimulation of pathogen-associated molecular patterns and various inflammatory mediators secreted by immunocytes. Further research on the link between microbial inflammation and cancer progression is needed to drive a paradigm shift in cancer treatment.

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Role of MicroRNAs in Colon Cancer Progression and Metastasis

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530320666200825184924 ◽

2020 ◽

Vol 20 ◽

Author(s):

Shruthi Sanjitha Sampath ◽

Sivaramakrishnan Venkatabalsubramanian ◽

Satish Ramalingam

Keyword(s):

Colon Cancer ◽

Cancer Progression ◽

Target Genes ◽

Tumour Progression ◽

Intestinal Barrier ◽

Colon Cancer Progression ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Novel Therapeutic Strategies

: MicroRNAs regulate gene expression at the posttranscriptional level by binding to the mRNA of their target genes. The dysfunction of miRNAs is strongly associated with the inflammation of the colon. Besides, some microRNAs are shown to suppress tumours while others promote tumour progression and metastasis. Inflammatory bowel diseases include Crohn’s disease and Ulcerative colitis which increase the risk factor for inflammation-associated colon cancer. MicroRNAs are shown to be involved in gastrointestinal pathologies, by targeting the transcripts encoding proteins of the intestinal barrier and their regulators that are associated with inflammation and colon cancer. Detection of these microRNAs in the blood, serum, tissues, faecal matter, etc will enable us to use these microRNAs as biomarkers for early detection of the associated malignancies and design novel therapeutic strategies to overcome the same. Information on MicroRNAs can be applied for the development of targeted therapies against inflammation-mediated colon cancer.

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Human Mucosal Mast Cells Capture HIV-1 and Mediate Viraltrans-Infection of CD4+T Cells

Journal of Virology ◽

10.1128/jvi.03008-15 ◽

2015 ◽

Vol 90 (6) ◽

pp. 2928-2937 ◽

Cited By ~ 16

Author(s):

Ai-Ping Jiang ◽

Jin-Feng Jiang ◽

Ji-Fu Wei ◽

Ming-Gao Guo ◽

Yan Qin ◽

...

Keyword(s):

T Cells ◽

Mast Cells ◽

Cell Surface ◽

Bacterial Infections ◽

Mucosal Mast Cells ◽

Mucosal Tissues ◽

Viral Particles ◽

Molecular Patterns ◽

Hiv 1

ABSTRACTThe gastrointestinal mucosa is the primary site where human immunodeficiency virus type 1 (HIV-1) invades, amplifies, and becomes persistently established, and cell-to-cell transmission of HIV-1 plays a pivotal role in mucosal viral dissemination. Mast cells are widely distributed in the gastrointestinal tract and are early targets for invasive pathogens, and they have been shown to have increased density in the genital mucosa in HIV-infected women. Intestinal mast cells express numerous pathogen-associated molecular patterns (PAMPs) and have been shown to combat various viral, parasitic, and bacterial infections. However, the role of mast cells in HIV-1 infection is poorly defined. In this study, we investigated their potential contributions to HIV-1 transmission. Mast cells isolated from gut mucosal tissues were found to express a variety of HIV-1 attachment factors (HAFs), such as DC-SIGN, heparan sulfate proteoglycan (HSPG), and α4β7 integrin, which mediate capture of HIV-1 on the cell surface. Intriguingly, following coculture with CD4+T cells, mast cell surface-bound viruses were efficiently transferred to target T cells. Prior blocking with anti-HAF antibody or mannan before coculture impaired viraltrans-infection. Cell-cell conjunctions formed between mast cells and T cells, to which viral particles were recruited, and these were required for efficient cell-to-cell HIV-1 transmission. Our results reveal a potential function of gut mucosal mast cells in HIV-1 dissemination in tissues. Strategies aimed at preventing viral capture and transfer mediated by mast cells could be beneficial in combating primary HIV-1 infection.IMPORTANCEIn this study, we demonstrate the role of human mast cells isolated from mucosal tissues in mediating HIV-1trans-infection of CD4+T cells. This finding facilitates our understanding of HIV-1 mucosal infection and will benefit the development of strategies to combat primary HIV-1 dissemination.

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The host response to infection in the critically ill

10.1093/med/9780199600830.003.0303 ◽

2016 ◽

Author(s):

W. Joost Wiersinga ◽

Tom van der Poll

Keyword(s):

Critically Ill ◽

Host Response ◽

Inflammatory Responses ◽

Coagulation Cascade ◽

Microbial Infection ◽

Pathogen Invasion ◽

New Therapeutic Approaches ◽

Microbial Invasion ◽

Molecular Patterns

Infection continues to be a leading cause of intensive care unit death. The host response to infection can be seen as a pattern recognition receptor (PRR)-mediated dysregulation of the immune system following pathogen invasion in which a careful balance between inflammatory and anti-inflammatory responses is vital. A measured and rapid response to microbial invasion is essential to health. The same immunological and coagulation systems that protect against localized infection can act to our disadvantage when these systems are activated systemically during generalized microbial infection. Toll-like receptors (TLR), the inflammasomes and other PRRs initiate the host response after recognition of pathogen-associated-molecular-patterns (PAMPs) or endogenous danger-associated-molecular-patterns (DAMPs). The systemic host response to infection will result in activation of coagulation, downregulation of physiological anticoagulant mechanisms, and inhibition of fibrinolysis. Further dissection of the role of host–pathogen interactions, the cytokine response, the coagulation cascade and their multidirectional interactions in sepsis should lead towards the development of new therapeutic approaches in the critically ill who are faced with infection.

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Role of Heparan Sulfate 2-O-Sulfotransferase in Prostate Cancer Cell Proliferation, Invasion, and Growth Factor Signaling

Prostate Cancer ◽

10.1155/2011/893208 ◽

2011 ◽

Vol 2011 ◽

pp. 1-14 ◽

Cited By ~ 14

Author(s):

Brent W. Ferguson ◽

Sumana Datta

Keyword(s):

Prostate Cancer ◽

Growth Factor ◽

Heparan Sulfate ◽

Cancer Progression ◽

Metastatic Potential ◽

Growth Factor Signaling ◽

Cancer Cell Proliferation ◽

Determining Factors ◽

Proliferation And Invasion

Heparan-sulfate proteoglycans (HSPGs) are required for maximal growth factor signaling in prostate cancer progression. The degree of sulfate modification on the covalently attached heparan sulfate (HS) chains is one of the determining factors of growth factor-HSPG interactions. Sulfate groups are transferred to HS chains via a series of O-sulfotransferases. In the present study, we demonstrate that Heparan sulfate 2-O-sulfotransferase (2OST) is essential for maximal proliferation and invasion of prostate cancer cells in the LNCaP-C4-2B model. We also show that a decrease in invasion due to 2OST siRNA is associated with an increase in actin and E-cadherin accumulation at the cell surface. 2OST expression correlates with increasing metastatic potential in this model. We demonstrate that 2OST expression is upregulated by the stress-inducible transcription factors HIF1α, ATF2, and NFκB. Chromatin immunoprecipitation analysis suggests that HIF1αand ATF2 act directly on the 2OST promoter, while NFκB acts indirectly.

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Nerves in the Tumor Microenvironment: Origin and Effects

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.601738 ◽

2020 ◽

Vol 8 ◽

Author(s):

Wenjun Wang ◽

Lingyu Li ◽

Naifei Chen ◽

Chao Niu ◽

Zhi Li ◽

...

Keyword(s):

Tumor Microenvironment ◽

Cancer Cells ◽

Cancer Progression ◽

Perineural Invasion ◽

Vital Role ◽

Cancer Growth ◽

Alternative Route ◽

Sympathetic Nervous ◽

Molecular Bases

Studies have reported the vital role of nerves in tumorigenesis and cancer progression. Nerves infiltrate the tumor microenvironment thereby enhancing cancer growth and metastasis. Perineural invasion, a process by which cancer cells invade the surrounding nerves, provides an alternative route for metastasis and generation of tumor-related pain. Moreover, central and sympathetic nervous system dysfunctions and psychological stress-induced hormone network disorders may influence the malignant progression of cancer through multiple mechanisms. This reciprocal interaction between nerves and cancer cells provides novel insights into the cellular and molecular bases of tumorigenesis. In addition, they point to the potential utility of anti-neurogenic therapies. This review describes the evolving cross-talk between nerves and cancer cells, thus uncovers potential therapeutic targets for cancer.

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Salmonella Typhimurium impairs glycolysis-mediated acidification of phagosomes to evade macrophage defense

PLoS Pathogens ◽

10.1371/journal.ppat.1009943 ◽

2021 ◽

Vol 17 (9) ◽

pp. e1009943

Author(s):

Saray Gutiérrez ◽

Julia Fischer ◽

Raja Ganesan ◽

Nina Judith Hos ◽

Gökhan Cildir ◽

...

Keyword(s):

Bacterial Infections ◽

Glycolytic Enzyme ◽

Metabolic Adaptation ◽

Adaptive Immune ◽

Adaptive Immune Cells ◽

Serovar Typhimurium ◽

Extracellular Stimuli ◽

Molecular Patterns ◽

Aldolase A

Regulation of cellular metabolism is now recognized as a crucial mechanism for the activation of innate and adaptive immune cells upon diverse extracellular stimuli. Macrophages, for instance, increase glycolysis upon stimulation with pathogen-associated molecular patterns (PAMPs). Conceivably, pathogens also counteract these metabolic changes for their own survival in the host. Despite this dynamic interplay in host-pathogen interactions, the role of immunometabolism in the context of intracellular bacterial infections is still unclear. Here, employing unbiased metabolomic and transcriptomic approaches, we investigated the role of metabolic adaptations of macrophages upon Salmonella enterica serovar Typhimurium (S. Typhimurium) infections. Importantly, our results suggest that S. Typhimurium abrogates glycolysis and its modulators such as insulin-signaling to impair macrophage defense. Mechanistically, glycolysis facilitates glycolytic enzyme aldolase A mediated v-ATPase assembly and the acidification of phagosomes which is critical for lysosomal degradation. Thus, impairment in the glycolytic machinery eventually leads to decreased bacterial clearance and antigen presentation in murine macrophages (BMDM). Collectively, our results highlight a vital molecular link between metabolic adaptation and phagosome maturation in macrophages, which is targeted by S. Typhimurium to evade cell-autonomous defense.

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Aryl hydrocarbon receptor protects against viridans streptococci infection by activation of immune system through IL-17RA signaling

American Journal of BioMedicine ◽

10.18081/2333-5106/015-02/400-410 ◽

2015 ◽

Vol 3 (2) ◽

pp. 400-410

Author(s):

Guowei Liang ◽

Keyword(s):

Immune Responses ◽

Aryl Hydrocarbon Receptor ◽

Bacterial Infections ◽

High Dose Chemotherapy ◽

High Dose ◽

Microbial Infection ◽

Viridans Streptococci ◽

Coagulase Negative Staphylococci ◽

Aryl Hydrocarbon

The majority of bacterial infections during neutropenia following high-dose chemotherapy or stem cell transplantation are caused by coagulase-negative staphylococci, a large number are due to viridans streptococci. Despite considerable progress in the understanding of the AhR-mediated regulation of immune responses, the role of AhR in bacterial infections has not been clearly demonstrated. In the study presented here, we sought to determine whether the aryl hydrocarbon receptor (AhR) would protect mice from infection with viridans streptococci. AhR enhances the inflammatory response to viridans streptococci stimuli. Specifically, neutrophil numbers and levels of inflammatory cytokines are often increased in mice treated with viridans streptococci. Furthermore, AhR activation through the IL-17RA is required for protection against viridans streptococcal infection. Taken together, we concluded that AhR plays an important role in optimal innate immunoprotection against microbial infection through the down-regulation of immune response.

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Emerging Role of Exosomes in Diagnosis and Treatment of Infectious and Inflammatory Bowel Diseases

Cells ◽

10.3390/cells9051111 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1111 ◽

Cited By ~ 4

Author(s):

Anaïs Larabi ◽

Nicolas Barnich ◽

Hang Thi Thu Nguyen

Keyword(s):

Inflammatory Bowel Diseases ◽

Bacterial Infections ◽

Pathogenic Bacteria ◽

Intestinal Inflammation ◽

Current Knowledge ◽

Biological Fluids ◽

Bowel Diseases ◽

Therapeutic Molecules ◽

Inflammatory Bowel

To communicate with each other, cells release exosomes that transfer their composition, including lipids, proteins and nucleic acids, to neighboring cells, thus playing a role in various pathophysiological processes. During an infection with pathogenic bacteria, such as adherent-invasive E. coli (AIEC) associated with Crohn disease, exosomes secreted by infected cells can have an impact on the innate immune responses of surrounding cells to infection. Furthermore, inflammation can be amplified via the exosomal shuttle during infection with pathogenic bacteria, which could contribute to the development of the associated disease. Since these vesicles can be released in various biological fluids, changes in exosomal content may provide a means for the identification of non-invasive biomarkers for infectious and inflammatory bowel diseases. Moreover, evidence suggests that exosomes could be used as vaccines to prime the immune system to recognize and kill invading pathogens, and as therapeutic components relieving intestinal inflammation. Here, we summarize the current knowledge on the role of exosomes in bacterial infections and highlight their potential use as biomarkers, vaccines and conveyers of therapeutic molecules in inflammatory bowel diseases.

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Cell surface carbohydrates of symbiotic dinoflagellates and their role in the establishment of cnidarian–dinoflagellate symbiosis

The ISME Journal ◽

10.1038/s41396-021-01059-w ◽

2021 ◽

Author(s):

Giada Tortorelli ◽

Carsten Rautengarten ◽

Antony Bacic ◽

Gabriela Segal ◽

Berit Ebert ◽

...

Keyword(s):

Cell Surface ◽

Algal Cell ◽

Algal Species ◽

Microbial Infection ◽

Array Technology ◽

Lectin Array ◽

Symbiotic Dinoflagellates ◽

Nucleotide Sugars ◽

Molecular Patterns

AbstractSymbiodiniaceae algae are often photosymbionts of reef-building corals. The establishment of their symbiosis resembles a microbial infection where eukaryotic pattern recognition receptors (e.g. lectins) are thought to recognize a specific range of taxon-specific microbial-associated molecular patterns (e.g. glycans). The present study used the sea anemone, Exaiptasia diaphana and three species of Symbiodiniaceae (the homologous Breviolum minutum, the heterologous-compatible Cladocopium goreaui and the heterologous-incompatible Fugacium kawagutii) to compare the surface glycomes of three symbionts and explore the role of glycan–lectin interactions in host–symbiont recognition and establishment of symbiosis. We identified the nucleotide sugars of the algal cells, then examined glycans on the cell wall of the three symbiont species with monosaccharide analysis, lectin array technology and fluorescence microscopy of the algal cell decorated with fluorescently tagged lectins. Armed with this inventory of possible glycan moieties, we then assayed the ability of the three Symbiodiniaceae to colonize aposymbiotic E. diaphana after modifying the surface of one of the two partners. The Symbiodiniaceae cell-surface glycome varies among algal species. Trypsin treatment of the alga changed the rate of B. minutum and C. goreaui uptake, suggesting that a protein-based moiety is an essential part of compatible symbiont recognition. Our data strongly support the importance of D-galactose (in particular β-D-galactose) residues in the establishment of the cnidarian–dinoflagellate symbiosis, and we propose a potential involvement of L-fucose, D-xylose and D-galacturonic acid in the early steps of this mutualism.

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KDM6A-ARHGDIB axis blocks metastasis of bladder cancer by inhibiting Rac1

Molecular Cancer ◽

10.1186/s12943-021-01369-9 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Lei Liu ◽

Jianfeng Cui ◽

Yajing Zhao ◽

Xiaochen Liu ◽

Lipeng Chen ◽

...

Keyword(s):

Bladder Cancer ◽

Cancer Progression ◽

Critical Role ◽

Metastatic Potential ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Tissue Specimens ◽

Invasion Assays

Abstract Background KDM6A, a histone demethylase, is frequently mutated in bladder cancer (BCa). However, the role and detailed molecular mechanism of KDM6A involved in bladder cancer progression remains unknown. Methods Tissue specimens were used to determine the expression levels and prognostic values of KDM6A and ARHGDIB. The MTT, colony formation, wound healing and Transwell migration and invasion assays were employed to detect the BCa cell proliferation, migration and invasion, respectively. Chemotaxis of macrophages was used to evaluate the ability of KDM6A to recruit macrophages. A subcutaneous tumour model and tail vein tumour injection in nude mice were used to assess the role of KDM6A in vivo. RNA sequencing, qPCR, Western blot, ChIP and phalloidin staining assay were performed to investigate the molecular functions of KDM6A. Dual-luciferase reporter assay was used to determine the effects of KDM6A and FOXA1 on the promoters of the ARHGDIB and KDM6A. Results We showed that the KDM6A inhibited the motility and invasiveness of the BCa cells. Mechanistically, KDM6A promotes the transcription of ARHGDIB by demethylating histone H3 lysine di/trimethylation (H3K27me2/3) and consequently leads to inhibition of Rac1. EZH2, which catalyses the methylation of H3K27, functions to silence ARHGDIB expression, and an EZH2 inhibitor can neutralize the metastatic effect caused by KDM6A deficiency. Furthermore, we demonstrated that FOXA1 directly binds to the KDM6A promoter and thus transactivates KDM6A, leading to diminished metastatic potential. Conclusion Our findings establish the critical role of the FOXA1-KDM6A-ARHGDIB axis in restraining the malignancy of BCa and identify KDM6A and EZH2 as potential therapeutic targets in the management of BCa.

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