scholarly journals Toll-Like Receptor 2 at the Crossroad between Cancer Cells, the Immune System, and the Microbiota

2020 ◽  
Vol 21 (24) ◽  
pp. 9418
Author(s):  
Antonino Di Lorenzo ◽  
Elisabetta Bolli ◽  
Lidia Tarone ◽  
Federica Cavallo ◽  
Laura Conti
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
Immune Cell ◽  
Primary Response ◽  
Toll Like Receptor ◽  
Scientific Debate ◽  
Anti Cancer ◽  
Double Edge Sword ◽  
Toll Like Receptor 2 ◽  
Immunosuppressive Microenvironment

Toll-like receptor 2 (TLR2) expressed on myeloid cells mediates the recognition of harmful molecules belonging to invading pathogens or host damaged tissues, leading to inflammation. For this ability to activate immune responses, TLR2 has been considered a player in anti-cancer immunity. Therefore, TLR2 agonists have been used as adjuvants for anti-cancer immunotherapies. However, TLR2 is also expressed on neoplastic cells from different malignancies and promotes their proliferation through activation of the myeloid differentiation primary response protein 88 (MyD88)/nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) pathway. Furthermore, its activation on regulatory immune cells may contribute to the generation of an immunosuppressive microenvironment and of the pre-metastatic niche, promoting cancer progression. Thus, TLR2 represents a double-edge sword, whose role in cancer needs to be carefully understood for the setup of effective therapies. In this review, we discuss the divergent effects induced by TLR2 activation in different immune cell populations, cancer cells, and cancer stem cells. Moreover, we analyze the stimuli that lead to its activation in the tumor microenvironment, addressing the role of danger, pathogen, and microbiota-associated molecular patterns and their modulation during cancer treatments. This information will contribute to the scientific debate on the use of TLR2 agonists or antagonists in cancer treatment and pave the way for new therapeutic avenues.

scholarly journals Mitochondria-Targeted Antioxidants MitoQ and MitoTEMPO Do Not Influence BRAF-Driven Malignant Melanoma and KRAS-Driven Lung Cancer Progression in Mice

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 163
Author(s):  
Kristell Le Gal ◽  
Clotilde Wiel ◽  
Mohamed X. Ibrahim ◽  
Marcus Henricsson ◽  
Volkan I. Sayin ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Malignant Melanoma ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Nuclear Dna ◽  
Human Melanoma ◽  
Oxygen Species ◽  
Lung Cancer Cell ◽  
Primary Tumors ◽  
Anti Cancer

Cancer cells produce high levels of mitochondria-associated reactive oxygen species (ROS) that can damage macromolecules, but also promote cell signaling and proliferation. Therefore, mitochondria-targeted antioxidants have been suggested to be useful in anti-cancer therapy, but no studies have convincingly addressed this question. Here, we administered the mitochondria-targeted antioxidants MitoQ and MitoTEMPO to mice with BRAF-induced malignant melanoma and KRAS-induced lung cancer, and found that these compounds had no impact on the number of primary tumors and metastases; and did not influence mitochondrial and nuclear DNA damage levels. Moreover, MitoQ and MitoTEMPO did not influence proliferation of human melanoma and lung cancer cell lines. MitoQ and its control substance dTPP, but not MitoTEMPO, increased glycolytic rates and reduced respiration in melanoma cells; whereas only dTPP produced this effect in lung cancer cells. Our results do not support the use of mitochondria-targeted antioxidants for anti-cancer monotherapy, at least not in malignant melanoma and lung cancer.

scholarly journals Campylobacter jejuni Drives MyD88-Independent Interleukin-6 Secretion via Toll-Like Receptor 2

2009 ◽  
Vol 77 (4) ◽  
pp. 1553-1560 ◽  
Author(s):  
Lorna M. Friis ◽  
Monika Keelan ◽  
Diane E. Taylor
Keyword(s):  
Epithelial Cells ◽  
Campylobacter Jejuni ◽  
Interleukin 6 ◽  
Fluid Transport ◽  
Gastrointestinal Disease ◽  
Primary Response ◽  
Intestinal Epithelial ◽  
Toll Like Receptor ◽  
Independent Manner ◽  
Toll Like Receptor 2

ABSTRACT Gastrointestinal disease caused by Campylobacter jejuni is characterized by localized inflammation and the destruction of the epithelial cell barrier that forms host innate protection against pathogens. This can lead to an imbalance in fluid transport across the gastrointestinal tract, resulting in severe diarrhea. The mechanisms of host cell receptor recognition of C. jejuni and downstream immune signaling pathways leading to this inflammatory disease, however, remain unclear. The aim of this study was to analyze the mechanisms involved in C. jejuni induction of the acute-phase inflammatory response regulator interleukin-6 (IL-6). Polarized intestinal epithelial Caco-2 monolayers responded to infections with Salmonella enterica serovar Typhimurium and eight isolates of C. jejuni by an increase in levels of expression and secretion of IL-6. No such IL-6 response, however, was produced upon infection with the human commensal organism Lactobacillus rhamnosus GG. The IL-6 signaling pathway was further characterized using short interfering RNA complexes to block gene expression. The inhibition of myeloid differentiation primary response protein 88 (MyD88) expression in this manner did not affect C. jejuni-induced IL-6 secretion, suggesting a MyD88-independent route to IL-6 signal transduction in C. jejuni-infected human epithelial cells. However, a significant reduction in levels of IL-6 was evident in the absence of Toll-like receptor 2 (TLR-2) expression, implying a requirement for TLR-2 in C. jejuni recognition. Caco-2 cells were also treated with heat-inactivated and purified membrane components of C. jejuni to isolate the factor responsible for triggering IL-6 signaling. The results demonstrate that C. jejuni surface polysaccharides induce IL-6 secretion from intestinal epithelial cells via TLR-2 in a MyD88-independent manner.

scholarly journals Development of a Cationic Amphiphilic Helical Peptidomimetic (B18L) As A Novel Anti-Cancer Drug Lead

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2448 ◽  
Author(s):  
Yuan Lyu ◽  
Steven Kopcho ◽  
Folnetti A. Alvarez ◽  
Bryson C. Okeoma ◽  
Chioma M. Okeoma
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Cancer Drug ◽  
Cancer Cell Death ◽  
Drug Lead ◽  
Anti Cancer ◽  
Cancer Agent ◽  
Caspase Substrate ◽  
Dynamics Simulations

BST-2 is a novel driver of cancer progression whose expression confers oncogenic properties to breast cancer cells. As such, targeting BST-2 in tumors may be an effective therapeutic approach against breast cancer. Here, we sought to develop potent cytotoxic anti-cancer agent using the second-generation BST-2-based anti-adhesion peptide, B18, as backbone. To this end, we designed a series of five B18-derived peptidomimetics. Among these, B18L, a cationic amphiphilic α-helical peptidomimetic, was selected as the drug lead because it displayed superior anti-cancer activity against both drug-resistant and drug-sensitive cancer cells, with minimal toxicity on normal cells. Probing mechanism of action using molecular dynamics simulations, biochemical and membrane biophysics studies, we observed that B18L binds BST-2 and possesses membranolytic characteristics. Furthermore, molecular biology studies show that B18L dysregulates cancer signaling pathways resulting in decreased Src and Erk1/2 phosphorylation, increased expression of pro-apoptotic Bcl2 proteins, caspase 3 cleavage products, as well as processing of the caspase substrate, poly (ADP-ribose) polymerase-1 (PARP-1), to the characteristic apoptotic fragment. These data indicate that through the coordinated regulation of membrane, mitochondrial and signaling events, B18L executes cancer cell death and thus has the potential to be developed into a potent and selective anti-cancer compound.

scholarly journals Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion

Science ◽  
2019 ◽  
Vol 366 (6468) ◽  
pp. 1013-1021 ◽  
Author(s):  
Robert D. Leone ◽  
Liang Zhao ◽  
Judson M. Englert ◽  
Im-Meng Sun ◽  
Min-Hee Oh ◽  
...  
Keyword(s):  
T Cells ◽  
Cancer Cells ◽  
Cell Function ◽  
Immune Cell ◽  
Effector T Cells ◽  
Tumor Immune Evasion ◽  
Metabolic Characteristics ◽  
Metabolic Plasticity ◽  
Tumor Bearing ◽  
Immunosuppressive Microenvironment

The metabolic characteristics of tumors present considerable hurdles to immune cell function and cancer immunotherapy. Using a glutamine antagonist, we metabolically dismantled the immunosuppressive microenvironment of tumors. We demonstrate that glutamine blockade in tumor-bearing mice suppresses oxidative and glycolytic metabolism of cancer cells, leading to decreased hypoxia, acidosis, and nutrient depletion. By contrast, effector T cells responded to glutamine antagonism by markedly up-regulating oxidative metabolism and adopting a long-lived, highly activated phenotype. These divergent changes in cellular metabolism and programming form the basis for potent antitumor responses. Glutamine antagonism therefore exposes a previously undefined difference in metabolic plasticity between cancer cells and effector T cells that can be exploited as a “metabolic checkpoint” for tumor immunotherapy.

scholarly journals 3,3′-Diindolylmethane Promotes Gastric Cancer Progression via β-TrCP-Mediated NF-κB Activation in Gastric Cancer-Derived MSCs

2021 ◽  
Vol 11 ◽  
Author(s):  
Hui Shi ◽  
Yaoxiang Sun ◽  
Hongru Ruan ◽  
Cheng Ji ◽  
Jiahui Zhang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Multiple Drug Resistance ◽  
Cancer Drug ◽  
Multiple Drug ◽  
High Morbidity ◽  
Related Factors ◽  
Anti Cancer

Gastric cancer is a malignant tumor characterized by high morbidity and invasion. Surgery combined with chemo-radiotherapy is the most common treatment for gastric cancer, while multiple drug resistance always results in treatment failure. Once the anti-tumor drugs enter the tumor foci, tumor cells as well as those found in the microenvironment are affected. However, the effects of drugs on tumor microenvironment (TME) are easily overlooked. In this study, we investigated the effects of the anti-cancer drug 3,3’-diindolylmethane (DIM) on gastric cancer-derived mesenchymal stem cells (GC-MSCs) and their subsequent impact on cancer progression. Surprisingly, we found that the therapeutic concentration of DIM upregulated the expression level of tumor-related factors such as CCL-2, IL-6, and IL-8 in GC-MSCs. The conditioned medium of DIM-treated GC-MSCs promoted the proliferation, invasion, and migration of gastric cancer cells in vitro and tumor growth in vivo. Mechanistically, DIM enhanced the expression of β-TrCP, an E3 ubiquitin ligase leading to IκBα degradation and NF-κB activation in GC-MSCs. The β-TrCP knockdown partially eliminated positive results caused by DIM. Our results showed that the therapeutic dosage of DIM induced cell death in cancer cells, while enhancing MSC paracrine functions in the stroma to offset the original DIM effect on cancer cells. These findings provide a new mechanism of anti-cancer drug resistance and remind us to adjust the chemotherapeutic scheme by combining the anti-cancer drug with an appropriate signaling pathway inhibitor to block the side effects of drug on targeted TME cells.

scholarly journals Difference in Strain Pathogenicity of Septicemic Yersinia pestis Infection in a TLR2−/− Mouse Model

2020 ◽  
Vol 88 (3) ◽  
Author(s):  
Kyle L. O’Donnell ◽  
Peter L. Knopick ◽  
Riley Larsen ◽  
Sanghita Sarkar ◽  
Matthew L. Nilles ◽  
...  
Keyword(s):  
Yersinia Pestis ◽  
Cytokine Production ◽  
Immune Cell ◽  
Neutrophil Infiltration ◽  
Cell Trafficking ◽  
Toll Like Receptor ◽  
Inflammatory Cytokine Production ◽  
Content Type ◽  
Immune Cell Trafficking ◽  
Toll Like Receptor 2

ABSTRACT Yersinia pestis is the causative agent of bubonic, pneumonic, and septicemic plague. We demonstrate that Toll-like receptor 2-deficient (TLR2−/−) mice are resistant to septicemic infection by the KIM5 strain of Y. pestis but not to infection by the CO92 Δpgm strain. This resistance is dependent on TLR2, the route of infection, and the isoform of YopJ. Elevated bacterial burdens were found in the spleens of CO92 Δpgm-infected animals by 24 h postinfection and in the livers by 4 days. The YopJ isoform present contributed directly to cytotoxicity and inflammatory cytokine production of bone marrow-derived macrophages from TLR2−/− mice. Immune cell trafficking is altered in CO92 Δpgm infections, with an increased neutrophil infiltration to the spleen 5 days postinfection. Immune cell infiltration to the liver was greater and earlier in KIM5-infected TLR2−/− mice. The functionality of the immune cells was assessed by the ability to develop reactive oxygen and nitrogen species. Our data suggest an inhibition of granulocytes in forming these species in CO92 Δpgm-infected TLR2−/− mice. These findings suggest that resistance to KIM5 in TLR2−/− mice is dependent on early immune cell trafficking and functionality.

Toll-like receptor 2 mediates invasion via activating NF-κB in MDA-MB-231 breast cancer cells

2009 ◽  
Vol 379 (4) ◽  
pp. 1027-1032 ◽  
Author(s):  
Wenjie Xie ◽  
Yongsheng Wang ◽  
Yafang Huang ◽  
Hongzhen Yang ◽  
Jiaping Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Toll Like Receptor ◽  
Toll Like Receptor 2

scholarly journals Sialidase and Sialyltransferase Inhibitors: Targeting Pathogenicity and Disease

2021 ◽  
Vol 8 ◽  
Author(s):  
William H. D. Bowles ◽  
Tracey M. Gloster
Keyword(s):  
Sialic Acid ◽  
Cell Surface ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Cell Function ◽  
Development Of Resistance ◽  
Anti Cancer ◽  
Virus Progeny ◽  
Recent Developments ◽  
Specific Inhibitors

Sialidases (SAs) and sialyltransferases (STs), the enzymes responsible for removing and adding sialic acid to other glycans, play essential roles in viruses, bacteria, parasites, and humans. Sialic acid is often the terminal sugar on glycans protruding from the cell surface in humans and is an important component for recognition and cell function. Pathogens have evolved to exploit this and use sialic acid to either “cloak” themselves, ensuring they remain undetected, or as a mechanism to enable release of virus progeny. The development of inhibitors against SAs and STs therefore provides the opportunity to target a range of diseases. Inhibitors targeting viral, bacterial, or parasitic enzymes can directly target their pathogenicity in humans. Excellent examples of this can be found with the anti-influenza drugs Zanamivir (Relenza™, GlaxoSmithKline) and Oseltamivir (Tamiflu™, Roche and Gilead), which have been used in the clinic for over two decades. However, the development of resistance against these drugs means there is an ongoing need for novel potent and specific inhibitors. Humans possess 20 STs and four SAs that play essential roles in cellular function, but have also been implicated in cancer progression, as glycans on many cancer cells are found to be hyper-sialylated. Whilst much remains unknown about how STs function in relation to disease, it is clear that specific inhibitors of them can serve both as tools to gain a better understanding of their activity and form the basis for development of anti-cancer drugs. Here we review the recent developments in the design of SA and ST inhibitors against pathogens and humans.

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