TLR4/IFNγ pathways induce tumor regression via NOS II-dependent NO and ROS production in murine breast cancer models

Lamrani, Myriam; Sassi, Néjia; Paul, Catherine; Yousfi, Nadhir; Boucher, Jean‐Luc; Gauthier, Nolwenn; Labbé, Jérôme; Seignez, Cédric; Racoeur, Cindy; Athias, Anne; Guerreiro, Romain; Vergely, Catherine; Rochette, Luc; Bettaieb, Ali; Jeannin, Jean–François

doi:10.1080/2162402x.2015.1123369

Cited by 26 publications

(17 citation statements)

References 39 publications

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“…Although, the role NO plays in tumors is difficult to predict, the evidence suggests that it depends on the organ of primary tumor [6, 14], stage of disease progression [7, 8] and the types of cancer-associated stromal cells within the TME [16, 20]. Sufficient interest has been generated in developing anticancer drugs that target NO metabolism, but progress towards clinical applications of NOS inhibitors or NO-donors has been limited.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, an anticancer drug, OM-174 a Toll-like receptor (TLR) 4 agonist, has been found to induce NOS2 expression in mouse breast cancer models. Inhibiting NOS2 expression diminishes the antitumor effect of OM-174 indicating that NO synthesis is essential to the tumor-suppressive properties of the TLR agonist [16]. Similarly, a study on T-cell immunotherapy in lymphoma tumor-bearing mice also discovered that NO production in the TME was essential for anti-tumor activity of CD8+ T-cells [17].…”

Section: No: Modulator Of the Tmementioning

confidence: 99%

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Nitric Oxide: The Forgotten Child of Tumor Metabolism

2017

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Nitric oxide (NO) is a signaling molecule with pleiotropic physiological roles in normal cells and pathophysiological roles in cancer. NO synthetase expression and NO synthesis are linked to altered metabolism, neoplasticity, invasiveness, chemoresistance, immune evasion, and ultimately to poor prognosis of cancer patients. Exogenous NO in the microenvironment facilitates paracrine signaling, mediates immune responses, and triggers angiogenesis. NO regulates posttranslational protein modifications, S-nitrosation, and genome-wide epigenetic modifications that can have both tumor-promoting and tumor-suppressing effects. We review mechanisms that link NO to cancer hallmarks, with a perspective of co-targeting NO metabolism with first-line therapies for improved outcome. We highlight the need for quantitative flux analysis to study NO in tumors.

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Section: Discussionmentioning

confidence: 99%

Section: No: Modulator Of the Tmementioning

confidence: 99%

Nitric Oxide: The Forgotten Child of Tumor Metabolism

2017

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“…In accordance with this point of view, Davis et al concluded that administration of a TLR4 agonist improves the antitumor responses in head and neck SCC and melanoma tumor models (37). Moreover, Lamrani et al (38) in their study on a breast cancer model found that TLR4/IFNγ pathways induce tumor regression rather than progression.…”

Section: Discussionmentioning

confidence: 86%

EXPRESSION OF TLR4 IN ORAL SQUAMOUS CELL CARCINOMA AND ITS CORRELATION WITH LYMPH NODE METASTASIS (An Immunohistochemical Study)

Youssef

Raslan

El‐Sheikh

et al. 2018

Alexandria Dental Journal

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INTRODUCTION: Oral squamous cell carcinoma (OSCC) accounts for more than 90% of all oral cancers with high mortality and morbidity rates. Lymph node (LN) metastasis is one of the most important factors in the treatment and prognosis of patients with OSCC. It reduces the overall survival by nearly half. Toll like receptors (TLRs) are evolutionarily conserved proteins and major type of receptors involved in both innate and adaptive immunities and defense against pathogens. TLR4 was the first member of the TLR family to be discovered. It was verified that TLR4 is expressed in many types of tumors including OSCC. The correlation between the expression of this receptor and the presence of nodal metastasis has been studied. Involvement of TLR4 in the invasion and metastasis potentials may thus suggest the use of this protein as a prognostic marker for OSCC and may provide a new insight in the treatment strategy. OBJECTIVES: The aim of the present study was to assess the expression of TLR4 in the primary tumor of OSCC and correlate it with the lymph node status. MATERIALS AND METHODS: TLR4 expression was calculated in 30 OSCC cases. The specimens were taken from the primary tumor of 15 cases proved to have positive lymph nodes and another 15 cases with negative lymph nodes. Immunohistochemical (IHC) staining was performed using the Labeled Strept-Avidin Biotin complex method (LSAB), using the anti-TLR4 antibody. RESULTS: TLR4 was expressed in the OSCC cases and was significantly higher in cases with positive lymph node metastasis than those without. CONCLUSIONS: TLR4 expression could be used as a prognostic marker for OSCC as an indicator for metastasis.

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“…Expression or upregulation of TLR4 has been identified in tumor cells, and although it is not always the case (Lamrani et al, 2016), TLR4 activation is mostly reported to stimulate cancer cell aggressive behavior (Molteni et al, 2006; Ikebe et al, 2009; Liao et al, 2012; Chung and Kim, 2016; Sun et al, 2016). It has been proposed that activation of TLR4 on immune cell is protective, while activation of cancer cell TLR4 promotes aggressiveness (Afsharimoghaddam et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

The TLR4-Active Morphine Metabolite Morphine-3-Glucuronide Does Not Elicit Macrophage Classical Activation In Vitro

Khabbazi

Xie

et al. 2016

Front. Pharmacol.

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Macrophages are abundant in the tumor microenvironment where they adopt a pro-tumor phenotype following alternative polarization induced by paracrine factors from cancer and stromal cells. In contrast, classically activated macrophages have tumoricidal activities, such that the polarization of tumor-associated macrophages has become a novel therapeutic target. Toll-like receptor 4 engagement promotes classical activation of macrophages, and recent literature suggests TLR4 agonism to prevent metastasis and promote survival in experimental metastasis models. A growing number of studies indicate that TLR4 can respond to opioids, including the opioid receptor-inactive morphine metabolite morphine-3-glucuronide (M3G). We measured the activation of TLR4 in a reporter cell line exogenously expressing TLR4 and TLR4 co-receptors, and confirmed that M3G weakly but significantly activates TLR4. We hypothesized that M3G would promote the expression of classical activation signature genes in macrophages in vitro. We exposed mouse and human macrophage cell lines to M3G or the TLR4 activator lipopolysaccharide (LPS), alone or in combination with interferon gamma (IFN-γ). The classical macrophage activation markers tested were iNOS, CD86, IL-6, or TNF-α in RAW 264.7 cells and IL-6, IL-12, IL-23, TNF-α, CXCL10, and CXCL11 in THP1 cells. Our results show that despite exhibiting TLR4-activation ability, M3G does not elicit the expression of classical activation markers in LPS-responsive macrophages.

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TLR4/IFNγ pathways induce tumor regression via NOS II-dependent NO and ROS production in murine breast cancer models

Cited by 26 publications

References 39 publications

Nitric Oxide: The Forgotten Child of Tumor Metabolism

Nitric Oxide: The Forgotten Child of Tumor Metabolism

EXPRESSION OF TLR4 IN ORAL SQUAMOUS CELL CARCINOMA AND ITS CORRELATION WITH LYMPH NODE METASTASIS (An Immunohistochemical Study)

The TLR4-Active Morphine Metabolite Morphine-3-Glucuronide Does Not Elicit Macrophage Classical Activation In Vitro

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