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

Xie, Wenjie; Wang, Yongsheng; Huang, Yu‐Chen; Yang, Huiling; Wang, Jiaping; Hu, Zhuowei

doi:10.1016/j.bbrc.2009.01.009

Cited by 79 publications

(78 citation statements)

References 24 publications

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“…However, the combination regimen does not suppress tumor growth. This result may be due to the following: 1) the importance of TLR2 and TLR9 on host immune cells and tumor cells for positively modulating metastatic behavior compared to their minimal influence on primary subcutaneously implanted tumor growth [12,13,21,22] ; 2) the failure of the combination regimen to promote sufficient immune cell infiltration into the primary tumor to produce a potent cytotoxic suppression of tumor growth due to the anatomical site of administration [23] ; 3) the inability of the therapeutic administration of the combination regimen to overcome the immunosuppressive barrier after the suitable microenvironment for tumor growth has been established [14] . The TLR9 agonist CpG ODN is a promising anti-cancer immunotherapy based on its ability to safely stimulate Th1-dominant innate and adaptive immunity in humans [7] .…”

Section: Discussionmentioning

confidence: 99%

Simultaneous TLR2 inhibition and TLR9 activation synergistically suppress tumor metastasis in mice

Yan

Hua²,

Liu³

et al. 2012

Acta Pharmacol Sin

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Aim: To develop a rational immunotherapy against tumor metastasis by combining a Toll-like-receptor 2 (TLR2)-neutralizing antibody with a TLR9 agonist CpG ODN, and then investigate the mechanism of action for this combinational regimen. Methods: After mouse melanoma B16-F10 cell inoculation, female C57BL/6 mice were treated with either CpG ODN (0.5 mg/kg) or the anti-TLR2 antibody (200 μg/kg), or with a combination of the two agents. Pulmonary metastases were evaluated by counting metastatic nodes on the lung surface using anatomical microscopy. Flow cytometry was used to evaluate the cytotoxicity of the immune cells in tumor-draining lymph nodes, the cell population in the spleen, and the infiltration of immune cells within the lungs. Cytokine and enzyme expression in the lung tissue was evaluated using ELISA or immunostaining. Results: Anti-metastatic effects were detected in mice treated with either CpG ODN or the anti-TLR2 antibody alone. However, treatment with CpG ODN plus the anti-TLR2 antibody synergistically suppressed the metastasis as compared with treatment with either single agent. The combinational treatment resulted in enhanced infiltration of natural killer cells and cytotoxic T cells, reduced recruitment of type 2 macrophages and Tregs, and decreased expression of immunosuppressive factors including TGF-β1, cyclooxygenase-2 and indoleamine 2,3-dioxygenase, thus stimulated tumor cytotoxicity and suppressed metastasis. The anti-metastatic effect of the combinational regimen was further confirmed in spontaneous metastatic mouse model of Lewis lung carcinoma. Conclusion: Our studies suggest that combining a TLR9 agonist with an anti-TLR2 antibody, which eliminates immunosuppressive factors from the tumor environment, is critical for an effective anti-metastatic immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Simultaneous TLR2 inhibition and TLR9 activation synergistically suppress tumor metastasis in mice

Yan

Hua²,

Liu³

et al. 2012

Acta Pharmacol Sin

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“…Furthermore, treatment of OC-3-VGH ovarian cancer cells and C-33A cervical cancer cells with RP215 or anti-antigen receptor antibodies resulted in upregulation of NFκB, which is also activated by the TLR signalling cascade [28]. NFκB is known to be a significant transcription factor involved in the gene regulations/expression of both antigen receptors and TLRs, as well as more than 200 other genes in a variety of biological functions in different cell types [29,[49][50][51][68][69][70][71]. Currently, the exact mechanism by which cancerous immunoglobulins alter TLR gene expression and cause upregulation of NFκB in cancer cells remains to be elucidated.…”

Section: Possible Roles Of Cancerous Immunoglobulins and Toll-like Rementioning

confidence: 99%

Roles of antigen receptors and CA215 in the innate immunity of cancer cells

Lee¹,

Liu²

2013

OJI

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Antigen receptors, including immunoglobulins and T-cell receptors, are known to be widely expressed by cancer cells through unconfirmed mechanisms and for unknown purposes. Recently, a monoclonal antibody, designated as RP215, was generated against the ovarian cancer cell line, OC-3-VGH, and was shown to react with CA215, which consisted mainly of these cancer cell-expressed antigen receptors. Experimental evidence has clearly indicated that cancerous immunoglobulins play significant roles in the growth and proliferation of cancer cells in vitro and in vivo. RP215 and anti-antigen receptor antibodies were equally effective in inducing apoptosis and complement-dependent cytotoxicity reactions to cultured cancer cells. Through gene regulation studies, both RP215 and antibodies against antigen-receptors were shown to affect more than a dozen of genes involved in cell proliferation (such as NFκB-1, IgG, P21, cyclin D1, ribosomal P 1 , and c-fos). Furthermore, selected toll-like receptor genes (TLR-2, -3, -4, and -9) were also found to be highly regulated by both RP215 and anti-antigen receptor antibodies. For example, RP215 and antiantigen receptor antibodies were found to both up-regulate TLR-2 and/or TLR-3 and downregulate TLR-4 and TLR-9 in two types of cancer cells. Based on these studies, it is reasonable to postulate that cancerous immunoglobulins play important roles in the modulation of the innate immune system to allow the growth and survival of cancer cells within the human body. Consequently, RP215 in its humanized forms may be utilized to target cancer cells for potential therapeutic purposes.

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“…As previously described, chronic TLR activation and signaling in both immune and nonimmune cells by environmental antigens are now linked to oncogenesis, tumor growth, and invasive spread (Schmausser et al, 2005;Kelly et al, 2006;Fukata et al, 2007;He et al, 2007;Ilvesaro et al, 2007;Goto et al, 2008;Kim et al, 2008;Yoneda et al, 2008;Curtin et al, 2009;Xie et al, 2009;Zhou et al, 2009). Activation of TLR signaling results in the activation of transcription factors NF-ĸB and AP-1, as well as Type I Interferon (IFN) signaling pathways with subsequent production of "oncogenic" cytokines, and the activation of MAPK and AKT signaling pathways (Figure 1 prostate and many others ).…”

Section: Mechanisms Of Tlr Regulation Of Carcinogenesismentioning

confidence: 86%

Toll-Like Receptors as Novel Therapeutic Targets for the Treatment of Pancreatic Cancer

McCall¹,

Benencia²,

Kohn³

et al. 2012

Pancreatic Cancer - Molecular Mechanism and Targets

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

Cited by 79 publications

References 24 publications

Simultaneous TLR2 inhibition and TLR9 activation synergistically suppress tumor metastasis in mice

Simultaneous TLR2 inhibition and TLR9 activation synergistically suppress tumor metastasis in mice

Roles of antigen receptors and CA215 in the innate immunity of cancer cells

Toll-Like Receptors as Novel Therapeutic Targets for the Treatment of Pancreatic Cancer

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