Activation of Toll-like Receptor 4 on Tumor Cells<i>In vitro</i>Inhibits Subsequent Tumor Growth<i>In vivo</i>

Andreani, Virginia; Gatti, Gerardo; Simonella, Lucio; Rivero, Virginia; Maccioni, Mariana

doi:10.1158/0008-5472.can-07-0079

Cited by 75 publications

(72 citation statements)

References 45 publications

(49 reference statements)

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“…In murine melanoma cells, TLR4 activation before inoculation significantly inhibits in vivo tumor growth through T cell activation (Andreani et al 2007;Nunez et al 2012). By contrast, other studies suggest that TLR activation induces tumor cell proliferation and promotes angiogenesis, invasion, and metastasis.…”

Section: Discussionmentioning

confidence: 97%

Toll-Like Receptor 4 Signaling Promotes the Migration of Human Melanoma Cells

Takazawa

Kiniwa

Ogawa

et al. 2014

Tohoku J. Exp. Med.

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Immune cell Toll-like receptors (TLRs) recognize conserved microbial components, leading to immune and inflammatory responses. However, TLRs are also expressed in cancer cells, including melanoma cells, which express TLR2-4. TLR4 ligands have received attention as immunotherapies; therefore, we assessed the expression of TLR4 in human melanoma specimens (29 primary lesions and 28 metastatic lesions) representing different types of melanoma. A high percentage (≥ 90%) of melanoma lesions expressed TLR4, as judged by immunohistochemistry. Next, the role of TLR4 in cell proliferation and migration was assessed using the TLR4-positive (TLR4 + ) melanoma cell lines 501mel and 888mel, and TLR4-negative (TLR4 -) 928mel melanoma cells. Lipopolysaccharide (LPS), a TLR4 agonist, increased the proliferation of TLR4 + melanoma cells but not of TLR4 -928mel cells. The proliferation-inducing effect of LPS in 888mel cells was abolished by blockade of TLR4 signaling via treatment with short interfering RNA (siRNA) targeting TLR4 or myeloid differentiation primary response gene 88 (MyD88), a molecule downstream of TLR4. However, knockdown of TLR4 or MyD88 expression did not affect the LPS-induced proliferation of 501mel cells, suggesting that residual TLR4 signaling is sufficient to maintain cell proliferation. By contrast, LPS increased the migration of TLR4 + melanoma cells, and this effect was substantially inhibited by TLR4 or MyD88 knockdown. Furthermore, TLR4 knockdown decreased cell migration even in the absence of LPS, suggesting the presence of an endogenous TLR4 ligand(s) in melanoma cells. TLR4 signaling may contribute to melanoma progression, and caution should be exercised when using TLR4 ligands as adjuvant therapy for cancer.

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Section: Discussionmentioning

confidence: 97%

Toll-Like Receptor 4 Signaling Promotes the Migration of Human Melanoma Cells

Takazawa

Kiniwa

Ogawa

et al. 2014

Tohoku J. Exp. Med.

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“…Simiantonaki et al concluded that reduced TLR-4 expression is positively associated with metastasis of human colorectal cancer (Simiantonaki et al, 2007). Andereani and colleagues found that the activation of TLR-4 in tumor cells in vitro inhibited tumor growth in vivo (Andreani et al, 2007 DOI:http://dx.doi.org/10.7314/APJCP.2014.15.5.2329 Curcumin Induces MHCC97H Liver Cancer Cell Apoptosis by Activating ROS/TLR-4/Caspase Signaling brief, these studies focused on cancer immunity including inflammation, immune cell function, lymphocytes infiltration and so on when exploring related mechanism (s) and forming hypothesis. The effects of conducting TLR-4 signaling pathway in tumor cells themselves are rarely investigated.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, TLR-4 signaling is involved in cancer development and progression (Kelly et al, 2006). It was reported that activation of TLR-4 signaling suppressed the proliferative capacity of cancer cells (Andreani et al, 2007). Considering that TLR-4 is linked directly to cell apoptosis by stimulating cleavage of caspase-8 (Han et al, 2004), and ROS was supposed to be one of the causes of up-regulating TLR-4 expression (Yu et al, 2008), TLR-4 induced apoptosis could be one of the potential mechanisms which merit further investigation.…”

Section: Introductionmentioning

confidence: 99%

Curcumin Inhibits MHCC97H Liver Cancer Cells by Activating ROS/TLR-4/Caspase Signaling Pathway

Li²,

Liu³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Curcumin can inhibit proliferation of liver cancer cells by inducing apoptosis, but the specific signaling pathways involved are not completely clear. Here, we report that curcumin inhibited proliferation of MHCC97H liver cancer cells by induction of apoptosis in a concentration dependent manner via stimulating intracellular reactive oxygen species (ROS) generation. Also, we showed that increased intracellular ROS formation activated the TLR-4/MyD-88 signaling pathway, resulting in activation of caspase-8 and caspase-3, which eventually led to apoptosis in MHCC97H cells. These results showed that as an prooxidant, curcumin exerts anti-cancer effects by inducing apoptosis via the TLR-4/MyD-88 signaling pathway.

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“…XAF1 has been suggested to contribute to prostate cancer pathogenesis by disrupting the balance of the apoptosis machinery (30). TLR4 is implicated in tumor cell invasion, survival, and metastasis in a variety of cancers (31,48,49). Furthermore, knockdown of TLR4 in Pc3 cells has been reported to result in a reduction of cell migration and invasion (31).…”

Section: Discussionmentioning

confidence: 99%

Comprehensive gene expression microarray analysis of Ets-1 blockade in PC3 prostate cancer cells and correlations with prostate cancer tissues: Insights into genes involved in the metastatic cascade

Shaikhibrahim

Lindstrot²,

Langer³

et al. 2011

Int J Mol Med

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Abstract. Ets-1 is the prototype of the ETS family of transcription factors and is suggested to play an important role in the malignant progression of prostatic carcinomas. Therefore, in this study we investigated the effect of blocking Ets-1 in Pc3 prostate cancer cells on genes involved in the metastatic cascade, and correlated these findings with prostate cancer tissues. Two stable Pc3 cell cultures were established by transfection with either an Ets-1 inverse antisense expression vector or a mock control vector. The effect of blocking Ets-1 on genes involved in the metastatic cascade was assessed by a comprehensive gene expression microarray analysis of Ets-1 inverse and mock control cells. correlating the sets of genes found in the Pc3 microarray data with prostate cancer tissues was performed by verifying the genes in a comprehensive gene expression microarray analysis of RNA extracted from laser microdissected normal prostate glands and from carcinoma glands taken from prostate cancer patients. Western blot analysis confirmed the presence of Ets-1 in mock cells and its absence in Ets-1 inverse cells. In the Ets-1 blockade microarray, many differentially expressed genes were found; however, only genes with a greater than 10-fold up-or downregulation between the Ets-1 blockade and mock control were considered significant. The genes were placed into four groups that play a role in the so-called metastatic cascade based on their known functions in proliferation, apoptosis, migration and angiogenesis. The genes found in the Ets-1 blockade microarray analysis were verified for their presence in the microarray analysis of prostate cancer tissues. Genes found in the microarray analysis of prostate cancer tissues with an >2-fold change and a p-value <0.01 were considered significant. We identified sets of genes that are involved in the metastatic cascade and are known to be implicated in prostate cancer to show changes in the expression patterns due to the Ets-1 blockade in Pc3 cells. correlating these sets of genes with the findings in prostate cancer tissues, we identified 16 genes that are up-or down-regulated in healthy compared to tumor prostate glands. Further investigation revealed that 4 out of the 16 genes have been reported to be regulated by members of the ETS family. These findings provide in vitro and in vivo evidence for the importance of Ets-1 in the development and progression of prostate cancer.

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Activation of Toll-like Receptor 4 on Tumor CellsIn vitroInhibits Subsequent Tumor GrowthIn vivo

Cited by 75 publications

References 45 publications

Toll-Like Receptor 4 Signaling Promotes the Migration of Human Melanoma Cells

Toll-Like Receptor 4 Signaling Promotes the Migration of Human Melanoma Cells

Curcumin Inhibits MHCC97H Liver Cancer Cells by Activating ROS/TLR-4/Caspase Signaling Pathway

Comprehensive gene expression microarray analysis of Ets-1 blockade in PC3 prostate cancer cells and correlations with prostate cancer tissues: Insights into genes involved in the metastatic cascade

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