Blockade of interleukin-6 receptor suppresses the proliferation of H460 lung cancer stem cells

Yi, Hee; Cho, Hee Jung; Cho, Soo Min; Jo, Kyul; Park, Jin A.; Kim, Na Hyun; Amidon, Gordon L.; Kim, Jin Suk; Shin, Ho‐Chul

doi:10.3892/ijo.2012.1447

Cited by 33 publications

(25 citation statements)

References 34 publications

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“…Also, the IL-6 levels in serum were investigated in patients with lung cancer before and during radiotherapy (RT). They found that IL-6 levels were higher compared to controls and were further elevated during RT [40][41][42][43]. In addition, IL-1β and IL-8 both are known to promote tumour progression through regulating tumour growth and invasion [44,45].…”

Section: Discussionmentioning

confidence: 99%

Characterization of M1/M2 Tumour-Associated Macrophages (TAMs) and Th1/Th2 Cytokine Profiles in Patients with NSCLC

Almatroodi

McDonald

Darby

et al. 2015

Cancer Microenvironment

121

107

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Lung cancer is one of the most commonly reported cancers, and is known to be associated with a poor prognosis. The function of tumour-associated macrophages (TAMs) in lung cancer patients is multifaceted and the literature shows conflicting roles. (I) To analyze the Th1 and Th2 cytokine levels that contribute to the differentiation of M1 and M2 macrophage populations in the serum of patients with NSCLC versus non-cancer controls; and (II) To characterize the M1 and M2 macrophage populations within TAMs in different subtypes of NSCLC compared to non-tumour tissue. The Th1 and Th2 cytokine levels were analyzed in serum using the Bio-Plex assay. In addition, TAMs subsets from nontumour and tumour tissues were analyzed using immunohistochemistry (IHC). The level of IL-1β, IL-4, IL-6 and IL-8 was found to be increased in the serum of patients with large cell carcinoma but not in other NSCLC subtypes compared to non-cancer controls. In addition, the expression of CD68 and M2 marker CD163 was found to be increased (P≤0.0001) in all NSCLC subtypes compared to non-tumour tissues. In contrast, the expression of iNOS (M1 marker) was decreased in the tumour tissue of patients with adenocarcinoma (P≤0.01) and squamous carcinoma (P≤0.05) but not in large cell carcinoma compared to non-tumour tissue. The results of this study indicate that NSCLC might have the ability to alter phenotype within the lung tumour areas in the local environment (TAMs) but not in the bloodstream in the systemic environment (serum) except for large cell carcinoma.

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Section: Discussionmentioning

confidence: 99%

Characterization of M1/M2 Tumour-Associated Macrophages (TAMs) and Th1/Th2 Cytokine Profiles in Patients with NSCLC

Almatroodi

McDonald

Darby

et al. 2015

Cancer Microenvironment

121

107

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“…Some studies have suggested that IL-6 may be important in lung cancer stem cells, as opposed to the bulk tumor cells. 32 Beyond direct targeting of tumor cells, targeting IL-6-related inflammation may have beneficial effects on patient quality of life through improvement in cachexia and lung cancer-related anemia. 33 In conclusion, our results and those of others suggest that further study of IL-6 targeting with siltuximab should be considered in human clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Antitumor Efficacy of the Anti-Interleukin-6 (IL-6) Antibody Siltuximab in Mouse Xenograft Models of Lung Cancer

Song

Smith

Doshi

et al. 2014

Journal of Thoracic Oncology

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Introduction Interleukin-6 (IL-6) can activate downstream signaling pathways in lung cancer cells, such as the STAT3 pathway, and is reported to be produced by tumor cells with activating EGFR mutations. We examined IL-6/STAT3 in lung cancer tumor tissues and the effects of siltuximab, a neutralizing antibody to human IL-6, in mouse models of lung cancer. Methods IL-6 and STAT3 activation levels were compared to tumor histology and presence of KRAS mutations in snap-frozen non-small cell lung cancer (NSCLC) tumors. The effects of siltuximab alone or in combination with erlotinib were examined in mouse xenograft models constructed using three cell line xenograft models and one primary explant mouse model. We examined the influence of cancer-associated fibroblasts (CAFs) on tumor growth and siltuximab effects. Results IL-6 levels were higher in tumors of squamous cell versus adenocarcinoma histology and were not associated with presence of KRAS mutations. Tyrosine phosphorylation status of STAT3 did not correlate with tumor IL-6 levels. Serine phosphorylation of STAT3 was correlated with KRAS mutation status. Both tumor and stromal cells contributed to total IL-6 within tumors. Siltuximab had minimal effect as a single agent in xenografts with tumor cells alone; however, in models co-administered with CAFs, siltuximab had more potent effects on tumor inhibition. We observed no effects of combined erlotinib and siltuximab. Conclusions IL-6 is elevated in subsets of human NSCLCs, especially with squamous cell histology. Tumors supported by stromal production of IL-6 appear to be the most vulnerable to tumor growth inhibition by siltuximab.

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“…Circulating IL-6 level is also a prognostic marker for survival in advanced NSCLC patients or those treated with chemotherapy [15]. Targeting IL-6 signaling via blocking the IL-6R and IL-6 with siRNA or mAbs resulted in reduced H460 cell (a cell line of human NSCLC) proliferation [16]. On the other hand, human lung adenocarcinomas cells can produce their own IL-6 to promote cell proliferation [17].…”

Section: Introductionmentioning

confidence: 99%

Reciprocal activation between IL-6/STAT3 and NOX4/Akt signalings promotes proliferation and survival of non-small cell lung cancer cells

Lan

Zhang

et al. 2015

Oncotarget

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Inflammatory cytokines and oxidative stress are two critical mediators in inflammation-associated cancer. Interleukin-6 (IL-6) is one of the most critical tumor-promoting cytokines in non-small cell lung cancer (NSCLC). In our recent study, we confirmed that NADPH oxidase 4 (NOX4), an important source of reactive oxygen species (ROS) production in NSCLC cells, promotes malignant progression of NSCLC. However, whether the crosstalk of NOX4 and IL-6 signalings exists in NSCLC remains undentified. In this study, we show that NOX4 expression is positively correlated with IL-6 expression in NSCLC tissues. Exogenous IL-6 treatment significantly enhances NOX4/ROS/Akt signaling in NSCLC cells. NOX4 also enhances IL-6 production and activates IL-6/STAT3 signaling in NSCLC cells. Specifically, NOX4 is confirmed to functionally interplay with IL-6 to promote NSCLC cell proliferation and survival. The in vivo results were similar to those obtained in vitro. These data indicate a novel NOX4-dependent link among IL-6 in the NSCLC microenvironment, oxidative stress in NSCLC cells and autocrined IL-6 in NSCLC cells. NOX4/Akt and IL-6/STAT3 signalings can reciprocally and positively regulate each other, leading to enhanced NSCLC cell proliferation and survival. Therefore, NOX4 may serve as a promising target against NSCLC alone with IL-6 signaling.

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Blockade of interleukin-6 receptor suppresses the proliferation of H460 lung cancer stem cells

Cited by 33 publications

References 34 publications

Characterization of M1/M2 Tumour-Associated Macrophages (TAMs) and Th1/Th2 Cytokine Profiles in Patients with NSCLC

Characterization of M1/M2 Tumour-Associated Macrophages (TAMs) and Th1/Th2 Cytokine Profiles in Patients with NSCLC

Antitumor Efficacy of the Anti-Interleukin-6 (IL-6) Antibody Siltuximab in Mouse Xenograft Models of Lung Cancer

Reciprocal activation between IL-6/STAT3 and NOX4/Akt signalings promotes proliferation and survival of non-small cell lung cancer cells

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