Autocrine IL-6-induced Stat3 activation contributes to the pathogenesis of lung adenocarcinoma and malignant pleural effusion

Yeh, Hsuan‐Hsien; Lai, Wu‐Wei; Chen, Helen H.W.; Liu, Hsiao Sheng; Su, Wu Chou

doi:10.1038/sj.onc.1209464

Cited by 201 publications

(192 citation statements)

References 29 publications

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“…Both infiltrating T cells in the tumor microenvironment and cancer cells can be the source of these molecules. 12,19,20 It has been shown that T H 2 cytokines downregulate antitumor immunity leading to cancer progression and metastasis formation. Accordingly, patients affected by a variety of human tumors express high levels of T H 2 cytokines in the periphery and in the tumor microenvironment, which correlate with the stage and grade of malignancy.…”

Section: Discussionmentioning

confidence: 99%

“…10,11 Several cytokines have been found to be secreted in the tumor microenvironment by cancer or infiltrating T cells. 12 We had previously found that in Graves' disease, infiltrating T helper type 2 (T H 2) cells produce interleukin-4 (IL-4) and interleukin-10 (IL-10), which make thyrocytes refractory to the apoptosis-inducing effects of the CD95 ligand (CD95L/ FasL). 13 We next examined the thyroid cancer microenvironment for a possible presence of these two cytokines and surprisingly found that the tumor cells themselves, rather than infiltrating T cells, produced both IL-4 and IL-10.…”

mentioning

confidence: 99%

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Apoptosis resistance in epithelial tumors is mediated by tumor-cell-derived interleukin-4

et al. 2008

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We investigated the mechanisms involved in the resistance to cell death observed in epithelial cancers. Here, we identify that primary epithelial cancer cells from colon, breast and lung carcinomas express high levels of the antiapoptotic proteins PED, cFLIP, Bcl-xL and Bcl-2. These cancer cells produced interleukin-4 (IL-4), which amplified the expression levels of these antiapoptotic proteins and prevented cell death induced upon exposure to TRAIL or other drug agents. IL-4 blockade resulted in a significant decrease in the growth rate of epithelial cancer cells and sensitized them, both in vitro and in vivo, to apoptosis induction by TRAIL and chemotherapy via downregulation of the antiapoptotic factors PED, cFLIP, Bcl-xL and Bcl-2. Furthermore, we provide evidence that exogenous IL-4 was able to upregulate the expression levels of these antiapoptotic proteins and potently stabilized the growth of normal epithelial cells rendering them apoptosis resistant. In conclusion, IL-4 acts as an autocrine survival factor in epithelial cells. Our results indicate that inhibition of IL-4/IL-4R signaling may serve as a novel treatment for epithelial cancers.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Apoptosis resistance in epithelial tumors is mediated by tumor-cell-derived interleukin-4

et al. 2008

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“…31 Constitutively activated STAT3 reportedly was detected in several human lung cancer cell lines and in tumor cells that infiltrated the pleurae of patients who had malignant pleural effusionassociated lung adenocarcinoma. 32 Several reports have indicated the synergistic effect of cucurbitacin with known chemotherapeutic agents, such as doxorubicin and gemcitabine. 33 In the current study, our data revealed that treatment with cucurbitacin I in CD133-positive NSCLC cells effectively improved their chemoresistance to cisplatin, doxorubicin, 5-FU, and paclitaxel (Fig.…”

Section: Discussionmentioning

confidence: 99%

Cucurbitacin I inhibits tumorigenic ability and enhances radiochemosensitivity in nonsmall cell lung cancer‐derived CD133‐positive cells

Hsu¹,

Huang

Chang

et al. 2011

Cancer

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BACKGROUND: Signal transducer and activator of transcription 3 (STAT3) signaling reportedly promotes tumor malignancy and recurrence in nonsmall cell lung cancer (NSCLC). It was demonstrated previously that the STAT3 pathway maintains the tumorigenicity and therapeutic resistance of malignant tumors as well as cancer stem cells (CSCs). The objective of the current study was to investigate the effect of the strong STAT3 inhibitor, cucurbitacin I, in prominin-1 (CD133)-positive lung cancer cells. METHODS: CD133-positive and CD133-negative NSCLC-derived cells were isolated from 7 patients with NSCLC. CD133-positive NSCLC cells that were treated with or without cucurbitacin I were evaluated for their expression of phosphorylated STAT3 (p-STAT3), tumorigenicity, stemness properties, and resistance to chemotherapeutic drugs and ionizing radiation. RESULTS: Compared with parental or CD133-negative NSCLC cells, CD133-positive NSCLC cells had greater tumorigenicity, greater radioresistance, and higher expression of octamer-binding transcription factor 4 (Oct-4), Nanog homeobox, and sex-determining region Y, box 2 (Sox2) at high p-STAT3 levels. Cucurbitacin I treatment at 100 nM effectively abrogated STAT3 activation, tumorigenic capacity, sphere formation ability, radioresistance, and chemoresistance in CD133-positive NSCLC cells. Microarray data suggested that cucurbitacin I inhibited the stemness gene signature of CD133-positive NSCLC cells and facilitated the differentiation of CD133-positive NSCLC cells into CD133-negative NSCLC cells. It is noteworthy that 150 nM cucurbitacin I effectively blocked STAT3 signaling and downstream survival targets, such as B-cell chronic lymphocytic leukemia/lymphoma 2 (Bcl-2) and Bcl-2-like 1 (Bcl-xL) expression and induced apoptosis in CD133-positive NSCLC cells. Finally, xenotransplantation experiments revealed that cucurbitacin I plus radiotherapy or chemotherapeutic drugs significantly suppressed tumorigenesis and improved survival in NSCLC-CD133-positive-transplanted, immunocompromised mice. CONCLUSIONS: Targeting STAT3 signaling in CD133-positive NSCLC cells with cucurbitacin I suppressed CSC-like properties and enhanced chemoradiotherapy response. The potential of cucurbitacin I should be verified further in future anti-CSC therapy.

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“…For these experiments, we used non-TB pleural fluid (PE-nonTB) as a positive control since it is known to activate STAT3 and serve a chemoattractant [50]. As illustrated in Figure 5F, freshly isolated monocytes from healthy donors displayed a greater capacity to infiltrate Matrigel when PE-TB and PE-nonTB were used as chemoattractants.…”

Section: The Cd16 + Cd163 + Mertk + Pstat3 + Monocyte-macrophages Dismentioning

confidence: 99%

Tuberculosis is associated with expansion of a motile, permissive and immunomodulatory CD16+ monocyte population via the IL-10/STAT3 axis

et al. 2015

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The human CD14 + monocyte compartment is composed by two subsets based on CD16 expression. We previously reported that this compartment is perturbed in tuberculosis (TB) patients, as reflected by the expansion of CD16 + monocytes along with disease severity. Whether this unbalance is beneficial or detrimental to host defense remains to be elucidated. Here in the context of active TB, we demonstrate that human monocytes are predisposed to differentiate towards an anti-inflammatory (M2-like) macrophage activation program characterized by the CD16 + CD163 + MerTK + pSTAT3 + phenotype and functional properties such as enhanced protease-dependent motility, pathogen permissivity and immunomodulation. This process is dependent on STAT3 activation, and loss-of-function experiments point towards a detrimental role in host defense against TB. Importantly, we provide a critical correlation between the abundance of the CD16 + CD163 + MerTK + pSTAT3 + cells and the progression of the disease either at the local level in a non-human primate tuberculous granuloma context, or at the systemic level through the detection of the soluble form of CD163 in human sera. Collectively, this study argues for the pathogenic role of the CD16 + C-D163 + MerTK + pSTAT3 + monocyte-to-macrophage differentiation program and its potential as a target for TB therapy, and promotes the detection of circulating CD163 as a potential biomarker for disease progression and monitoring of treatment efficacy.

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Autocrine IL-6-induced Stat3 activation contributes to the pathogenesis of lung adenocarcinoma and malignant pleural effusion

Cited by 201 publications

References 29 publications

Apoptosis resistance in epithelial tumors is mediated by tumor-cell-derived interleukin-4

Apoptosis resistance in epithelial tumors is mediated by tumor-cell-derived interleukin-4

Cucurbitacin I inhibits tumorigenic ability and enhances radiochemosensitivity in nonsmall cell lung cancer‐derived CD133‐positive cells

Tuberculosis is associated with expansion of a motile, permissive and immunomodulatory CD16+ monocyte population via the IL-10/STAT3 axis

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