Interleukin-6 induces an epithelial–mesenchymal transition phenotype in human breast cancer cells

Sullivan, Nicholas J.; Sasser, A. Kate; Axel, Amy; Vesuna, Farhad; Raman, Venu; Ramirez, Nilsa C.; Oberyszyn, Tatiana M.; Hall, Brett M.

doi:10.1038/onc.2009.180

Cited by 647 publications

(570 citation statements)

References 32 publications

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“…In this study, transient expression of IL-6 dramatically reduced E-cadherin protein by 24 h, and constitutive expression of IL-6 led to an EMT in which Snail, Twist, vimentin and N-cadherin were induced, along with the development of more invasive tumors in mice. Conversely, Twist overexpression in MCF-7 caused an EMT along with high IL-6 expression and STAT3 activation [25]. This finding illustrated that not only could IL-6 induce an EMT, but EMT itself could result in production of IL-6.…”

Section: Cancer-associated Fibroblasts As a Potential Source Of Il-6 mentioning

confidence: 85%

“…IL-6 induced significant migration of MDA-MB-231 human breast carcinoma cells, but not of MCF-7 or T-47D breast carcinoma cell lines [24], suggesting that it could potentiate the invasive phenotype. This work led to the key discovery by Sullivan and colleagues that IL-6 could induce EMT in ER alpha positive MCF-7 breast cancer cell lines cultured in three-dimensions (3D) [25]. In this study, transient expression of IL-6 dramatically reduced E-cadherin protein by 24 h, and constitutive expression of IL-6 led to an EMT in which Snail, Twist, vimentin and N-cadherin were induced, along with the development of more invasive tumors in mice.…”

Section: Cancer-associated Fibroblasts As a Potential Source Of Il-6 mentioning

confidence: 99%

“…On the other hand, it is becoming increasingly evident that mast cells contribute to tumor growth through their positive effects on tumor blood vessel development, extracellular matrix remodelling (as a subversion to ECM remodelling in wound healing) and ability to modulate immune responses (reviewed in [35]). In addition, activated mast cells release IL-6 (reviewed in [31,36,37]), which could contribute to breast tumor invasiveness [25].…”

Section: Mast Cells As a Potential Source Of Il-6 Within The Tumor MImentioning

confidence: 99%

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Contribution of Fibroblast and Mast Cell (Afferent) and Tumor (Efferent) IL-6 Effects within the Tumor Microenvironment

Hugo

Lebret

Tomaskovic-Crook

et al. 2012

Cancer Microenvironment

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Hyperactive inflammatory responses following cancer initiation have led to cancer being described as a 'wound that never heals'. These inflammatory responses elicit signals via NFκB leading to IL-6 production, and IL-6 in turn has been shown to induce epithelial to mesenchymal transition in breast cancer cells in vitro, implicating a role for this cytokine in cancer cell invasion. We previously have shown that conditioned medium derived from cancerassociated fibroblasts induced an Epithelial to Mesenchymal transition (EMT) in PMC42-LA breast cancer cells and we have now identify IL-6 as present in this medium. We further show that IL-6 is expressed approximately 100 fold higher in a cancer-associated fibroblast line compared to normal fibroblasts. Comparison of mouse-specific (stroma) and human-specific (tumor) IL-6 mRNA expression from MCF-7, MDA MB 468 and MDA MB 231 xenografts also indicated the stroma rather than tumor as a significantly higher source of IL-6 expression. Mast cells (MCs) feature in inflammatory cancer-associated stroma, and activated MCs secrete IL-6. We observed a higher MC index (average number of mast cells per xenograft section/average tumor size) in MDA MB 468 compared to MDA MB 231 xenografts, where all MC were observed to be active (degranulating). This higher MC index correlated with greater mouse-specific IL-6 expression in the MDA MB 468 xenografts, implicating MC as an important source of stromal IL-6. Furthermore, immunohistochemistry on these xenografts for pSTAT3, which lies downstream of the IL-6 receptor indicated frequent correlations between pSTAT3 and mast cell positive cells. Analysis of publically available databases for IL-6 expression in patient tissue revealed higher IL-6 in laser capture microdissected stroma compared to adjacent tissue epithelium from patients with inflammatory breast cancer (IBC) and invasive non-inflammatory breast cancer (non-IBC) and we show that IL-6 expression was significantly higher in Basal versus Luminal molecular/phenotypic Microenvironment (2012) 5:83-93 DOI 10.1007 groupings of breast cancer cell lines. Finally, we discuss how afferent and efferent IL-6 pathways may participate in a positive feedback cycle to dictate tumor progression.

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Section: Cancer-associated Fibroblasts As a Potential Source Of Il-6 mentioning

confidence: 85%

Section: Cancer-associated Fibroblasts As a Potential Source Of Il-6 mentioning

confidence: 99%

Section: Mast Cells As a Potential Source Of Il-6 Within The Tumor MImentioning

confidence: 99%

See 1 more Smart Citation

Contribution of Fibroblast and Mast Cell (Afferent) and Tumor (Efferent) IL-6 Effects within the Tumor Microenvironment

Hugo

Lebret

Tomaskovic-Crook

et al. 2012

Cancer Microenvironment

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“…These changes in cell morphology are associated with several human cancers and may result in metastasis. 11,13,14 Cancer cells must breach the basement membrane to invade the surrounding tissue. Studies have shown that cancer cells increase secretion of matrix metalloproteinases (MMPs), which are enzymes that degrade the basement membrane, thereby facilitating their ability to invade.…”

Section: Introductionmentioning

confidence: 99%

Obesity-related systemic factors promote an invasive phenotype in prostate cancer cells

Price

Cavazos

Angel

et al. 2012

Prostate Cancer Prostatic Dis

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BACKGROUND: Obesity is associated with larger tumors, shorter time to PSA failure, and higher Gleason scores. However, the mechanism(s) by which obesity promotes aggressive prostate cancer remains unknown. We hypothesize that circulating factors related to obesity promote prostate cancer progression by modulating components of the metastatic cascade.METHODS: Male C57BL/6 mice (6 weeks) were fed an ad libitum diet-induced obesity (60% fat) or control diet (10% fat) for 12 weeks. Serum was collected, metabolic and inflammatory proteins were measured by an antibody array. Sera were used to measure, in vitro, characteristics of a metastatic phenotype. RESULTS:Comparable to obese men, obese sera contained higher levels or leptin, vascular endothelial growth factor, PAI-1, interleukin-6 (IL-6) and lower levels of testosterone. In prostate cells, serum was used to assess: proliferation, invasion, migration, epithelial-mesenchymal-transition (EMT) and matrix metalloproteinase (MMP) activity. LNCaP and PacMetUT1 cells exposed to obese sera increased proliferation, whereas PrEC and DU145 were unaffected. LNCaP, PacMetUT1 and DU145 cancer cells exposed to obese sera resulted in increased invasion, migration and MMP-9 activity. Prostate cancer cells exposed to obese sera showed increased vimentin, dispersion of e-cadherin and b-catenin from the plasma membrane. CONCLUSION:We report, prostate cancer cells exposed to sera from obese mice increases proliferation, invasion, migration, MMP activity and induces changes in proteins critical for EMT.

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“…NF-κB may influence Snail expression through the AKT pathway and directly stabilize Snail activity [73]. This is particularly important for integrating inflammation pathways, such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), which have been linked to EMT in pathological conditions [74]. Other pathways such as Notch have also been shown to act synergistically with TGF-β to express Slug in the developing embryo [75].…”

Section: Discussionmentioning

confidence: 99%

Population heterogeneity in the epithelial to mesenchymal transition is controlled by NFAT and phosphorylated Sp1

Gould

Chakrabarti

Varner

et al. 2015

Preprint

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Epithelial to mesenchymal transition (EMT) is an essential differentiation program during tissue morphogenesis and remodeling. EMT is induced by soluble transforming growth factor β (TGF-β) family members, and restricted by vascular endothelial growth factor family members. While many downstream molecular regulators of EMT have been identified, these have been largely evaluated individually without considering potential crosstalk. In this study, we created an ensemble of dynamic mathematical models describing TGF-β induced EMT to better understand the operational hierarchy of this complex molecular program. We used ordinary differential equations (ODEs) to describe the transcriptional and post-translational regulatory events driving EMT. Model parameters were estimated from multiple data sets using multiobjective optimization, in combination with cross-validation. TGF-β exposure drove the model population toward a mesenchymal phenotype, while an epithelial phenotype was enhanced following vascular endothelial growth factor A (VEGF-A) exposure. Simulations predicted that the transcription factors phosphorylated SP1 and NFAT were master regulators promoting or inhibiting EMT, respectively. Surprisingly, simulations also predicted that a cellular population could exhibit phenotypic heterogeneity (characterized by a significant fraction of the population with both high epithelial and mesenchymal marker expression) if treated simultaneously with TGF-β and VEGF-A. We tested this prediction experimentally in both MCF10A and DLD1 cells and found that upwards of 45% of the cellular population acquired this hybrid state in the presence of both TGF-β and VEGF-A. We experimentally validated the predicted NFAT/Sp1 signaling axis for each phenotype response. Lastly, we found that cells in the hybrid state had significantly different functional behavior when compared to VEGF-A or TGF-β treatment alone. Together, these results establish a predictive mechanistic model of EMT susceptibility, and potentially reveal a novel signaling axis which regulates carcinoma progression through an EMT versus tubulogenesis response. Funding:The project described was supported by Award Number #U54CA143876 from the National Cancer Institute to JDV, National Science Foundation CBET-0955172 to JB, National Science Foundation Graduate research fellowship to DMB, Author SummaryTissue formation and remodeling requires a complex and dynamic balance of interactions between epithelial cells, which reside on the surface, and mesenchymal cells that reside in the tissue interior. During embryonic development, wound healing, and cancer, epithelial cells transform into a mesenchymal cell to form new types of tissues. It is important to understand this process so that it can be controlled to generate beneficial effects and limit pathological differentiation. Much research over the past 20 years has identified many different molecular species that are relevant, but these have mainly been studied one at a time. In this study, we developed and implement...

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Interleukin-6 induces an epithelial–mesenchymal transition phenotype in human breast cancer cells

Cited by 647 publications

References 32 publications

Contribution of Fibroblast and Mast Cell (Afferent) and Tumor (Efferent) IL-6 Effects within the Tumor Microenvironment

Contribution of Fibroblast and Mast Cell (Afferent) and Tumor (Efferent) IL-6 Effects within the Tumor Microenvironment

Obesity-related systemic factors promote an invasive phenotype in prostate cancer cells

Population heterogeneity in the epithelial to mesenchymal transition is controlled by NFAT and phosphorylated Sp1

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