Ras Promotes Transforming Growth Factor-β (TGF-β)-induced Epithelial-Mesenchymal Transition via a Leukotriene B4 Receptor-2-linked Cascade in Mammary Epithelial Cells

Kim, Hyun-Ju; Choi, Jung A.; Kim, Jae Hong

doi:10.1074/jbc.m114.556126

Cited by 42 publications

(27 citation statements)

References 43 publications

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“…Thus, the RAS oncoproteins, products of the most frequently mutated oncogenes in human cancers, have been demonstrated to induce cancer cells to produce proinflammatory cytokines and chemokines, such as IL-8 and the CXCL1 (REFS 109,110). The resulting RAS-induced inflammatory tumour microenvironment contributes reciprocally to disease progression through several distinct mechanisms, including EMT-programme activation 109,111 .…”

Section: Microenvironmental Regulation Of Emtmentioning

confidence: 99%

EMT, CSCs, and drug resistance: the mechanistic link and clinical implications

2017

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The success of anticancer therapy is usually limited by the development of drug resistance. Such acquired resistance is driven, in part, by intratumoural heterogeneity — that is, the phenotypic diversity of cancer cells co-inhabiting a single tumour mass. The introduction of the cancer stem cell (CSC) concept, which posits the presence of minor subpopulations of CSCs that are uniquely capable of seeding new tumours, has provided a framework for understanding one dimension of intratumoural heterogeneity. This concept, taken together with the identification of the epithelial-to-mesenchymal transition (EMT) programme as a critical regulator of the CSC phenotype, offers an opportunity to investigate the nature of intratumoural heterogeneity and a possible mechanistic basis for anticancer drug resistance. In fact, accumulating evidence indicates that conventional therapies often fail to eradicate carcinoma cells that have entered the CSC state via activation of the EMT programme, thereby permitting CSC-mediated clinical relapse. In this Review, we summarize our current understanding of the link between the EMT programme and the CSC state, and also discuss how this knowledge can contribute to improvements in clinical practice.

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Section: Microenvironmental Regulation Of Emtmentioning

confidence: 99%

EMT, CSCs, and drug resistance: the mechanistic link and clinical implications

2017

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“…In a normal cell TGFβ poses certain growth restrictions, however in subpopulations of eg. [121], pancreatic cancer cells NF-κB can substitute for TGFβ signaling in epithelial-mesenchymal transition [120] and thus increase metastatic tumor burden. Furthermore, by inducing overexpression of myc as we discussed in the previous chapter, dysregulated NF-κB activity can overcome restrictions on angiogenesis and neovascularisation, which are normally imposed by TGFβ [122].…”

Section: Nf-κb Effects On Tissue: Shaping the Microenvironmentmentioning

confidence: 99%

Dynamic aberrant NF-κB spurs tumorigenesis: A new model encompassing the microenvironment

Vlahopoulos¹,

Çen²,

Hengen³

et al. 2015

Cytokine & Growth Factor Reviews

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Recently it was discovered that a transient activation of transcription factor NF-κB can give cells properties essential for invasiveness and cancer initiating potential. In contrast, most oncogenes to date were characterized on the basis of mutations or by their constitutive overexpression. Study of NF-κB actually leads to a far more dynamic perspective on cancer: tumors caused by diverse oncogenes apparently evolve into cancer after loss of feedback regulation for NF-κB. This event alters the cellular phenotype and the expression of hormonal mediators, modifying signals between diverse cell types in a tissue. The result is a disruption of stem cell hierarchy in the tissue, and pervasive changes in the microenvironment and immune response to the malignant cells.

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“…Recent studies have suggested that LTB 4 and its receptor BLT2 are associated with tumor progression [12-17]. An increased abundance of LTB 4 and BLT2 has been observed in many types of tumors, including neuroblastomas, as well as pancreatic, bladder, breast and ovarian cancers [12-14, 18, 19].…”

Section: Introductionmentioning

confidence: 99%

Myeloid differentiation primary response gene 88-leukotriene B4 receptor 2 cascade mediates lipopolysaccharide-potentiated invasiveness of breast cancer cells

Park

Kim

2015

Oncotarget

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Inflammation and local inflammatory mediators are inextricably linked to tumor progression through complex pathways in the tumor microenvironment. Lipopolysaccharide (LPS) exposure to tumor cells has been suggested to promote tumor invasiveness and metastasis. However, the detailed signaling mechanism involved has not been elucidated. In this study, we showed that LPS upregulated the expression of leukotriene B4 receptor-2 (BLT2) and the synthesis of BLT2 ligands in MDA-MB-231 and MDA-MB-435 breast cancer cells, thereby promoting invasiveness. BLT2 depletion with siRNA clearly attenuated LPS-induced invasiveness. In addition, we demonstrated that myeloid differentiation primary response gene 88 (MyD88) lies upstream of BLT2 in LPS-potentiated invasiveness and that this ‘MyD88-BLT2’ cascade mediates activation of NF-κB and the synthesis of IL-6 and IL-8, which are critical for the invasiveness and aggression of breast cancer cells. LPS-driven metastasis of MDA-MB-231 cells was also markedly suppressed by the inhibition of BLT2. Together, our results demonstrate, for the first time, that LPS potentiates the invasiveness and metastasis of breast cancer cells via a ‘MyD88-BLT2’-linked signaling cascade.

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Ras Promotes Transforming Growth Factor-β (TGF-β)-induced Epithelial-Mesenchymal Transition via a Leukotriene B4 Receptor-2-linked Cascade in Mammary Epithelial Cells

Cited by 42 publications

References 43 publications

EMT, CSCs, and drug resistance: the mechanistic link and clinical implications

EMT, CSCs, and drug resistance: the mechanistic link and clinical implications

Dynamic aberrant NF-κB spurs tumorigenesis: A new model encompassing the microenvironment

Myeloid differentiation primary response gene 88-leukotriene B4 receptor 2 cascade mediates lipopolysaccharide-potentiated invasiveness of breast cancer cells

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