Loss of transforming growth factor-β type II receptor promotes metastatic head-and-neck squamous cell carcinoma

Lu, Shi; Herrington, Heather; Reh, Douglas D.; Weber, Samuël; Bornstein, Sophia; Wang, Donna; Li, Allen G.; Tang, Chin Fang; Siddiqui, Yasmin; Nord, Jo; Andersen, Peter E.; Corless, Christopher L.; Wang, Xiao Jing

doi:10.1101/gad.1413306

Cited by 190 publications

(253 citation statements)

References 45 publications

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“…Loss of TβRII in the epithelium is not sufficient to induce tumorigenesis, 44 though loss of TβRII in the underlying stroma can do so in some organs. 11 To our knowledge, this is the first report that loss of TβRI can lead to spontaneous tumor formation.…”

Section: Discussionmentioning

confidence: 99%

TGFβ Receptor I Conditional Knockout Mice Develop Spontaneous Squamous Cell Carcinoma

Honjo

Bian²,

Kawakami³

et al. 2007

Cell Cycle

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We generated a mouse model with a conditional deletion of TGF-β signaling in the neurons by crossing TGF-β receptor I (TβRI) floxed mice with neurofilament-H (NF-H) Cre mice. 35% of F1 conditional knockout (COKO) mice developed spontaneous squamous cell carcinomas (SCCs) in periorbital and/or perianal regions. Transplantation of these tumors into athymic nude mice resulted in 62% tumorigenicity. To determine whether evasion of the immune response plays any role in this tumorigenesis, we analyzed the expression levels of receptors for interleukin-13 (mIL-13R), a key negative regulator of tumor immunosurveillance, and found that 33% of COKO tumors expressed the IL-13Ra2 chain. Primary cultures of the SCCs expressing IL-13Ra2 were sensitive to the cytotoxic effect of IL-13R-directed cytotoxin treatment. This is the first demonstration that loss of TβRI can lead to spontaneous tumor formation. These mice can serve as a unique mouse model of SCC to evaluate the tumorigenicity and effect of anti-cancer therapeutics.

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Section: Discussionmentioning

confidence: 99%

TGFβ Receptor I Conditional Knockout Mice Develop Spontaneous Squamous Cell Carcinoma

Honjo

Bian²,

Kawakami³

et al. 2007

Cell Cycle

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“…However, experiments in mice reveal that TGFb is not a universal proliferation regulator; rather TGFb elicits its antiproliferative effects in specific contexts. For example, tissue-specific inactivation of TGFBR2 in mouse models rarely leads to spontaneous tumor formation with little to no pathology in mouse mammary epithelium, oral cavity esophagus, forestomach, pancreas, intestine, and skin [35][36][37][38][39]. Instead, TGFb's potent anti-proliferative effects only become apparent under conditions of tissue injury or oncogenic stress.…”

Section: Tgfβ Tumor-suppressive Functionsmentioning

confidence: 99%

Roles of TGFβ in metastasis

2008

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The TGFβ signaling pathway is conserved from flies to humans and has been shown to regulate such diverse processes as cell proliferation, differentiation, motility, adhesion, organization, and programmed cell death. Both in vitro and in vivo experiments suggest that TGFβ can utilize these varied programs to promote cancer metastasis through its effects on the tumor microenvironment, enhanced invasive properties, and inhibition of immune cell function. Recent clinical evidence demonstrating a link between TGFβ signaling and cancer progression is fostering interest in this signaling pathway as a therapeutic target. Anti-TGFβ therapies are currently being developed and tested in preclinical studies. However, targeting TGFβ carries a substantial risk as this pathway is implicated in multiple homeostatic processes and is also known to have tumor-suppressor functions. Additionally, clinical and experimental results show that TGFβ has diverse and often conflicting roles in tumor progression even within the same tumor types. The development of TGFβ inhibitors for clinical use will require a deeper understanding of TGFβ signaling, its consequences, and the contexts in which it acts.

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“…Transgenic mice expressing a dominant-negative T␤R-II in epidermis exhibit malignant conversion of epithelial cells and promotion of tumor formation (Gorska et al, 2003). Resistance to the antiproliferative effects of TGF-␤ is observed in numerous types of cancer (Park et al, 1994;Heldin et al, 1997;Lu et al, 2006). The refractoriness of many carcinomas to effects of TGF-␤ is due to mutations in or loss of expression of receptors for it and to mutations in R-Smads and Smad4.…”

Section: Introductionmentioning

confidence: 99%

Differential Regulation of Epithelial and Mesenchymal Markers by δEF1 Proteins in Epithelial–Mesenchymal Transition Induced by TGF-β

Shirakihara

Saitoh

Miyazono

2007

MBoC

291

298

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Epithelial-mesenchymal transition (EMT), a crucial event in cancer progression and embryonic development, is induced by transforming growth factor (TGF)-␤ in mouse mammary NMuMG epithelial cells. Id proteins have previously been reported to inhibit major features of TGF-␤-induced EMT.In this study, we show that expression of the ␦EF1 family proteins, ␦EF1 (ZEB1) and SIP1, is gradually increased by TGF-␤ with expression profiles reciprocal to that of E-cadherin. SIP1 and ␦EF1 each dramatically down-regulated the transcription of E-cadherin in NMuMG cells through direct binding to the E-cadherin promoter. Silencing of the expression of both SIP1 and ␦EF1, but not either alone, completely abolished TGF-␤-induced E-cadherin repression. However, expression of mesenchymal markers, including fibronectin, N-cadherin, and vimentin, was not affected by knockdown of SIP1 and ␦EF1. TGF-␤-induced the expression of Ets1, which in turn activated ␦EF1 promoter activity. Moreover, up-regulation of SIP1 and ␦EF1 expression by TGF-␤ was suppressed by knockdown of Ets1 expression. In addition, Id2 suppressed the TGF-␤-and Ets1-induced up-regulation of ␦EF1. Taken together, these findings suggest that the ␦EF1 family proteins, SIP1 and ␦EF1, are necessary, but not sufficient, for TGF-␤-induced EMT and that Ets1 induced by TGF-␤ may function as an upstream transcriptional regulator of SIP1 and ␦EF1. INTRODUCTIONTransforming growth factor (TGF)-␤, a prototypical member of the TGF-␤ family, regulates a broad range of cellular responses, including cell proliferation, differentiation, adhesion, migration, and apoptosis (Bierie and Moses, 2006). TGF-␤ and related factors exhibit their pleiotropic effects through binding to transmembrane serine-threonine kinase receptors type I (T␤R-I) and type II (T␤R-II). On ligand-induced heteromeric complex formation between T␤R-I and T␤R-II, T␤R-I is phosphorylated and activated by T␤R-II kinase and mediates specific intracellular signaling through phosphorylation of receptor-regulated Smads (R-Smads). Phosphorylated R-Smads interact with coSmad (Smad4) and translocate into the nucleus, where they regulate transcription of target genes in cooperation with various transcription factors and transcriptional coactivators or corepressors (Miyazawa et al., 2002;Miyazono et al., 2003;Shi and Massague, 2003).TGF-␤ has potent antiproliferative effects on a wide variety of cells, including epithelial cells, endothelial cells, and hematopoietic cells, although under certain conditions it promotes the proliferation of mesenchymal cells, including fibroblasts, chondrocytes, and osteoblasts. TGF-␤ also induces the deposition of extracellular matrix proteins. In early stages of tumorigenesis, TGF-␤ inhibits the growth of epithelial cells, and insensitivity to this growth-inhibitory effect is associated with progression of tumors Derynck et al., 2001). Transgenic mice expressing a dominant-negative T␤R-II in epidermis exhibit malignant conversion of epithelial cells and promotion of tumor formation (Gorska et al., 20...

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Loss of transforming growth factor-β type II receptor promotes metastatic head-and-neck squamous cell carcinoma

Cited by 190 publications

References 45 publications

TGFβ Receptor I Conditional Knockout Mice Develop Spontaneous Squamous Cell Carcinoma

TGFβ Receptor I Conditional Knockout Mice Develop Spontaneous Squamous Cell Carcinoma

Roles of TGFβ in metastasis

Differential Regulation of Epithelial and Mesenchymal Markers by δEF1 Proteins in Epithelial–Mesenchymal Transition Induced by TGF-β

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