Lu SL, Herrington H, Reh D, Weber S, Bornstein S, Wang D et al.. Loss of transforming growth factor-beta type II receptor promotes metastatic head-and-neck squamous cell carcinoma. Genes Dev 20: 1331-1342

Department of Cell & Developmental Biology, Oregon Health and Science University, Portland, Oregon, United States
Genes & Development (Impact Factor: 10.8). 06/2006; 20(10):1331-42. DOI: 10.1101/gad.1413306
Source: PubMed


The prognosis of head-and-neck squamous cell carcinoma (HNSCC) has not been improved in the past 20 years. Validation of HNSCC biomarkers for targeted therapy has been hindered by a lack of animal models mimicking human HNSCC at both the pathological and molecular levels. Here we report that overexpression of K-ras or H-ras and loss of transforming growth factor-beta type II receptor (TGFbetaRII) are common events in human HNSCC. Activation of either K-ras or H-ras in combination with TGFbetaRII deletion from mouse head-and-neck epithelia caused HNSCC with complete penetrance, some of which progressed to metastases. These tumors displayed pathology indistinguishable from human HNSCCs and exhibited multiple molecular alterations commonly found in human HNSCCs. Additionally, elevated endogenous TGFbeta1 in these lesions contributed to inflammation and angiogenesis. Our data suggest that targeting common oncogenic pathways in tumor epithelia together with blocking the effect of TGFbeta1 on tumor stroma may provide a novel therapeutic strategy for HNSCC.

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    • "The limitations of conventional treatments in advanced, recurrent or distant metastases HNC have necessitated a search for novel potential approaches. Recently, several research groups have reported certain genes and signaling molecules that were potentially involved in HNC initiation and progression [21-24]. These molecular targets could provide significant clues for early diagnosis, prognosis and new targeted therapies [25-30]. "
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    ABSTRACT: In our previous study using oligonucleotide microarrays, we revealed that transglutaminase 3 (TGM3) was remarkably down-regulated in head and neck cancer (HNC). However, the potential of TGM3 as a useful biomarker or molecular target for HNC is unclear. The transcriptional and post-translational status of TGM3 in HNC cell lines and specimens was detected using real-time PCR and western blot analysis. Bisulfate-treated DNA sequencing was used to analyze the molecular mechanism of TGM3 gene silencing. In addition, the effects of TGM3 on the proliferation, colony formation and induction of apoptosis in vitro and tumorigenicity in vivo were investigated through exogenous expression of TGM3 in HNC cells. Immunohistochemistry was used to evaluate TGM3 expression in large HNC samples. TGM3 was down-regulated in HNC samples and cell lines (P < 0.0001). The hypermethylation of a promoter CpG island was one of the mechanisms of silencing the TGM3 gene in HNC. Exogenous expression of TGM3 in HNC cells could inhibit the proliferation and enhance the apoptosis of HNC cells in vitro and suppress tumor growth in vivo. In addition, TGM3 protein levels were strongly associated with the pathological differentiation of HNC tissues (P = 0.0037). Survival analysis revealed that low TGM3 expression was associated with worse overall survival (P = 0.0002), and TGM3 expression level was an independent predictor in patients with HNC. The studies prove that TGM3, as a candidate tumor suppressor, contributes to the carcinogenesis and development of HNC and may serve as a useful biomarker for patients with HNC.
    Full-text · Article · Dec 2013 · Molecular Cancer
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    • "When carcinogenesis protocols are applied to transgenic mice or CKO mice that disrupt all TGF-b signaling, skin tumorigenesis is promoted, suggesting that loss of Tgfbr2 is not an initiating event in skin tumorigenesis. Furthermore, cancer progression occurs rapidly when oncogenes are activated (often oncogenic Ha-Ras) in Tgfbr2 null epithelial tissues (Guasch et al., 2007; Lu et al., 2006), and invasive squamous cell carcinoma of the forestomach appears when the Tgfbr2 gene is conditionally inactivated in mouse fibroblasts (Bhowmick et al., 2004). Thus, activation of various growth factors is one of the possible mechanisms for stimulation of epithelial proliferation in selected tissues after disruption of TGF-b signaling. "
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    ABSTRACT: Background: The transforming growth factor-β (TGF-β) signaling pathway is generally believed to be a potent inhibitor of proliferation. However, many epithelia lacking the essential Tgfbr2 gene still maintain normal tissue homeostasis. Here, transgenic mice expressing rtTA from the human keratin 14 (K14) promoter were used to generate an inducible dominant-negative TGF-β receptor type II (Tgfbr2) mutant model, which allowed us to distinguish between the primary and secondary effects of TGF-β signaling disruption by Doxycycline treatment in K14+ epithelial stem cells. Results: We showed that in mice lacking TGF-β signaling in K14+ cells, invasive carcinomas developed on the ventral surface of the tip of the tongue, while filiform papillae on the dorsal surface showed different pathological changes from the tip to the posterior of the tongue. In addition, acetylation levels of histone H4 and histone H3 rapidly increased, while pMAPK activity was enhanced and Jagged2 inactivated in lingual epithelia after disruption of TGF-β signaling. Conclusions: Our results contribute to the understanding of TGF-β signaling in regulating homeostasis and carcinogenesis in lingual epithelia.
    Full-text · Article · May 2013 · Developmental Dynamics
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    • "We have studied the role of transforming growth factor beta (TGFβ) pathway in HNSCC using both human HNSCC samples and GEMM approaches [7] [8] [9] [10]. Our studies indicate that inactivation of the type II receptor of TGFβ (TGFβRII) and the downstream signal mediator of TGFβ, Smad4, plays a crucial role in HNSCC development and progression [8] [10]. Perhaps the most comprehensive studies on molecular alterations of HNSCC came from two recent publications describing whole exome sequencing on human HNSCC samples [11] [12]. "
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    ABSTRACT: Activation of the phosphatidylinositol-3-kinase (PI3K) pathway is one of the most frequently observed molecular alterations in many human malignancies, including head and neck squamous cell carcinoma (HNSCC). A growing body of evidence demonstrates the prime importance of the PI3K pathway at each stage of tumorigenesis, that is, tumor initiation, progression, recurrence, and metastasis. Expectedly, targeting the PI3K pathway yields some promising results in both preclinical studies and clinical trials for certain cancer patients. However, there are still many questions that need to be answered, given the complexity of this pathway and the existence of its multiple feedback loops and interactions with other signaling pathways. In this paper, we will summarize recent advances in the understanding of the PI3K pathway role in human malignancies, with an emphasis on HNSCC, and discuss the clinical applications and future direction of this field.
    Full-text · Article · May 2012 · Journal of Oncology
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