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

ArticleinGenes & Development 20(10):1331-42 · June 2006with11 Reads
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.
    • "Conditional genetic loss of TGF-βRII reveals the tumor suppressor characteristics of TGF-β signaling pathway in several epithelial tissues (Biswas et al., 2004; Guasch et al., 2007). However, epidermal or hair follicle abnormalities are not observed in those transgenic mice expressing a dominant-negative form of TGF-βRII (Amendt et al., 1998) or conditional genetic deletion of TGF-βRII in K14+ cells (Guasch et al., 2007) or in K5+ cells (Lu et al., 2006). It seems that TGF-β signaling pathway Feng Li * Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508 Email: lifeng30286@shaphc.org "
    [Show abstract] [Hide abstract] ABSTRACT: In mammalian tongue, all the compartments of the lingual epithelium are turned over throughout adult life. There is a continual requirement for proliferation to replace cells lost by differentiation within each compartment. In contrast to remarkably elucidating to the molecular basis for taste perception, too little is known about the mechanism of lingual epithelium and papillae. In this article, we briefly summarize what is known about the different stem cell compartments in lingual epithelium and papillae, and discuss the evidence for existence of stem cell in lingual epithelium and taste bud. We then consider a new model of homeostasis in lingual epithelium and papillae, in which tissue maintenance depends on multiple-stem cell population. Problems revealed by the application of epigenetic marker are also discussed.
    Full-text · Article · Oct 2016 · Cell Reports
    • "The dichotomy of TGFβ1's anti-proliferative yet pro-tumor activities can be explained by the acquisition of tumor cell resistance to the negative regulatory effects of this cytokine during tumor progression. Indeed, decreased expression of TGFβRI/II receptors or mutations in these proteins that abrogate TGFβ1 signaling in tumor cells have been observed in many cancer types [48][49][50][51][52][53]. Similarly, tumor cells may escape growth inhibition by autocrine/paracrine TGFβ1 signaling through alterations to SMAD signaling components. "
    [Show abstract] [Hide abstract] ABSTRACT: TGFβ1 is a pleiotropic cytokine that exhibits a variety of physiologic and immune regulatory functions. Although its influence on multiple cell types is critical for the regulation of numerous biologic processes in the host, dysregulation of both TGFβ1 expression and activity is frequently observed in cancer and contributes to various aspects of cancer progression. This review focuses on TGFβ1's contribution to tumor immune suppression and escape, with emphasis on the influence of this regulatory cytokine on the differentiation and function of dendritic cells and T cells. Clinical trials targeting TGFβ1 in cancer patients are also reviewed, and strategies for future therapeutic interventions that build on our current understanding of immune regulation by TGFβ1 are discussed.
    Full-text · Article · Aug 2016
    • "Consistent with these paradoxical effects, TbR2 was earlier demonstrated to be a tumor suppressor gene in early tumor stages, but also it can behave as a tumor promoter (Massagué , 2012). Loss of TbR2, for example, promotes metastatic squamous cell carcinoma and aggressive tumor behavior (Lu et al., 2006; Malkoski et al., 2012 ), whereas, in HER2 mammary carcinogenesis, a dominant-negative TbR2 mutant delayed tumor onset (Novitskiy et al., 2014). The other downstream target of GTF2IRD1 is BMPR1b, which has not been directly linked to tumorigenesis. "
    [Show abstract] [Hide abstract] ABSTRACT: The broad implementation of precision medicine in cancer is impeded by the lack of a complete inventory of the genes involved in tumorigenesis. We performed in vivo screening of ∼1,000 genes that are associated with signaling for positive roles in breast cancer, using lentiviral expression vectors in primary MMTV-ErbB2 mammary tissue. Gain of function of five genes, including RET, GTF2IRD1, ADORA1, LARS2, and DPP8, significantly promoted mammary tumor growth. We further studied one tumor-promoting gene, the transcription factor GTF2IRD1. The mis-regulation of genes downstream of GTF2IRD1, including TβR2 and BMPR1b, also individually promoted mammary cancer development, and silencing of TβR2 suppressed GTF2IRD1-driven tumor promotion. In addition, GTF2IRD1 is highly expressed in human breast tumors, correlating with high tumor grades and poor prognosis. Our in vivo approach is readily expandable to whole-genome annotation of tumor-promoting genes.
    Full-text · Article · May 2016
Show more