Enhanced tumorigenesis and reduced transforming growth factor-? type II receptor in lung tumors from mice with reduced gene dosage of transforming growth factor-?1

Yang, Kang; Mariano, Jennifer; Angdisen, Jerry; Moody, Terry W.; Diwan, Bhalchandra A.; Wakefield, Lalage M.; Jakowlew, Sonia B.

doi:10.1002/1098-2744(200010)29:2<112::aid-mc8>3.0.co;2-9

Cited by 23 publications

(18 citation statements)

References 46 publications

(32 reference statements)

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“…Such perturbations may occur as a consequence of the loss of the tumour suppressor functions of TGF-b. Reduced expression of TbRII has been reported in poorly differentiated lung adeno, and squamous cell carcinoma by immunohistochemical studies (Kang et al, 2000). In contrast, another study reported that a reduced expression of TGF-b1, TbRI and TbRII correlated with less lung tumour aggressiveness and a better prognosis (Takanami et al, 1997).…”

Section: Discussionmentioning

confidence: 98%

Restoration of TGF-β signalling reduces tumorigenicity in human lung cancer cells

et al. 2005

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Members of the transforming growth factor-b (TGF-b) family regulate a wide range of biological processes including cell proliferation, migration, differentiation, apoptosis, and extracellular matrix deposition. Resistance to TGF-b-mediated tumour suppressor function in human lung cancer may occur through the loss of type II receptor (TbRII) expression. In this study, we investigated the expression pattern of TbRII in human lung cancer tissues by RT -PCR and Western blot analyses. We observed downregulation of TbRII in 30 out of 46 NSCLC samples (65%) by semiquantitative RT -PCR. Western blot analyses with tumour lysates showed reduced expression of TbRII in 77% cases. We also determined the effect of TbRII expression in lung adenocarcinoma cell line (VMRC-LCD) that is not responsive to TGF-b due to lack of TbRII expression. Stable expression of TbRII in these cells restored TGF-b-mediated effects including Smad2/3 and Smad4 complex formation, TGF-b-responsive reporter gene activation, inhibition of cell proliferation and increased apoptosis. Clones expressing TbRII showed reduced colony formation in soft-agarose assay and significantly reduced tumorigenicity in athymic nude mice. Therefore, these results suggest that reestablishment of TGF-b signalling in TbRII null cells by stable expression of TbRII can reverse malignant behaviour of cells and loss of TbRII expression may be involved in lung tumour progression.

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Section: Discussionmentioning

confidence: 98%

Restoration of TGF-β signalling reduces tumorigenicity in human lung cancer cells

et al. 2005

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“…To gain insight into the role of transforming growth factor-␤1 (TGF-␤1) and the TGF-␤ type II receptor (TGF-␤ RII) as tumorsuppressor genes in lung tumorigenesis, two different models have been explored. Mice hemizygous for TGF-␤1 showed an increased incidence of adenocarcinomas compared to their wild-type littermates (Kang et al 2000;McKenna et al 2001), and transgenic mice with dominantnegative TGF-␤ RII transgene under control of a MMTV promoter showed an increase in the number of adenocarcinomas after carcinogen treatment (Bottinger et al 1997).…”

Section: Genes and Development 649mentioning

confidence: 99%

Mouse models for human lung cancer

Meuwissen

Berns²

2005

Genes Dev.

272

243

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In recent years several new mouse models for lung cancer have been described. These include models for both non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Tumorigenesis in these conditional mouse tumor models can be initiated in adult mice through Cre-recombinase-induced activation of oncogenic mutations in a subset of the cells. They present a marked improvement over mouse models that depend on carcinogen induction of tumors. These models permit us to study the consecutive steps involved in initiation and progression and allow us to address questions like the cell of origin, and the role of cancer stem cells in the maintenance of these tumors. They now need to be validated as suitable preclinical models for intervention studies in which questions with respect to therapy response and resistance can be addressed.During the last decades lung cancer has become the leading cause of cancer deaths in the world, accounting for even more solid tumor deaths than breast, pancreatic, prostate, and colorectal combined (Landis et al. 1999). More then 170,000 new cases are being diagnosed each year in the United States alone, of whom ∼160,000 will eventually die, representing 28% of all cancer deaths (Jemal et al. 2004). Worldwide more than a million deaths are due to lung cancer. Tobacco smoking is the major causal agent, being responsible for ∼85% of the lung cancer incidence. Other respiratory exposure to occupational or environmental carcinogens, such as asbestos or radon, and yet unknown genetic factors contribute to the remaining 15% . Although smoking cessation before the age of 30 does substantially reduce the risk of lung cancer, this is significantly less for those who stop smoking at 50 or 60 yr (Peto et al. 2000;Doll et al. 2004). Interestingly, nearly 50% of all first diagnosed lung cancers in the United States are from people who stopped smoking at least 5 or more years ago (Peto and Lopez 2001). This indicates that extensive damage to the respiratory tract can persist over many years. Indeed, recent studies (Mao 2002;Pfeifer et al. 2002;Wistuba et al. 2002) showed the presence of multiple genetic lesions, often manifested in clonal patches of cells in respiratory epithelium of current and former smokers.Lung cancer can be divided into two major histopathological groups: non-small-cell lung cancer (NSCLC) (Van Zandwijk et al. 1995) SCLC and NSCLC show major differences in histopathologic characteristics that can be explained by the distinct patterns of genetic lesions found in both tumor classes . Responsiveness to treatment with chemotherapy and/or radiation also differs significantly between NSCLC and SCLC and has a dramatic effect on clinical treatment outcome. The overall 5-yr survival rate for lung cancer is ∼14% (Travis et al. 1995); for SCLC alone it is even worse, ∼5% (Worden and Kalemkerian 2000).Spontaneous lung tumors in mice are similar in morphology, histopathology, and molecular characteristics to human adenocarcinomas. Mouse models for lung cancer can thus serve as a valua...

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“…A more frequent event is a reduction in the expression of TβRII [75]. This is evident in knockout mouse models where there is an increase in the penetrance and rate of tumor formation, and metastases in various tissues [76][77][78][79][80][81][82][83][84]. TβRII expression has been shown to be affected by: a) mutations in the promoter region of the gene [85,86]; b) activated oncogene activity, including Cyclin D1, and Ras [87,88]; c) epigenetic regulation [89].…”

Section: Genetic Alteration In Preneoplastic Lesionsmentioning

confidence: 99%

Molecular mechanisms of head and neck cancer

Deshpande

Wong²

2008

Expert Review of Anticancer Therapy

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Background-With a global incidence rank of eight and a significant portion of head and neck malignancies (~90%), oral squamous cell carcinoma (OSCC) poses a major health risk and is one of the leading cause of mortality in developing nations [1]. Distribution of the incidence of OSCC varies across the world with south-central Asia and Africa leading, followed by eastern and central Europe, and to a lesser extent Australia, Japan, and the United States. Over the past few years there has been a drastic increase in the incidence of oral cancer in most parts of the world [2]. In the United States alone, with about 17 new cases/100,000, oral cancer is the fifth most common and sixth leading cause of cancer-related mortality per year [3].While men tend to have a higher incidence of OSCC (6.6/100,000) compared to women (2.9/100,000), there is an equal mortality rate between the sexes (50%).

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Enhanced tumorigenesis and reduced transforming growth factor-? type II receptor in lung tumors from mice with reduced gene dosage of transforming growth factor-?1

Cited by 23 publications

References 46 publications

Restoration of TGF-β signalling reduces tumorigenicity in human lung cancer cells

Restoration of TGF-β signalling reduces tumorigenicity in human lung cancer cells

Mouse models for human lung cancer

Molecular mechanisms of head and neck cancer

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