Attenuated type II TGF‐β receptor signalling in human malignant oral keratinocytes induces a less differentiated and more aggressive phenotype that is associated with metastatic dissemination

Huntley, Suzy; Davies, Malcolm; Matthews, J. B.; Thomas, Gareth J.; Marshall, John; Robinson, Max; Eveson, J.W.; Paterson, Ian C.; Prime, Stephen S.

doi:10.1002/ijc.20111

Cited by 28 publications

(21 citation statements)

References 30 publications

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“…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]. Thus, signaling via the TβRII has been suggested to have tumor suppressive function in the tumorigenic process.…”

Section: Genetic Alteration In Preneoplastic Lesionsmentioning

confidence: 99%

“…Thus, signaling via the TβRII has been suggested to have tumor suppressive function in the tumorigenic process. Reduced expression and hence attenuation of TβRII signaling will result in increased resistance to TGF-β mediated growth suppression, increased cell proliferation, decreased differentiation and increased transformation capacity of the tumor cells [87,90,91].…”

Section: Genetic Alteration In Preneoplastic Lesionsmentioning

confidence: 99%

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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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Section: Genetic Alteration In Preneoplastic Lesionsmentioning

confidence: 99%

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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“…These observations highlight the complex nature of the functions of TGF-βRII in carcinogenesis, which could be stage and/or tissue specific. Although TGF-β 1 overexpression and loss of TGF-βRII have been observed in human HaCaT keratinocytes with oncogenic potential (17,18), whether these changes occur in primary SCCs in the skin has not been reported.…”

Section: Introductionmentioning

confidence: 99%

Distinct mechanisms of TGF- 1-mediated epithelial-to-mesenchymal transition and metastasis during skin carcinogenesis

Han¹

2005

Journal of Clinical Investigation

210

186

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In the present study, we demonstrated that human skin cancers frequently overexpress TGF-β 1 but exhibit decreased expression of the TGF-β type II receptor (TGF-βRII). To understand how this combination affects cancer prognosis, we generated a transgenic mouse model that allowed inducible expression of TGF-β 1 in keratinocytes expressing a dominant negative TGF-βRII (∆βRII) in the epidermis. Without ∆βRII expression, TGF-β 1 transgene induction in late-stage, chemically induced papillomas failed to inhibit tumor growth but increased metastasis and epithelial-to-mesenchymal transition (EMT), i.e., formation of spindle cell carcinomas. Interestingly, ∆βRII expression abrogated TGF-β 1 -mediated EMT and was accompanied by restoration of membrane-associated E-cadherin/catenin complex in TGF-β 1 /∆βRII compound tumors. Furthermore, expression of molecules thought to mediate TGF-β 1 -induced EMT was attenuated in TGF-β 1 /∆βRII-transgenic tumors. However, TGF-β 1 /∆βRII-transgenic tumors progressed to metastasis without losing expression of the membrane-associated E-cadherin/catenin complex and at a rate higher than those observed in nontransgenic, TGF-β 1 -transgenic, or ∆βRII-transgenic mice. Abrogation of Smad activation by ∆βRII correlated with the blockade of EMT. However, ∆βRII did not alter TGF-β 1 -mediated expression of RhoA/Rac and MAPK, which contributed to increased metastasis. Our study provides evidence that TGF-β 1 induces EMT and invasion via distinct mechanisms. TGF-β 1 -mediated EMT requires functional TGF-βRII, whereas TGF-β 1 -mediated tumor invasion cooperates with reduced TGF-βRII signaling in tumor epithelia.

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“…The effect of stable transfection of TGF-b RIIDN cDNA was also examined in a human oral carcinoma cell line that contained normal Ras and was growth-inhibited by TGF-b1. Treatment of cells with exogenous TGF-b1 resulted in a decrease in ligand-induced growth inhibition and loss of c-myc downregulation in test cells compared to controls (Huntley et al 2004). Cells containing TGF-b RIIDN grew faster in monolayer culture, expressed less keratin-10, and exhibited increased motility and invasion in vitro compared to control cell lines.…”

Section: Transforming Growth Factor-b Receptorsmentioning

confidence: 93%

Transforming Growth Factor-β in Lung Cancer, Carcinogenesis, and Metastasis

Jakowlew

2010

The Tumor Microenvironment

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Transforming growth factor-beta (TGF-b) is a multifunctional regulatory polypeptide that is the prototypical member of a large family of cytokines that controls many aspects of cellular function, including cellular proliferation, differentiation, migration, apoptosis, adhesion, angiogenesis, immune surveillance, and survival. Contrary to the initial concept that these proteins may be down-regulated in cancer cells to promote their growth, a marked increase in the expression of TGF-b has often been found in human cancers in vivo, including cancer of the lung. Moreover, in lung cancer, increased expression of TGF-b correlates with more advanced stages of malignancy and metastasis and with decreased survival. Increased expression of TGF-b is usually accompanied by a loss in the growth inhibitory response to TGF-b. Indeed, some lung cancer cells in culture demonstrate a progressive loss of the growth inhibitory response to TGF-b that varies directly with the malignant stage of the original tumor. The study of the molecular events associated with the escape of cancer cells from growth regulation by TGF-b has provided insight into mechanisms underlying carcinogenesis. Specific defects in TGF-b receptors, TGF-b-related signal transduction/gene activation, and TGF-b-regulated cell cycle proteins, have been implicated in the oncogenesis of human lung cancer and metastasis. This review provides background information on TGF-b and updates the status of our knowledge of the role of TGF-b in lung cancer, carcinogenesis, and metastasis.

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Attenuated type II TGF‐β receptor signalling in human malignant oral keratinocytes induces a less differentiated and more aggressive phenotype that is associated with metastatic dissemination

Cited by 28 publications

References 30 publications

Molecular mechanisms of head and neck cancer

Molecular mechanisms of head and neck cancer

Distinct mechanisms of TGF- 1-mediated epithelial-to-mesenchymal transition and metastasis during skin carcinogenesis

Transforming Growth Factor-β in Lung Cancer, Carcinogenesis, and Metastasis

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