Missense mutations of the transforming growth factor beta type II receptor in human head and neck squamous carcinoma cells (original) (raw)
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Transforming Growth Factor-β in Cancer Therapy, Volume II, 2008
The transforming growth factor-B (TGF-~) pathway is a critical regulator of cell growth and proliferation (J). The key players in this pathway include the heteromeric TGF-~transmembrane receptor complex that, following binding to TGF-~, phosphorylates and activates a family of intracellular signaling molecules known as the Smads. Several molecules, including c-Ski and SnoN, negatively regulate TGF-~signaling. Given the key role that transforming growth factor-f (TGF-~) plays in cell growth and survival, it is not unexpected that alterations in this pathway at different levels can result in a loss of regulated cell growth, facilitating the accumulation of further genetic insults, which can result in malignant transformation. It is thought that human head and neck squamous cell carcinoma (HNSCC) like other cancer models, results from multiple genetic insults as a multistep process. Alterations of the TGF-p athway, among others, have been identified in a large proportion of primary human HNSCC tumors. This chapter reviews the current understanding of known alterations in the TGF-~signaling pathway and their role in the pathogenesis of HNSCC. Further, a novel approach for developing genetically engineered mouse models of HNSCC is described and the current thinking about TGF-~as a therapeutic target in HNSCC is discussed.
Clinical Cancer Research, 1999
Transforming growth factor (TGF)- is a potent regulator of growth and differentiation in normal squamous epithelium. TGF- exerts its antiproliferative effect via the TGF- type II receptor (TR-II). A decrease in TR-II expression is believed to be responsible, in part, for the resistance of squamous cell carcinoma (SqCC) to the antiproliferative effects of TGF-. In the present study, we used immunohistochemistry and in situ hybridization to analyze the expression of TR-II along the successive oncogenic stages of head and neck squamous neoplasia, from normal epithelium to dysplasia to carcinoma. Quantitation of TR-II expression in 38 SqCCs was assessed on a visual scale ranging from negative (absence of staining) to 3؉ (strong staining). Normal squamous epithelium and squamous epithelium in the vicinity of the tumors showed homogenous receptor expression with moderate intensity. Dysplastic epithelium and carcinoma in situ showed a mild decrease in receptor expression intensity. Well-differentiated to moderately differentiated carcinomas showed heterogeneous expression of variable intensity, and poorly differentiated carcinomas were completely devoid of TR-II. In every tumor, the superficial component showed more intense receptor expression than the invasive component. These results indicate that TR-II expression inversely correlates with disease aggressiveness and suggest that aberrant TR-II expression is a contributing factor to the pathogenesis of SqCC.
1999
Transforming growth factor (TGF)b is a potent regulator of growth and differentiation in normal squamous epithelium. TGF-b exerts its antiproliferative effect via the TGF-b type II receptor (T bR-II). A decrease in TbR-II expression is believed to be responsible, in part, for the resistance of squamous cell carcinoma (SqCC) to the antiproliferative effects of TGF-b. In the present study, we used immunohistochemistry and in situ hybridization to analyze the expression of TbR-II along the successive oncogenic stages of head and neck squamous neoplasia, from normal epithelium to dysplasia to carcinoma. Quantitation of TbR-II expression in 38 SqCCs was assessed on a visual scale ranging from negative (absence of staining) to 3 1 (strong staining). Normal squamous epithelium and squamous epithelium in the vicinity of the tumors showed homogenous receptor expression with moderate intensity. Dysplastic epithelium and carcinoma in situ showed a mild decrease in receptor expression intensity...
Genes & Development, 2006
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- type II receptor (TGFRII) are common events in human HNSCC. Activation of either K-ras or H-ras in combination with TGFRII 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 TGF1 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 TGF1 on tumor stroma may provide a novel therapeutic strategy for HNSCC. [Keywords: HNSCC; head-and-neck-specific knockout; metastasis; Ras; TGFRII; TGF1] Supplemental material is available at http://www.genesdev.org. Corresponding author. E-MAIL wangxiao@ohsu.edu; FAX (503) 402-2817. Article and publication are at http://www.genesdev.org/cgi/
Downregulation of transforming growth factor β type II receptor in laryngeal carcinogenesis
Journal of Clinical Pathology
Background: Cervical carcinogenesis is a multistep process initiated by "high risk" human papillomaviruses (HR-HPV), most commonly HPV16. The infection per se is, however, not sufficient to induce malignant conversion. Transforming Growth Factor β (TGF-β) inhibits epithelial proliferation and altered expression of TGF-β or its receptors may be important in carcinogenesis. One cofactor candidate to initiate neoplasia in cervical cancer is the prolonged exposure to sex hormones. Interestingly, previous studies demonstrated that estrogens suppress TGF-β induced gene expression. To examine the expression of TGF-β2, TGF-βRII, p15 and c-myc we used in situ RT-PCR, real-time PCR and immunohistochemistry in transgenic mice expressing the oncogene E7 of HPV16 under control of the human Keratin-14 promoter (K14-E7 transgenic mice) and nontransgenic control mice treated for 6 months with slow release pellets of 17β-estradiol. Results: Estrogen-induced carcinogenesis was accompanied by an increase in the incidence and distribution of proliferating cells solely within the cervical and vaginal squamous epithelium of K14-E7 mice. TGF-β2 mRNA and protein levels increased in K14-E7 transgenic mice as compared with nontransgenic mice and further increased after hormone-treatment in both nontransgenic and transgenic mice. In contrast, TGF-βRII mRNA and protein levels were decreased in K14-E7 transgenic mice compared to nontransgenic mice and these levels were further decreased after hormone treatment in transgenic mice. We also observed that c-myc mRNA levels were high in K14-E7 mice irrespective of estrogen treatment and were increased in estrogen-treated nontransgenic mice. Finally we found that p15 mRNA levels were not increased in K14-E7 mice. Conclusion: These results suggest that the synergy between estrogen and E7 in inducing cervical cancer may in part reflect the ability of both factors to modulate TGF-β signal transduction. Background Cervical cancer (CC) is one of the most frequent cancers affecting women worldwide and is an important public health problem for adult women in developing countries [1].
Targeted deletion of the TGF-beta 1 gene causes rapid progression to squamous cell carcinoma
Genes & Development, 1994
To study the contribution of autocrine and paracrine TGF-pi to tumor progression in a well-defined system of multistage carcinogenesis, keratinocytes with a targeted deletion of the TGF-pi gene were initiated in vitro with the v-ras"^^ oncogene and their in vivo tumorigenic properties were determined by skin grafting initiated cells onto athymic mice in combination with either wild-type or null dermal fibroblasts. Grafts of v-ras""-initiated null keratinocytes progressed rapidly to multifocal squamous cell carcinomas within dysplastic papillomas irrespective of the fibroblast genotype, whereas the initiated control genotypes formed well-differentiated papillomas. Malignant progression was not associated with mutations in the c-ras^' gene, alterations in p53 protein, or loss of responsiveness to TGF-pi. The tumor cell labeling index was elevated in grafts of initiated null keratinocytes with wild-type fibroblasts compared to tumors of other genotypes. However, labeling index in all tumors was reduced when TGF-pi null fibroblasts formed the stroma. The null tumor cells could not accumulate TGF-pi from the host, but grafts of uninitiated null keratinocytes, which formed a normal epidermis, became TGF-pl positive even though they did not express TGF-pi mRNA. These results demonstrate that autocrine TGF-pl suppresses the frequency and rate of malignant progression, and that autocrine and paracrine TGF-pi can have opposing effects on tumor cell proliferation. The lack of paracrine inhibition of tumor cell progression appears to result from the inability of tumor cells to localize host-derived TGF-pi by a mechanism that operates in normal cells.
1999
Transforming growth factor (TGF)b is a potent regulator of growth and differentiation in normal squamous epithelium. TGF-b exerts its antiproliferative effect via the TGF-b type II receptor (T bR-II). A decrease in TbR-II expression is believed to be responsible, in part, for the resistance of squamous cell carcinoma (SqCC) to the antiproliferative effects of TGF-b. In the present study, we used immunohistochemistry and in situ hybridization to analyze the expression of TbR-II along the successive oncogenic stages of head and neck squamous neoplasia, from normal epithelium to dysplasia to carcinoma. Quantitation of TbR-II expression in 38 SqCCs was assessed on a visual scale ranging from negative (absence of staining) to 3 1 (strong staining). Normal squamous epithelium and squamous epithelium in the vicinity of the tumors showed homogenous receptor expression with moderate intensity. Dysplastic epithelium and carcinoma in situ showed a mild decrease in receptor expression intensity...