Expression of Transforming Growth Factor β Type II Receptors in Head and Neck Squamous Cell Carcinoma (original) (raw)
Related papers
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...
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...
Journal of Oral Pathology and Medicine, 2003
Background: Transforming growth factor b1 (TGFb1) is a negative growth regulator in keratinocytes, and in vitro studies lead to the concept that loss of TGFb1 responsiveness is a critical step in epithelial carcinogenesis. Objective: To investigate the prognostic relevance of TGFb1 expression in head and neck squamous cell carcinoma (HNSCC). Materials and methods: TGFb1 distribution was determined by immunohistochemistry in oral cavity/oropharynx (n ¼ 79), larynx (n ¼ 36) and hypopharynx (n ¼ 25) tumors and in matched normal adjacent mucosa. TGFb-type I and II receptors were determined in 20 cases of differentiated oral cavity/hypopharynx tumors. Cases were considered positive if displaying reactivity in >10% of the cells. Results: TGFb1-positive expression was found in 47.2% of larynx, 36.7% of oral cavity/oropharynx and in 24% of the hypopharynx tumors. Reactivity in >60% of the cells was displayed only by 11.4% of HNSCC. All normal controls were positive. TGFb1positive expression did not correlate with clinico pathological parameters. An association with differentiation was verified only in oral cavity/oropharynx tumors (P 0.001). TGFb1 was also not related to 5 years survival (Kaplan-Meier). Strong and diffuse expression of TGFb-RII was identified in 19/20 cases regardless of TGFb1 immunoreactivity. Out of 17 TGFb1-positive oral cavity/ oropharynx tumors, only nine expressed TGFb-RI suggesting a disruption of the TGFb1 pathway. We conclude that TGFb1 protein immunostaining is not a useful biomarker in assessment of prognosis in HNSCC. Squamous cell carcinomas are the most frequent head and neck neoplasms and the sixth most frequent cancer in the world (1). In Brazil, the disease represents 15.7% of all human primary cancer in men (2). Clinical and pathological parameters are still inadequate for prognostic characterization since patients with equivalent tumor site, TNM stage and pathological variables (differentiation, thickness, vascular embolization, or perineural infiltration) may differ widely in the course of the disease and survival. Thus, the identification of other factors related to the à P-value obtained from chi-square test with significance of 95%. à By Fisher's exact test.
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.
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/
The Egyptian Journal of Hospital Medicine
Objective: The present study aimed to investigate the pattern of expression of transforming growth factor & (TGF-&) and epidermal growth factor receptor (EGFR) in oral squamous cell carcinoma (OSCC) and to correlate their expression with tumor grading. Methods: ' (') *! +#,,))) Results:For both markers, positive staining reaction was characterized by cytoplasmic or cytoplasmic and membranous staining. EGFR was expre-' ./-& ' 0 1!-2)) ' particularly strong at the margin of invading cords and nests of tumour cells and poorly differentiated malignant cells. The expression of both markers was significantly correlated with histological grading; while the staining intensity showed no correlation with tumor grading. Conclusion: This study showed that OSCC express both EGFR and TGF-& and their expression indicated that these markers may have a potential diagnostic value in histologic examination. In addition their increased expression in high tumour grades suggest that they may be used as indicators of tumor aggressiveness.
Cancer research, 2004
In the present study, we show that transforming growth factor beta1 (TGF-beta1) was frequently overexpressed in human head and neck squamous cell carcinomas (HNSCCs) and adjacent tissues in comparison with normal head and neck tissues. To determine the role of TGF-beta1 overexpression in HNSCC carcinogenesis, we generated transgenic mice in which TGF-beta1 transgene expression can be induced in head and neck epithelia. TGF-beta1 transgene induction in head and neck epithelia, at levels similar to those in human HNSCCs, caused severe inflammation and angiogenesis. Consequently, TGF-beta1-transgenic epithelia exhibited hyperproliferation. These phenotypes correlated with enhanced Smad signaling in transgenic epithelia and stroma. Our study suggests that TGF-beta1 overexpression at early stages of HNSCC formation provides a tumor promoting microenvironment.
Head & Neck, 1991
Epidermal growth factor (EGF) stimulates the growth of several types of epithelial tissues and possesses a strong mitogenic activity that is mediated through its cell surface receptor (EGFR). The aim of this study was to characterize EGFR and measure its levels in head and neck tumors biopsies (70 patients); use of a simplified competition technique with a radiolabeled ligand allowed evaluation of functional EGFR. Five samples (4 tumors and 1 control) were used to characterize EGF binding. Graphic representation identified a single family of binding sites. Kd values revealed high affinity for EGF binding: mean Kd, 0.156 f 0.1 08 nM (0.095-0.347 nM). EGF-binding characteristics (Kd) tion was found between EGFR levels and tumor size and stage. Controls exhibited a trend toward higher EGFR levels in elevated sizes and stages. According to a cutoff EGFR value of 100 frnol/rng protein, which separated all controls from tumors, EGFR-positive tumors (>lo0 fmol/mg protein) had a greater probability of complete response to chemotherapy than EGFRnegative tumors; other tumor characteristics, such as the degree of tumoral differentiation, tumor size, or stage, were unable to operate such a discrimination in the response to chemotherapy. EGFR may thus be an interesting biological marker for head and neck cancer. HEAD & NECK 1991;13:132-139 were similar in nontumoral tissue samples (controls) and in tumor material. In 59 of 60 cases, EGFR levels were higher in the tumor than in the corresponding controls. A significant correla-Epidermal growth factor (EGF) is a growth factor polypeptide with a molecular weight of 6,000 daltons, which was described by Cohen' in the mouse submaxillary gland. EGF stimulates the growth of several types of epithelial tissues and diated through its surface receptor (EGFR)* The intracellular component of EGFR is very similar to the V-erb p oncogene product2 In human cancer, the presence of EGFR has been reported in the b r e a~t ,~*~ lung: bladder,6 brain,7 ovaries,' thyroid,' and aerodigestive tract.lO." In these localizations, EGFR has been measured directly, by ligand-binding methods, or indirectly,
2004
In the present study, we show that transforming growth factor 1 (TGF-1) was frequently overexpressed in human head and neck squamous cell carcinomas (HNSCCs) and adjacent tissues in comparison with normal head and neck tissues. To determine the role of TGF-1 overexpression in HNSCC carcinogenesis, we generated transgenic mice in which TGF-1 transgene expression can be induced in head and neck epithelia. TGF-1 transgene induction in head and neck epithelia, at levels similar to those in human HNSCCs, caused severe inflammation and angiogenesis. Consequently, TGF-1-transgenic epithelia exhibited hyperproliferation. These phenotypes correlated with enhanced Smad signaling in transgenic epithelia and stroma. Our study suggests that TGF-1 overexpression at early stages of HNSCC formation provides a tumor promoting microenvironment.