Overexpression of E2F-1 is associated with increased disease-free survival in squamous cell carcinoma of the anterior tongue.
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PURPOSE: Overexpression of E2F-1 is associated with increased invasiveness in head and neck squamous cell carcinoma cell lines in vitro, but its significance in vivo is unknown. This study sought to determine the relationship between E2F-1 and retinoblastoma protein (pRb) expression and disease outcome in squamous cell carcinoma (SCC) of the anterior tongue. EXPERIMENTAL DESIGN: pRb and E2F-1 protein expression was assessed by immunohistochemistry in a cohort of 145 patients with SCC of the anterior tongue. The outcomes examined were time to disease recurrence or death. The relationships between E2F-1 or pRb expression and outcome were assessed by univariate and multivariate Cox's proportional hazards model, with or without clinicopathological covariates, including nodal status, disease stage, treatment status, and molecular markers (cyclin D1, p16(INK4A), and Ki-67) previously measured in this cohort. RESULTS: On univariate analysis, increased expression of E2F-1 (>35% of positive-stained nuclei) was associated with increased disease-free survival (DFS; hazard ratio [HR]: 0.35; P = 0.04) and increased overall survival (OS; HR: 0.33; P = 0.06). Decreased expression of pRb (<50% positive nuclei) was associated with increased DFS (HR: 1.81; P = 0.06) but not with OS (P = 0.11). However, when considered simultaneously with other significant factors, i.e. lymph node status, p16(INK4A) protein expression, and histopathological grade, in the multivariate Cox's proportional hazards model, the additional contributions of E2F-1 and/or pRb expression to DFS and OS were not statistically significant. CONCLUSIONS: These data demonstrate that in patients with SCC of the tongue, overexpression of E2F-1 is associated with increased DFS and OS. However, this association is not independent of lymph node status, tumor grade, and p16(INK4A) expression. Among the cell cycle-regulatory molecules studied, p16(INK4A) expression is the most predictive molecular marker of disease outcome. (+info)
p53 haploinsufficiency profoundly accelerates the onset of tongue tumors in mice lacking the xeroderma pigmentosum group A gene.
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Mice lacking the xeroderma pigmentosum group A gene (XPA-/- mice), which have a complete deficiency in nucleotide excision repair (NER), are highly predisposed to tongue squamous cell carcinoma (SCC) when exposed to 4-nitroquinoline 1-oxide (4NQO). To explore the effects of the interaction of the NER machinery with p53 in oral tumorigenesis, we generated an XPA-/- mouse strain carrying mutant alleles for p53. This mouse model of 4NQO carcinogenesis demonstrated that despite the same tumor frequency, XPA-/-p53+/- mice reached 100% SCC incidence at 25 weeks compared with 50 weeks for XPA-/-p53+/+ littermates. XPA-/-p53-/- mice succumbed to spontaneous thymic lymphomas before the development of tongue tumors (before 13 weeks of age). SCC originated in XPA-/-p53+/- mice maintained the p53+/- genotype and the retained wild-type p53 allele appeared to be structurally intact. Only one of 20 XPA-/-p53+/+ SCC showed a missense mutation of p53. Collectively, the accelerated tongue tumor growth may be a consequence of haploinsufficiency but not of mutation of p53 in the context of NER deficiency. (+info)
Oral cancer in Scotland: changing incidence and mortality.
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OBJECTIVES: To determine the incidence of oral cancer in Scotland between 1960 and 1989 and oral cancer mortality from 1911 to 1989. SETTING: Data were obtained on oral cancer incidence from the information and statistics division of the Common Services Agency of the Scottish Health Service and mortality data from the office of the registrar general for Scotland. RESULTS: Mortality from intraoral cancers in Scotland substantially declined throughout this century until the mid-1970s. This trend, however, was then reversed, and fourfold increases in incidence were observed in younger age groups after 1960. Death rates in these younger age groups increased to levels previously recorded in the 1940s. These increases seemed to be cohort based and may therefore continue into the future. CONCLUSIONS: Reasons for increasing rates among younger age groups are speculative and rely on combining knowledge about risk factors and available ecological data. Though increases in incidence at younger ages do not result in a large change in the number of cases diagnosed, possible similar increases continuing into older ages, when oral cancer is more common, will correspond to a much larger increase in the actual number of cases. Given that such a large attributable risk is associated with tobacco and alcohol, however, these increases may be preventable. (+info)
In vitro interaction between ecteinascidin 743 (ET-743) and radiation, in relation to its cell cycle effects.
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Ecteinascidin 743 (ET-743) is a new marine-derived agent with promising activity against a number of solid tumours. In four human tumour cell lines, the interaction between ET-743 and radiation was investigated in relation to the effects of ET-743 on the cell cycle, in vitro. Cell survival was measured based on quantitative staining of cellular protein by sulforhodamine B. A 24 h treatment with ET-743 before radiation resulted in a moderate increase in radiosensitivity in three out of four cell lines. Dose enhancement factors > or =1.8 were observed for concentrations resulting in 52, 46 and 30% cell kill in ECV304, H292 and CAL-27, respectively, whereas in A549 no radiosensitisation was observed (no significant increase in radiosensitivity). According to the combination index analysis, synergism was observed only in ECV304 and CAL-27 cells. A 24 h incubation with ET-743 resulted in a concentration-dependent G2/M block, which might explain the moderate radiosensitising effects in ECV304 and H292. The lack of radiosensitisation in A549 might be due to the S phase delay preceding the G2/M block at the moment of radiation, which only occurred in this cell line. In conclusion, ET-743 has moderate cell line-dependent radiosensitising properties; however, only when cytotoxic concentrations of ET-743 are used. In one of the four cell lines tested, no radiosensitisation was observed. (+info)
Dietary protocatechuic acid during the progression phase exerts chemopreventive effects on chemically induced rat tongue carcinogenesis.
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The modifying effects of dietary administration of protocatechuic acid (PCA) during the progression phase of tongue carcinogenesis initiated with 4-nitroquinoline 1-oxide (4-NQO) were investigated in male F344 rats. For tumor progression we developed a new animal model, where rats initiated by 4-week treatment of 20 ppm 4-NQO in drinking water, received four cycles of 20 ppm 4-NQO to induce advanced tongue cancer (one cycle: 2 weeks of 4-NQO followed by 2 weeks of tap water), starting at 14 weeks after the initiation. In this model, metastasis of tongue cancer occurred in lungs. Starting two weeks before the cycle treatment with 4-NQO, animals were fed the 2000 ppm PCA containing diet and continued on this diet until the end of the study. At the termination of the experiment (week 32), the incidences of tongue neoplasms and preneoplastic lesions, polyamine levels in the tongue tissue, and cell proliferation activity estimated by morphometric analysis of silver-stained nucleolar organizer regions protein were compared among the groups. Feeding with PCA containing diet during the progression phase significantly decreased the occurrence of advanced tongue squamous cell carcinoma with metastasis (P<0.05) and preneoplasia (hyperplasia and dysplasia) (P<0.001). In addition, PCA exposure decreased polyamine levels in the tongue tissue (P<0.001) during progression phase. Our results suggest that dietary PCA inhibits progression of 4-NQO-induced oral carcinogenesis, and such inhibition might be related to suppression of cell proliferation by PCA. (+info)
Predictive markers for late cervical metastasis in stage I and II invasive squamous cell carcinoma of the oral tongue.
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PURPOSE: Patients with oral tongue carcinoma treated by intraoral excision only should be followed up carefully for cervical lymph node metastasis and salvaged immediately if found, because some patients have a more aggressive clinical course. The purpose of this study was to find useful markers for predicting late cervical metastasis in patients with stage I and II invasive squamous cell carcinoma of the oral tongue. EXPERIMENTAL DESIGN: We investigated clinicopathologic factors and immunohistochemical biomarkers predicting late cervical metastasis in surgical specimens from 56 patients with T(1-2)N(0)M(0) invasive squamous cell carcinoma of the oral tongue who did not undergo elective neck dissection. Histopathologic factors including tumor thickness, mode of invasion, Broders grade, total score of three different malignancy grading systems, eight other clinicopathologic parameters, and immunohistochemical expression of p53, cyclin D1, Ki-67, epidermal growth factor receptor, microvessel density, cyclooxygenase-2, MUC1, laminin-5 gamma2, E-cadherin, and beta-catenin were examined. All of the clinicopathologic factors and immunohistochemical expression of biomarkers were compared in terms of survival. RESULTS: In the univariate analysis, tumor thickness (P = 0.009), Broders grade (P = 0.017), nest shape (P = 0.005), mode of invasion (P < 0.001), Anneroth score (P = 0.029), Bryne score (P < 0.001), and E-cadherin expression (P = 0.003) were correlated with late cervical metastasis. Multivariate analysis on late cervical metastasis revealed that tumor thickness >4 mm, mode of invasion grade 3 or 4, and E-cadherin expression were independent factors. Late cervical metastasis was the only prognostic factor for overall survival (P = 0.002). CONCLUSIONS: Our results indicate that patients with stage I and II invasive squamous cell carcinoma of the oral tongue with tumor thickness >4 mm, mode of invasion grade 3 or 4, and low expression of E-cadherin should be considered a high-risk group for late cervical metastasis when a wait-and-see policy for the neck is adopted. (+info)
Oral cavity and esophageal carcinogenesis modeled in carcinogen-treated mice.
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PURPOSE: Squamous cell carcinoma of the oral cavity is one of the most common human neoplasms, and prevention of these carcinomas requires a better understanding of the carcinogenesis process and a model system in which cancer chemoprevention agents can be tested. We have developed a mouse model using the carcinogen 4-nitroquinoline 1-oxide (4-NQO) in the drinking water to induce tumorigenesis in the mouse oral cavity. EXPERIMENTAL DESIGN: 4-NQO was delivered by tongue painting or drinking water to two mouse strains, CBA and C57Bl/6. The incidences of oral cavity carcinogenesis were then compared. In addition, we examined the expression of some of the molecular markers associated with the process of human oral cavity and esophageal carcinogenesis, such as keratin (K) 1, K14, p16, and epidermal growth factor receptor, by immunohistochemistry. RESULTS: After treatment with 4-NQO in the drinking water, massive tumors were observed on the tongues of both CBA and C57Bl/6 female mice. Pathological analyses indicated that flat squamous dysplasias, exophytic papillary squamous tumors (papillomas), and invasive squamous cell carcinomas were present. Immunohistochemistry analyses showed that 4-NQO changed the expression patterns of the intermediate filament proteins K14 and K1. K14 was expressed in the epithelial suprabasal layers, in addition to the basal layer, in tongues from carcinogen-treated animals. In contrast, control animals expressed K14 only in the basal layer. Moreover, we observed more bromodeoxyuridine staining in the tongue epithelia of 4-NQO-treated mice. Reduced expression of the cell cycle inhibitor, p16, was observed, whereas 4-NQO treatment caused an increase in epidermal growth factor receptor expression in the mouse tongues. Interestingly, similar features of carcinogenesis, including multiple, large (up to 0.5 cm) exophytic papillary squamous tumors and invasive squamous cell carcinomas, increased bromodeoxyuridine staining, and increased K14 expression, were also observed in the esophagi of 4-NQO-treated mice. However, no tumors were observed in the remainder of digestive tract (including the forestomach, intestine, and colon) or in the lungs or livers of 4-NQO-treated mice. These results indicate that this murine 4-NQO-induced oral and esophageal carcinogenesis model simulates many aspects of human oral cavity and esophageal carcinogenesis. CONCLUSIONS: The availability of this mouse model should permit analysis of oral cavity and esophageal cancer development in various mutant and transgenic mouse strains. This model will also allow testing of cancer chemopreventive drugs in various transgenic mouse strains. (+info)
Multifocal rhabdomyosarcomas within the tongue and oral cavity of a dog.
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A 10-year-old terrier crossbreed presented with a change in bark intonation of 3-4 month's duration and pronounced panting. Four variably sized masses were observed within the oral cavity. The largest mass was located within the parenchyma at the caudal region of the tongue. Others were located on the left arytenoid, within the soft palate, and in the oropharynx above the soft palate. Histopathologic specimens consisted of large round to polygonal cells occasionally containing multiple nuclei and rare faint cytoplasmic cross striations. Staining was weakly positive with periodic acid-Schiff. Immunocytochemistry was strongly diffusely positive for muscle-specific actin, myoglobin, and desmin and scattered positive for S-100 and vimentin. Phosphotungstic acid-hematoxylin staining enhanced cytoplasmic cross striations. The cytoplasm of all neoplastic cells was filled with mitochondria on electron microscopy. The final diagnosis was multifocal/metastatic rhabdomyosarcoma. (+info)