endothelin-1 and Carcinoma--Squamous-Cell

Cancer pain is an ever-present public health concern. With innovations in treatment, cancer patients are surviving longer, but uncontrollable pain creates a poor quality of life for these patients. Oral cancer is unique in that it causes intense pain at the primary site and significantly impairs speech, swallowing, and masticatory functions. We propose that oral cancer pain has underlying biologic mechanisms that are generated within the cancer microenvironment. A comprehensive understanding of key mediators that control cross-talk between the cancer and peripheral nervous system, and possible interventions, underlies effective cancer pain management. The purpose of this review is to explore the current studies on oral cancer pain and their implications in clinical management for cancer pain in general. Furthermore, we will explore the endogenous opioid systems and novel cancer pain therapeutics that target these systems, which could solve the issue of opiate tolerance and improve quality of life in oral cancer patients.

Topics: Analgesics, Opioid; Animals; Carcinoma, Squamous Cell; Drug Tolerance; Endothelin-1; Facial Pain; Humans; Mouth Neoplasms; Nerve Growth Factor; Nociceptors; Opioid Peptides; Pain Management; Pain, Intractable; Palliative Care; Quality of Life; Receptors, Proteinase-Activated

Mineral metabolism is dysregulated within days of acute renal injury in critically ill patients. On univariate analysis, high levels of calcitriol were associated with adverse clinical outcome in AKI. This association was not apparent after adjusting for age and APACHE II. Large controlled studies are needed to confirm these results, and determine if higher 1,25(OH). Los genotipos C/C y C/T en Colombia son tan variables como en otros grupos sanos en otras poblaciones. Los sujetos de nuestra población podrían tener riesgo para el desarrollo de enfermedades asociadas al polimorfismo del genMTHFR y con genotipos de riesgo de presentar toxicidad y efectos adversos del MTX, lo cual sugiere la necesidad de evaluar alternativas terapéuticas con estudios farmacogenéticos.

Topics: Acetaminophen; Administration, Oral; Adolescent; Adult; Advanced Oxidation Protein Products; Aged; Aged, 80 and over; Analgesics, Opioid; Animals; Antibodies, Monoclonal; Antioxidants; ATP Binding Cassette Transporter, Subfamily B, Member 1; Automation; Benzaldehydes; Bromates; Calcifediol; Calcitriol; Carcinoma, Squamous Cell; Catalase; Chromatography, Liquid; Coloring Agents; Cross-Over Studies; Cross-Sectional Studies; Cytochrome P-450 CYP3A; Cytokines; Diabetic Foot; Diabetic Neuropathies; Diagnostic Self Evaluation; Diosmin; DNA Damage; Double-Blind Method; Drug Combinations; Electrodes; Endothelin-1; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagectomy; Exercise; Female; Follow-Up Studies; Gene Expression Regulation; Glutathione; Hesperidin; Humans; Illicit Drugs; Indians, North American; Injections, Intravenous; Interferometry; Interleukin-1beta; Interleukin-6; Interviews as Topic; Ions; Jejunum; Kidney; Leukocyte Count; Lipid Peroxidation; Lithium; Liver; Luminescent Measurements; Male; Mice; Middle Aged; Monocytes; Nanostructures; Oklahoma; Organ Specificity; Oxidative Stress; Oxycodone; Photochemistry; Predictive Value of Tests; Pregnane X Receptor; Preoperative Period; Prescription Drugs; Receptors, Steroid; Reference Values; Reproducibility of Results; Retinoid X Receptor alpha; Retrospective Studies; RNA, Messenger; Rumen; Sheep, Domestic; Shoes; Solar Energy; Superoxide Dismutase; Survival Rate; Tandem Mass Spectrometry; Titanium; Treatment Outcome; Tumor Necrosis Factor-alpha; Varicose Veins; Vitamin D; Water Pollutants, Chemical; Weight-Bearing; Young Adult

Oral cancer is one of the highly prevalent cancers worldwide being. According to data of GLOBOCAN 2018, the estimated incidence, mortality and 5-year survival rates due to lip, oral cavity and salivary gland cancer in world is (2.0%), (0.5%) and (0.3%) respectively. (Bray, Ferlay and Soerjomataram, 2018). Endothelin-1 (ET-1) is a 21-amino acid peptide; its receptors have been implicated in the growth and progression of both primary and metastatic neoplasms throughout the human body. Studies have shown that ET-1 is expressed in tissue, serum and other body fluids.. To estimate the levels of salivary endothelin-1 in Oral potentially malignant disorders (oral leukoplakia and submucous fibrosis) and oral squamous cell carcinoma.. The study population included 60 subjects and were divided into 4 groups. All patients included in the study are clinically and histopathological diagnosed cases of oral leukoplakia, submucous fibrosis and oral cancer and assessed for salivary ET-1 levels using human ELISA kit. Significant differences between the groups were determined using one-way analysis of variance, LSD and Post HOC, unpaired t test, biserial and spearson's correlation.. The mean levels of salivary Endothelin-1 level in study groups were: 82.78 ± 5.9 pg/mL (OSCC), 65.02 ± 1.8 pg/mL (SMF), 57.76 ± 4.1 pg/mL (LEUKOPLAKIA), 29.72 ± 14.1 pg/mL (CONTROLS). The mean Salivary ET-1 levels among these four groups was compared and the difference was statistically significant (P < 0.001). We also found a significant difference in the means of ET-1 levels among the clinical and histopathological staging of the study groups.. Our results demonstrate potential utility of salivary analysis for ET-1 levels to monitor patients at risk for OSCC. Although provides the basis for a larger prospective study to determine the critical levels of salivary ET-1 necessary to diagnose and monitor OPMD's and its potential to undergo malignant transformation.

Topics: Biomarkers, Tumor; Carcinoma, Squamous Cell; Endothelin-1; Humans; Mouth Neoplasms; Oral Submucous Fibrosis; Prospective Studies

Patients with early stage tongue cancer do not frequently complain of tongue pain. Endothelin-1 signaling is upregulated in the cancerous tongue at the early stage. We tested the hypothesis that endothelin-1 signaling contributes to the modulation of tongue nociception.. Squamous cell carcinoma cells were inoculated into the tongue under general anesthesia. Lingual mechanical sensitivity under light anesthesia using forceps from days 1 to 21 (n = 8) and the amounts of endothelin-1 and β-endorphin in the tongue on days 6, 14, and 21 (n = 5 to 7) were examined after the inoculation. The effect of endothelin-A or µ-opioid receptor antagonism on the mechanical sensitivity was examined (n = 5 to 7).. Lingual mechanical sensitivity did not change at the early stage (days 5 to 6) but increased at the late stage (days 13 to 14). The amount of endothelin-1 increased (25.4 ± 4.8 pg/ml vs. 15.0 ± 5.2 pg/ml; P = 0.008), and endothelin-A receptor antagonism in the tongue induced mechanical hypersensitivity at the early stage (51 ± 9 g vs. 81 ± 6 g; P = 0.0001). The µ-opioid receptor antagonism enhanced mechanical hypersensitivity (39 ± 7 g vs. 81 ± 6 g; P < 0.0001), and the amount of β-endorphin increased at the early stage.. β-Endorphin released from the cancer cells via endothelin-1 signaling is involved in analgesic action in mechanical hypersensitivity at the early stage.

Topics: Animals; Carcinoma, Squamous Cell; Endothelin-1; Male; Narcotic Antagonists; Neoplasm Staging; Nociception; Rats; Rats, Inbred F344; Receptors, Opioid, mu; Signal Transduction; Tongue Neoplasms

Cervical cancer has an increasing incidence in developing countries with a predominance of squamous cell carcinoma. In this work, we aimed to analyze the role of EZH2, Endothelin-1, and CD34 as indicators of the aggressiveness in cervical squamous cell carcinoma.. Immunohistochemical expression of EZH2, Endothelin-1, and CD34 was studied in 54 paraffin-embedded tissue specimens of cervical squamous cell carcinoma. Their correlation to the clinicopathologic features and the potential angiogenic role were analyzed.. High EZH2 expression was noted in 78% of cervical squamous cell carcinoma with a significant relation with tumor grade, FIGO stage and lymph node metastasis (p= < 0.001, p=0.007, p=0.03 respectively). Endothelin-1 overexpression was detected in 63% of the studied cases with a significant association with tumor size, FIGO stage and lymph node metastasis (p=0.009, p=0.002, p=0.02 respectively). High CD34 expression (MVD) was noted in 56% of the cases and associated with the tumor size, FIGO stage and lymph node metastasis (p < 0.001, p < 0.001, p=0.04 respectively). The three markers were significantly associated (p < 0.05).. EZH2, ET-1, and CD34 may act as biomarkers of aggressive cervical squamous cell carcinoma. They may contribute to the signaling pathway of angiogenesis. Therefore, they could potentially be used in targeted therapy.

Topics: Adult; Aged; Antigens, CD34; Biomarkers, Tumor; Carcinoma, Squamous Cell; Endothelin-1; Enhancer of Zeste Homolog 2 Protein; Female; Humans; Immunohistochemistry; Middle Aged; Neovascularization, Pathologic; Retrospective Studies; Uterine Cervical Neoplasms

This study aimed to investigate the level of salivary endothelin-1 in premalignant and malignant lesions.. In this study, 75 cases were investigated of which 25 cases were healthy, 25 cases had oral lichen planus (OLP), and 25 cases had oral squamous cell carcinoma (OSCC). In order to collect the saliva samples, the unstimulated spitting was used. The samples were collected between 9 and 12 a.m. They were sent to the lab shortly after being collected and salivary endothelin-1 was recorded for each sample according to the instruction of factory by using enzyme-linked immunosorbent assay and optical density at a wavelength of 450 nm. SPSS version 20 and one-way ANOVA and LSD tests were used to analyze the data.. The mean of salivary endothelin-1 level in patients with OSCC was 163.98 pg/ml, in patients with OLP was 160.9 pg/ml, and in healthy people was 137.19 pg/ml. The analysis of one-way ANOVA suggested that the level of salivary endothelin-1 in both groups was the same and significantly higher than that in control group (p < 0.05).. The level of salivary endothelin-1 in patients with SCC and OLP was higher than that in healthy group. Thus, it can be used as the latest therapeutic protocol for oral premalignant and malignant lesions.

Topics: Adult; Biomarkers, Tumor; Carcinoma, Squamous Cell; Case-Control Studies; Cross-Sectional Studies; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Mouth Neoplasms; Precancerous Conditions; Saliva

Endothelin-1 is an autocrine growth factor for keratinocytes, an effect controlled by its A and B receptors, with no previous comparison of endothelin axis expression in inflammatory and neoplastic skin diseases showing keratinocyte proliferation. The aim of the study was to investigate endothelin-1 axis expression in skin lesions of psoriasis, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC).. This study included 40 subjects (8 patients with SCC, 12 patients with BCC, 10 patients with psoriasis, and 10 healthy controls). Biopsies from lesional skin of patients and normal skin of controls were examined immunohistochemically for endothelin-1 and its receptors A and B frequency and grade of expression.. Endothelin-1 and receptor A were detected in all patients with SCC and psoriasis, with a higher frequency and grade of expression than controls and BCC. The frequency of receptor B expression was significantly lower while higher staining grade was found in BCC (8.3%) rather than other studied groups.. A comparable higher frequency and grade of expression of endothelin-1 and its receptor A are documented in psoriasis and SCC than in BCC and controls denoting their involvement in keratinocyte proliferation in both diseases. Receptor A is the predominately expressed receptor in psoriasis and SCC.

Topics: Adolescent; Adult; Aged; Biopsy; Carcinoma, Squamous Cell; Endothelin-1; Female; Gene Expression Regulation, Neoplastic; Humans; Immunoenzyme Techniques; Keratinocytes; Male; Middle Aged; Neoplasm Grading; Neoplasm Proteins; Neoplasms, Basal Cell; Psoriasis; Receptor, Endothelin A; Receptor, Endothelin B; Sampling Studies; Skin Neoplasms; Young Adult

Detection of abnormally elevated levels of molecules in patients with oral cancer may be useful in early diagnosis. These markers can be included in current Histopathology grading and in TNM staging systems of Oral Squamous Cell Carcinoma (OSCC) to make it more efficient. Several pro-angiogenic molecules have been assessed for the same reason. Endothelin-1 (ET-1) is a vasoactive peptide associated with the development and spread of many solid tumors, including Squamous Cell Carcinoma (SCC), but its utility in OSCC has not been confirmed.. This study aims to evaluate the role of the serum big ET-1 as a biomarker of OSCC, by correlating it with the clinical staging and the histopathological grading.. Serum levels of big ET-1 measured by the sandwich Enzyme-Linked Immunosorbent Assay (ELISA) in 40 OSCC cases were compared with the levels from the control group using independent t-test. Clinical stages and histopathological grades of OSCC cases were compared in relation to their mean levels of serum big ET-1, one using the Analysis of Variance (ANOVA) test and the other the independent t-test, respectively. The significance of the mean difference between the groups was evaluated by Tukey's multiple comparison test. All statistical analyses were performed on GraphPad statistical software version 5.0.. By comparing the mean of the big ET-1 concentrations of cases and controls, the independent t-test revealed significant higher big ET-1 concentration of OSCC cases when compared to controls (p<0.0001). Tukey's multiple comparison test also revealed statistically significant difference among all OSCC stages in relation to the mean levels of serum big ET-1. However, the mean of the big ET-1 concentrations of cases of grade I and of grade II did not differ statistically (p=0.729).. Serum big ET-1 levels may be useful as a diagnostic tool in OSCC and as an adjunct to OSCC staging. However, its use as a prognostic marker warrants larger prospective studies.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Biomarkers, Tumor; Carcinoma, Squamous Cell; Case-Control Studies; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Mouth Neoplasms; Neoplasm Grading; Neoplasm Staging; Reference Values; Young Adult

The invasion and migration of cancer cells is increasingly recognised to be influenced by factors derived from adjacent tumour-associated stroma. The contextual signals regulating stromal-tumour interactions, however, remain poorly understood. Here, we identify a role for endothelin-1 (ET-1), a mitogenic peptide elevated in a number of malignancies, in promoting pro-metastatic cross-talk between head and neck cancer cells and adjacent fibroblasts. We demonstrate that treatment of oral fibroblasts with ET-1 activates ADAM17-mediated release of epidermal growth factor receptor (EGFR) ligands, triggering EGFR signalling and increased motility in neighbouring head and neck cancer cells. ET-1-mediated paracrine transactivation of EGFR also increased cyclo-oxygenase-2 levels in the cancer cells, providing a molecular insight into the mechanisms by which the elevated levels of ET-1 observed in head and neck cancers may contribute to disease progression.

Topics: ADAM Proteins; ADAM17 Protein; Blotting, Western; Carcinoma, Squamous Cell; Cell Communication; Cell Movement; Cells, Cultured; Cyclooxygenase 2; Endothelin-1; Epithelial Cells; ErbB Receptors; Female; Fibroblasts; Head and Neck Neoplasms; Humans; Mouth; Paracrine Communication; Real-Time Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Stromal Cells

The aims of this study were to examine the role of endothelin-1 (ET-1), a pleiotropic peptide found at elevated levels in a number of malignancies and which has been shown to influence oral cancer cell behaviour via paracrine signalling pathways, on the phenotype of oral fibroblasts.. The effect of ET-1 on proliferation and migration of human primary oral fibroblasts was assessed using MTS and scratch assays, respectively. The ability of ET-1 to affect fibroblast contractility was analysed using type-I collagen gels. Changes in gene expression in oral fibroblasts exposed to ET-1 were examined using quantitative PCR. The invasiveness of oral cancer cells in the presence of conditioned media collected from ET-1 treated fibroblasts was determined using 2D Matrigel assays.. Here we provide evidence that ET-1 increases the migration of oral fibroblasts and induces a more contractile phenotype which is not associated with changes in gene expression indicative of myofibroblast transdifferentiation. In addition we provide evidence that conditioned medium of ET-1-stimulated oral fibroblasts promotes invasion of OSCC cells in vitro.. In oral squamous cell carcinoma, a frequently fatal and increasingly common epithelial malignancy of the oral cavity, ET-1 is known to contribute to pro-migratory paracrine signalling between stromal fibroblasts and cancer cells. The ability of ET-1 to modulate the phenotype of human oral stromal fibroblasts, however, has not previously been reported. The findings presented here suggest that targeting the stromal endothelin system may be a viable and novel therapeutic strategy for invasive oral cancer.

Topics: Animals; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Movement; Cell Proliferation; Collagen; Endothelin-1; Fibroblasts; Humans; Mouth Neoplasms; Neoplasm Invasiveness; Paracrine Communication; Rats; Tail

To evaluate the expression of endothelin-1(ET-1) and matrix metalloproteinase-9 (MMP-9) in laryngeal carcinoma and their correlations with clinical features.. The expression of ET-1 and MMP-9 was detected by immunohistochemical method in 58 specimens of laryngeal carcinoma, 28 specimens of polyps of vocal cord and 19 specimens of normal laryngeal tissues.. The expressions of ET-1, MMP-9 in laryngeal carcinoma were remarkably higher,compared to polyps of vocal cord and normal laryngeal tissues (P < 0.05). The expression of ET-1, MMP-9 was associated with clinical stage, T stage and lymph node metastasis. Expression levels of ET-land MMP-9 correlated significantly with each other (r(s) = 0.693, P < 0.05).. The expression of ET-1 and MMP-9 may be the vital indexes in laryngeal carcinoma.

Topics: Adult; Aged; Carcinoma, Squamous Cell; Endothelin-1; Female; Humans; Laryngeal Neoplasms; Male; Matrix Metalloproteinase 9; Middle Aged; Neoplasm Staging

Oral squamous cell carcinoma (OSCC) is the most frequent malignant neoplasia of the oral cavity, which largely compromises the patient's life quality. Therefore, the identification of biomarkers for this kind of cancer is essential to provide a better diagnosis and prognosis for patients. Endothelin-1 is a peptide produced mainly by endothelial cells, and might be found in several body fluids, such as saliva, milk, urine, cerebrospinal fluid and plasma. It has been demonstrated that expression of this peptide is increased in a great number of neoplasias, including oral carcinoma. The identification of salivary biomarkers would be a useful tool for scanning and monitoring patients with risk of developing OSCC, as well to early detect recurrence, or the formation of a new primary tumor. In the present study, we have analyzed the levels of endothelin-1 in saliva obtained from patients with OSCC or oral leukoplakia, in comparison to healthy control patients. This study also evaluated the salivary ET-1 levels in patients with complete remission of OSCC. The results revealed no statistical difference in salivary endothelin-1 levels, neither in OSCC nor in oral leukoplakia, even when conditions such as elderly, sex and hypertension were taken into consideration. Although, ET-1 might display an important role in OSCC, its levels in saliva do not seem to be a good marker of neoplasias grade or malignant transformation.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Squamous Cell; Endothelin-1; Female; Humans; Leukoplakia, Oral; Male; Middle Aged; Mouth Neoplasms; Saliva

Endothelin-1 (ET-1) is a potent vasoconstrictor involved not only in vascular biology but also in carcinogenesis. Results of a study in 2007 suggested salivary ET-1 as a potential biomarker for oral squamous cell carcinoma (OSCC), but a later study showed conflicting results. The purpose of our pilot study was to investigate feasibility of using salivary ET-1 as a biomarker for OSCC in two groups: oral lichen planus (OLP) patients and patients with OSCC in remission. Saliva samples were collected from five groups of subjects: patients with newly diagnosed, active OSCC (Group A); patients with OSCC in remission (Group B); patients with active OLP lesions (Group C); patients with OLP in remission (Group D); and normal controls (Group E). Salivary ET-1 levels were determined by enzyme-linked immunosorbent assay, and the results were analyzed by the Mann-Whitney U test. The mean salivary ET-1 level in Group A was significantly higher than that found in Group C (p=0.001), Group D (p=0.015) or Group E (p=0.004). There were no significant differences (p>0.05) in the mean salivary ET-1 levels between Groups A and B; Groups B and C; Groups B and D; Groups B and E; Groups C and D; Groups C and E; or Groups D and E. Salivary ET-1 could be a good biomarker for OSCC development in OLP patients regardless of the degree of OLP disease activity. However, it appeared not to be a good biomarker for detecting recurrence of OSCC in patients in remission.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Carcinoma, Squamous Cell; Case-Control Studies; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Feasibility Studies; Female; Humans; Lichen Planus, Oral; Male; Middle Aged; Mouth Neoplasms; Neoplasm Recurrence, Local; Pilot Projects; Saliva

Endothelin(ET) axis plays a key role in many tumor progression and metastasis via various mechanisms such as angiogenesis, mediating extracellular matrix degradation and inhibition of apoptosis. However, there is limited information regarding the clinical significance of plasma big ET-1 levels in esophageal cancer patients. Circulating plasma big ET-1 levels were measured in patients with esophageal squamous cell carcinoma(ESCC) to evaluate the value of ET-1 as a biomarker for predicting tumor recurrence and patients survival.. Preoperative plasma big ET-1 concentrations were measured by an enzyme linked immunosorbent assay(ELISA) in 108 ESCC patients before surgery, and then again at 1,2,3,10 and 30 days after curative radical resection for ESCC. The association between preoperative plasma big ET-1 levels and clinicopathological features, tumor recurrence and patient survival, and their changes following surgery were evaluated.. The preoperative plasma big ET-1 levels in ESCC patients were significantly higher than those in controls. And there was a significant association between plasma big ET-1 levels and disease stage, as well as invasion depth of the tumor and lymph node status. Furthermore, plasma big ET-1 levels decreased significantly after radical resection of the primary tumor and patients with postoperative recurrence had significantly higher plasma big ET-1 levels than that of patients without recurrence. Finally, the survival rate of patients with higher plasma big ET-1 concentrations (>4.3 pg/ml) was significantly lower than that of patients with lower level (< or = 4.3 pg/ml). Multivariate regression analysis showed that plasma big ET-1 level is an independent prognostic factor for survival in patients with ESCC.. Plasma big ET-1 level in ESCC patients may reflect malignancy and predict tumor recurrence and patient survival. Therefore, the preoperative plasma big ET-1 levels may be a clinically useful biomarker for choice of multimodality therapy in ESCC patients.

Topics: Adult; Aged; Biomarkers, Tumor; Carcinoma, Squamous Cell; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Esophageal Neoplasms; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Recurrence, Local; Prognosis

In this study, we investigated the role of the peripheral endothelin-1 (ET-1) concentration in a cancer pain model. To test the hypothesis that the concentration of ET-1 in the tumor microenvironment is important in determining the level of cancer pain we used two cancer pain mouse models that differed significantly in production of ET-1. The two mouse cancer models were produced by injection of cells derived from a human oral squamous cell carcinoma (SCC) and melanoma into the hind paw of female mice. Pain, as indicated by reduction in withdrawal thresholds in response to mechanical stimulation, was significantly greater in the SCC group than the melanoma group. The peripheral concentration of ET-1 within the cancer microenvironment was significantly greater in the SCC group. Intra-tumor expression of both ET-1 mRNA and ET-1 protein were significantly higher in the SCC model compared to the melanoma model. ET receptor antagonism was effective as an analgesic for cancer pain in the SCC model only. To address the potential confounding factor of tumor volume we evaluated the contribution of tumor volume to cancer pain in the two models. The mean volumes of the tumors in the melanoma group were significantly greater than the tumors in the SCC group. In both groups, the pain level correlated with tumor volume, but the correlation was stronger in the melanoma group. We conclude that ET-1 concentration is a determinant of the level of pain in a cancer pain mouse model and it is a more important factor than tumor volume in producing cancer pain. These results suggest that future treatment regimens for cancer pain directed at ET-1 receptor antagonism show promise and may be tumor type specific.

Topics: Animals; Carcinoma, Squamous Cell; Cell Line, Tumor; Endothelin A Receptor Antagonists; Endothelin-1; Female; Hyperalgesia; Melanoma, Experimental; Mice; Mice, Nude; Mouth Neoplasms; Neoplasm Proteins; Organ Specificity; Pain; Pain Measurement; Peptides, Cyclic; Receptor, Endothelin A; RNA, Messenger; RNA, Neoplasm; Transplantation, Heterologous; Tumor Burden

The analysis of saliva has been proposed as a potentially rapid, non-invasive method to monitor and diagnose patients with oral disease. In this study we measured salivary endothelin-1 (ET-1) levels in patients diagnosed with oral squamous cell carcinoma (SCC) prior to treatment. We demonstrate significantly elevated salivary ET-1 levels in the oral SCC group (4.37+/-1.35pg/ml), relative to the control group (1.16+/-0.29pg/ml). ET-1 and ET-1 mRNA were also measured in oral SCC tissue specimens and compared to normal oral epithelial controls. The concentration of ET-1 in the oral SCC specimens was 17.87+/-4.0pg/ml and in the normal epithelial controls the concentration of ET-1 was 5.43+/-2.5pg/ml. ET-1 mRNA was significantly overexpressed in 80% (8/10) of the oral SCC specimens. Our results demonstrate the potential utility of salivary analysis for ET-1 levels to monitor patients at risk for oral SCC.

Topics: Adult; Aged; Biomarkers, Tumor; Carcinoma, Squamous Cell; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunohistochemistry; Leukoplakia, Oral; Male; Middle Aged; Mouth Neoplasms; Pilot Projects; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Saliva

Endothelin-1 (ET-1) and its receptors, entothelin-A (ETAR) and endothelin-B (ETBR), commonly referred to as the endothelin (ET)-axis, are involved in tumor biology and growth. We investigated the effects of the ET-axis on microvessel density (MVD) and the clinicopathological parameters of patients with invasive bladder cancer. Paraffin tumor sections of 120 patients who had undergone radical cystectomy were assessed immunohistochemically using mono- and polyclonal antibodies for ET-1, ETAR, ETBR and CD34 (MVD). Staining intensities were analyzed semiquantitatively and the MVD was calculated as vessels per field. The results were correlated with various pathological and clinical factors, as well as with disease-free and overall survival. Transitional cell carcinomas (MVD=23.7) were better vascularized than squamous cell carcinomas (MVD=17.8, p=0.04). Organ-confined tumors (MVD=32.2) were better vascularized than T3- and T4-tumors (MVD=21.2, p=0.02) and ET-1 was overexpressed in this subgroup (p=0.027). Patients with metastatic regional lymph nodes (MVD=20.9) tended to have less MVD than patients without regional lymph node metastases (MVD=24.1) (p=0.15). The account of MVD did not reveal any significant differences in disease-free or overall survival. Organ-confined tumors and ET-1 overexpression are associated with upregulated microvessel density. These results suggest that MVD and ET-1 could be considered good prognostic factors.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Squamous Cell; Carcinoma, Transitional Cell; Cystectomy; Endothelin-1; Female; Humans; Immunoenzyme Techniques; Lymph Nodes; Male; Middle Aged; Neoplasm Staging; Neovascularization, Pathologic; Prognosis; Receptor, Endothelin A; Receptor, Endothelin B; Survival Rate; Urinary Bladder Neoplasms

Overexpression of endothelin (ET)-1 and its receptors, ETAR and ETBR, commonly referred to as the 'ET-axis', has been demonstrated to play a role in cancer progression for various human tumours. Based on these results we propose a similar role of the expression of the ET-axis in vulvar cancer. Expression of the ET-axis was investigated immunohistochemically using tissue microarrays with tumour samples of 68 vulvar cancer patients. Samples were obtained from patients undergoing local excision or radical vulvectomy. ET-1 expression of tumour cells correlated highly significantly with early stages of vulvar cancer (p=0.004), whereas neither ETAR nor ETBR expression showed any association with TNM stages. High staining levels of ETBR in the tumour tissue were significantly related to tumour progression (p=0.01) and early metastases (p=0.09); low ETBR staining intensity correlated with longer relapse-free survival (p=0.019). In patients with ETBR overexpressing low-stage tumours (pT1-2) we observed a significantly reduced overall survival and disease-free survival (p=0.036 and 0.021, respectively). ETAR expression and ETBR expression were significantly correlative (p=0.018). Accordingly, co-expression of both receptors was related to tumour progression (p=0.022) and an increased risk for local recurrence (p=0.005). These results suggest that, in addition to established histological and clinical prognostic factors, analysis of ET-receptor and, in particular, of ETBR expression by means of simple immunohistochemical analysis might improve prediction of the prognosis for patients with vulvar squamous cell carcinoma.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Squamous Cell; Disease Progression; Endothelin-1; Female; Humans; Immunohistochemistry; Middle Aged; Neoplasm Staging; Prognosis; Receptor, Endothelin A; Receptor, Endothelin B; Survival Analysis; Vulvar Neoplasms

To investigate the effect of endothelin-1 in the invasion of esophageal cancer and determine whether cathepsin B plays a role in the course.. Western blotting was employed to detect the expression of ET-1 protein in 75 samples of esophageal squamous cell cancer and matched normal esophageal mucosa. Bosentan, a dual ET (A/B)-receptor antagonist, was used to inhibit the binding of endothelin-1 and its receptors and cut down its biological role. In vitro matrigel invasion assays were made to show the invasive ability of esophageal cancer cells with and without bosentan. Subsequently, we evaluated cathepsin B activity and expression in EC9706 cell with and without bosentan.. We found 74.7% (56/75) tumors had an overexpression of ET-1 protein by Western blotting. Bosentan significantly inhibited matrigel invasion of cancer cells in vitro. EC9706 cells have a positive expression of cathepsin B protein, and bosentan can down-regulate its expression and activity.. Endothelin-1 may enhance the invasive ability of human esophageal cancer cells, and its role is correlated with cathepsin B.

Topics: Antihypertensive Agents; Bosentan; Carcinoma, Squamous Cell; Cathepsin B; Cell Line, Tumor; Collagen; Disease Progression; Drug Combinations; Endothelin-1; Esophageal Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Laminin; Neoplasm Invasiveness; Neovascularization, Pathologic; Proteoglycans; Sulfonamides

We present here the clinical, morphological and immunohistochemical features of a pigmented squamous cell carcinoma (SCC) in the oral mucosa of the hard palate of a 76-year-old Japanese man. He underwent a partial resection of the maxilla subsequent to radiotherapy. The tumor was typical, moderately well-differentiated SCC but had many melanocytes (melanocytosis) within it. Immunohistochemical analysis for stem cell factor (SCF) and endothelin-1, both of which are known to stimulate proliferation and differentiation of melanocytes, revealed prominent expression of both factors in the neoplastic squamous cells of the pigmented SCC, while the non-pigmented oral SCC showed little sign of either factor. These findings strongly suggest that SCF and endothelin-1 secreted by neoplasmic squamous cells are involved in the emergence of a rare variant of oral SCC.

Topics: Aged; Carcinoma, Squamous Cell; Endothelin-1; Humans; Male; Melanocytes; Melanosis; Palatal Neoplasms; Stem Cell Factor

The present study focused on the endothelin axis in human oral squamous cell carcinoma (SCC) cells. We investigated the expression and distribution of endothelin-1 (ET-1), its receptors (endothelin-A receptor (ET(A)R) and endothelin-B receptor (ET(B)R)) and isoforms of its specific converting enzyme (ECE-1a, 1b, 1c) and the report on their relative influences on cell proliferation. We also investigated the effect of an ECE-specific inhibitor (ECE-i) and siRNA targeting of the ECE-1 gene on SCC cell proliferation. We observed the expression of ET-1, ET(A)R, ET(B)R and all endothelin-converting enzyme-1 (ECE-1) isoforms in oral SCC cells, but only the expression of ET-1, ET(B)R and ECE-1 was increased when compared to normal human epidermal keratinocytes. ET-1 alone stimulated proliferation of oral SCC cells. Antagonists of either ET(A)R or ET(B)R inhibited ET-1-mediated proliferation. Decreased ECE-1 expression after ECE siRNA treatment reduced SCC cell proliferation. Antiproliferative effects were also observed by inhibiting ECE activity with ECE-i. In conclusion, the present study demonstrates that modulation of the endothelin system in oral SCC cells might provide a novel therapeutic protocol for oral cancer.

Topics: Aspartic Acid Endopeptidases; Carcinoma, Squamous Cell; Cell Proliferation; Endothelin-1; Endothelin-Converting Enzymes; Humans; Metalloendopeptidases; Mouth Neoplasms; Protein Isoforms; Receptor, Endothelin A; Receptor, Endothelin B; RNA, Small Interfering; Tumor Cells, Cultured

To study the expression and clinical significance of Endothelin-1 in laryngeal carcinoma.. Immunohistochemical (SP) method was used to detect the expression of Endothelin-1 in 30 cases of laryngeal carcinoma,20 cases of laryngeal benign lesions and 10 cases of. The relationship between the expression of Endothelin-1 and the clinic stage was analysed by SPSS12. 0 software. RESULT. The positive expression of Endothelin-1 in all three type tissues. There is a significant difference between the laryngeal carcinoma and the laryngeal benign lesions, the laryngeal carcinoma and the normal laryngeal mucous membrane, the laryngeal benign lesions and the normal laryngeal mucous membrane( P <0. 05). The highest expression of Endothelin-1 is in laryngeal carcinoma tissue. In laryngeal carcinoma tissue, the advanced clinical stage, the more higher expression of endothelin-1.. Positive expression of Endothelin-1 in laryngeal carcinoma tissue was highest in three tissue. It may be play an important role in carcinogenesis and progress of laryngeal carcinoma.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Squamous Cell; Case-Control Studies; Endothelin-1; Humans; Laryngeal Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging

Aberrantly hypermethylated genes in human lung cancers were searched for by a genome scanning technique, methylation-sensitive-representational difference analysis (MS-RDA). A total of 59 DNA fragments were isolated as those methylated more heavily in either/both of two lung squamous cell carcinoma cell lines, EBC-1 and LK-2, than in a primary culture of normal human bronchial epithelium, NHBE. Thirty-four DNA fragments, whose hypermethylation was confirmed in primary squamous cell carcinomas, were sequenced. By database searches, 17 of them were shown to be located within 2 kb of putative CpG islands, and five of the 17 DNA fragments had transcribed regions of known genes in their vicinities. By RT-PCR of the five genes in the carcinoma cell lines and NHBE, decreased expression of HTR1B (5-hydroxytryptamine receptor 1B) and EDN1 (endothelin-1) was observed. Sequencing after bisulfite modification showed that the CpG island in the promoter region of HTR1B was hypermethylated, while that of EDN1 was not. Demethylation and re-expression of HTR1B were observed after treatment of LK-2 cells with 5-aza-2'-deoxycytidine. In primary lung cancers, decreased mRNA expression of HTR1B was observed in 11 of 20 cases, and that of EDN1 was in 16 of 20 cases. Immunohistochemical analysis of endothelin-1 confirmed that its immunoreactivity was reduced in squamous cell carcinoma cells compared with that in normal bronchial epithelial cells. Considering that endothelin-1 induces apoptosis in melanoma cells and that silencing of endothelin receptor B is observed in prostate cancers, its reduced expression was speculated to confer a growth advantage to lung cancer cells. MS-RDA was shown to isolate DNA fragments that are hypermethylated and silenced, such as HTR1B, and those whose expressions are altered and the methylation statuses outside the promoter region are altered, such as EDN1.

Topics: Aged; Blotting, Southern; Bronchi; Carcinoma, Squamous Cell; Cell Line; Cells, Cultured; CpG Islands; DNA; DNA Methylation; Endothelin-1; Epithelial Cells; Female; Gene Silencing; Humans; Immunohistochemistry; Introns; Lung Neoplasms; Male; Middle Aged; Models, Genetic; Physical Chromosome Mapping; Promoter Regions, Genetic; Receptor, Serotonin, 5-HT1B; Receptors, Serotonin; Reverse Transcriptase Polymerase Chain Reaction; Sequence Analysis, DNA; Sulfites; Transcription, Genetic; Tumor Cells, Cultured

In order to study endothelin-1 (ET-1) positive expression in lung cancer and the relationship between the ET-1 quantitative analysis and the types, grades of lung cancer.. ET-1 positive expression and quantitative analysis were detected using avidin-biotin-peroxidase complex method and image analysis technology.. The ET-1 positive expression were mainly located in the cytoplasm in 104 cases with various types of lung cancer. The positive rate of ET-1 in adenocarcinoma, squamous-cell carcinoma and large-cell-lung cancer were 71.4%, 57.1% and 40.0% respectively. The positive rate of ET-1 in small-cell-lung cancer was 21.4%, significantly lower than others. The results of image analysis on adenocarcinoma and squamous-cell carcinoma showed that the lower lung cancer differentiation, the higher ET-1 quantitative.. There is ET-1 positive expression in all of types of lung cancer, but there is a high ET-1 positive expression in adenocarcinoma and squamous-cell carcinoma. The results of image analysis indicated that ET-1 quantitive expression was somehow related to the differentiation degree of neoplasm, so ET-1 quantitative analysis may be as a monitoring index of adenocarcinoma and squamous-cell carcinoma growing.

Topics: Adenocarcinoma; Carcinoma, Large Cell; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cell Differentiation; Endothelin-1; Humans; Lung Neoplasms