endothelin-1 and Mouth-Neoplasms

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

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

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

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 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

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

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

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