metallothionein and Head-and-Neck-Neoplasms

Metallothionein (MT) has been extensively investigated as a molecular marker of various types of cancer. In spite of the fact that numerous reviews have been published in this field, no meta-analytical approach has been performed. Therefore, results of to-date immunohistochemistry-based studies were summarized using meta-analysis in this review. Web of science, PubMed, Embase and CENTRAL databases were searched (up to April 30, 2013) and the eligibility of individual studies and heterogeneity among the studies was assessed. Random and fixed effects model meta-analysis was employed depending on the heterogeneity, and publication bias was evaluated using funnel plots and Egger's tests. A total of 77 studies were included with 8,015 tissue samples (4,631 cases and 3,384 controls). A significantly positive association between MT staining and tumors (vs. healthy tissues) was observed in head and neck (odds ratio, OR 9.95; 95% CI 5.82-17.03) and ovarian tumors (OR 7.83; 1.09-56.29), and a negative association was ascertained in liver tumors (OR 0.10; 0.03-0.30). No significant associations were identified in breast, colorectal, prostate, thyroid, stomach, bladder, kidney, gallbladder, and uterine cancers and in melanoma. While no associations were identified between MT and tumor staging, a positive association was identified with the tumor grade (OR 1.58; 1.08-2.30). In particular, strong associations were observed in breast, ovarian, uterine and prostate cancers. Borderline significant association of metastatic status and MT staining were determined (OR 1.59; 1.03-2.46), particularly in esophageal cancer. Additionally, a significant association between the patient prognosis and MT staining was also demonstrated (hazard ratio 2.04; 1.47-2.81). However, a high degree of inconsistence was observed in several tumor types, including colorectal, kidney and prostate cancer. Despite the ambiguity in some tumor types, conclusive results are provided in the tumors of head and neck, ovary and liver and in relation to the tumor grade and patient survival.

Topics: Biomarkers, Tumor; Case-Control Studies; Databases, Bibliographic; Female; Head and Neck Neoplasms; Humans; Immunohistochemistry; Liver Neoplasms; Metallothionein; Neoplasm Grading; Neoplasm Metastasis; Odds Ratio; Ovarian Neoplasms; Prognosis

Human papillomaviruses (HPV) are small circular, double-stranded DNA viruses infecting epithelial tissues. HPV types can be classified both as high-risk or low-risk. Of the more than 120 different identified types of HPV, the majority are involved in infections of the genital tract, cancer of the cervix, vulva, vagina and penis, and of non-anogenital localizations, such as the head and neck areas. From the point of view of the infection, human papillomaviruses have developed several molecular mechanisms to enable infected cells to suppress apoptosis. This review provides a comprehensive and critical summary of the current literature that focuses on cervical carcinoma and cancer of the head and neck caused by HPV. In particular, we discuss HPV virology, the molecular mechanisms of carcinogenesis, the role of the tumor suppressor protein p53 and the E6/E7 zinc finger proteins. Classification of HPV according to diagnosis is also described.

Topics: Cell Transformation, Neoplastic; Female; Head and Neck Neoplasms; Humans; Metallothionein; Oncogene Proteins, Viral; Papillomaviridae; Papillomavirus E7 Proteins; Papillomavirus Infections; Protein-Tyrosine Kinases; Repressor Proteins; Tumor Suppressor Protein p53; Uterine Cervical Neoplasms; Zinc Fingers

The objective was to discover whether the oxygen-regulated protein, metallothionein, is expressed in the hypoxic cells of squamous cell carcinomas. Twenty patients with squamous cell carcinoma of the uterine cervix or head and neck were infused with a solution of the hypoxia marker, pimonidazole hydrochloride, at a dose of 0.5 g/m2. The following day, biopsies were collected, formalin fixed, paraffin embedded, and sectioned at 4 microm. Sections from each biopsy were immunostained for pimonidazole binding, metallothioneins I and II, involucrin, and proliferating cell nuclear antigen. A total of 84 biopsies were analyzed. Sixty-four of 84 biopsy sections contained hypoxia. Of the hypoxia-containing sections, 43 of 64 or 67% showed no microregional overlap between hypoxia and metallothionein; 7 of 64 showed overlap; and 14 of 64 showed a combination of overlap and no overlap. On a tumor-by-tumor basis, 5 of 7 head and neck and 7 of 13 cervix tumors showed no overlap between metallothionein and hypoxia at the microregional level. Ranges for the percentage of the area of hypoxia in head and neck (<0.9 to 17%) and cervix (<0.1 to 14%) tumors were similar. In the hypoxia-containing sections, immunostaining for involucrin, a molecular marker for differentiation, overlapped with that for hypoxia in 82% of the cases. The majority of hypoxic cells in squamous cell carcinomas do not express metallothionein protein, although metallothionein is induced by hypoxia in human tumor cells in vitro. Hypoxic cells in human tumors tend to be in regions immunostaining for involucrin, and it seems possible that differentiation of hypoxic cells in squamous cell carcinomas might affect metallothionein I and II expression.

Topics: Biomarkers; Carcinoma, Squamous Cell; Cell Hypoxia; Female; Head and Neck Neoplasms; Humans; Immunohistochemistry; Metallothionein; Neoplasm Staging; Nitroimidazoles; Proliferating Cell Nuclear Antigen; Protein Precursors; Uterine Cervical Neoplasms

Metallothioneins (MTs) gene polymorphisms have been associated with the ability of free radical scavenging and detoxification of heavy metals leading to cancer development. Our aim was to revisit, in a Brazilian population, single-nucleotide polymorphisms (SNPs) of the MT gene family previously associated with oral squamous cell carcinoma (OSCC).. A case-control investigation with 28 OSCC patients and 45 controls was conducted, using conventional risk factors (tobacco use and alcohol consumption) as covariates. SNPs genotyping for rs8052334 (MT1B), rs964372 (MT1B), and rs1610216 (MT2A) was performed by PCR-RFLP, and SNPs for rs11076161 (MT1A) were analyzed by TaqMan assay.. The only SNP associated with increased risk for OSCC was the MT-1A AA genotype (OR = 4.7; p = 0.01). We have also evidenced for the first time a significant linkage disequilibrium between the SNPs of MT-2A and MT-1A in this population with the highest frequency (30%) of the unfavorable haplotype G/A/C/T (rs1610216 / rs11076161 / rs964372 / rs8052334) of MT gene polymorphisms (OR = 6.2; p = 0.04). Interestingly, after removing the effects of conventional risk factors, we have uncovered the significance of the AA genotype of the rs11076161 with increased odds of 19-fold higher towards OSCC development.. This is the first demonstration that a significant linkage disequilibrium among gene polymorphisms of the MT family may affect susceptibility to oral cancer, which is conditioned by the G/A/C/T haplotype (rs1610216/rs11076161/rs964372/ rs8052334) and the MT-1A gene polymorphism has a potential clinical utility for the OSCC risk assessment.

Topics: Brazil; Carcinoma, Squamous Cell; Case-Control Studies; Genetic Predisposition to Disease; Genotype; Head and Neck Neoplasms; Humans; Metallothionein; Mouth Neoplasms; Polymorphism, Single Nucleotide; Risk Factors; Squamous Cell Carcinoma of Head and Neck

MCM2, MCM3 and MCM7 are minichromosome maintenance proteins found in dividing cells and they play a role in DNA synthesis. Increased MCM expression level is observed in cells of different cancer types. Additionally, metallothioneins (MT-I/II) are involved in control of cell proliferation and differentiation and changes of their expression are observed in many types of cancer. Ki-67 is known cancer cell proliferation antigen currently used in prognostic evaluation. The study material consisted of 83 laryngeal squamous cell cancer (LSCC) cases and 10 benign hypertrophic lesions of larynx epithelium as a control group. For the present study, laryngeal cancer cell line HEp-2 and human keratinocytes were employed, and to evaluate expression of all the markers, immunohistochemical method (IHC), immunofluorescence (IF) and western blot analysis were used. Statistical analysis showed strong positive correlation between expression of MCM2, MCM3, MCM7 and Ki-67 antigen in LSCC. Additionally, moderate positive correlation was observed between MCM3 and MT-I/II expression. In cancer cells, the level of expression of MCM3, MCM2, MCM7 and Ki-67 markers was increasing with the grade of LSCC malignancy. IF and western blot analysis showed higher MCM2, MCM3, MCM7 expression in HEp-2 cells in comparison to their expression in keratinocytes. MCM proteins might be useful markers of cell proliferation in LSCC.

Topics: Adult; Aged; Biomarkers, Tumor; Carcinoma, Squamous Cell; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; DNA-Binding Proteins; Female; Head and Neck Neoplasms; Humans; Keratinocytes; Ki-67 Antigen; Laryngeal Neoplasms; Male; Metallothionein; Middle Aged; Minichromosome Maintenance Proteins; Squamous Cell Carcinoma of Head and Neck

A novel microfluidic label-free bead-based metallothionein immunosensors was designed. To the surface of superparamagnetic agarose beads coated with protein A, polyclonal chicken IgY specifically recognizing metallothionein (MT) were immobilized via rabbit IgG. The Brdicka reaction was used for metallothionein detection in a microfluidic printed 3D chip. The assembled chip consisted of a single copper wire coated with a thin layer of amalgam as working electrode. Optimization of MT detection using designed microfluidic chip was performed in stationary system as well as in the flow arrangement at various flow rates (0-1800 μL/min). In stationary arrangement it is possible to detect MT concentrations up to 30 ng/mL level, flow arrangement allows reliable detection of even lower concentration (12.5 ng/mL). The assembled miniature flow chip was subsequently tested for the detection of MT elevated levels (at approx. level 100 μg/mL) in samples of patients with cancer. The stability of constructed device for metallothionein detection in flow arrangement was found to be several days without any maintenance needed.

Topics: Animals; Antibodies, Immobilized; Chickens; Electrochemical Techniques; Electrodes; Equipment Design; Head and Neck Neoplasms; Humans; Immunoglobulin G; Immunoglobulins; Immunomagnetic Separation; Male; Metallothionein; Middle Aged; Rabbits

Metallothionein (MT) has been shown to have pro-proliferative anti-apoptotic activity and to be involved in microenvironment remodeling. The aim of this study has been to determine whether the changes in MT and vimentin immunoreactivity observed in cancer and its microenvironment are related to the local spread of the disease. The immunoreactivity levels of both MT and vimentin were evaluated together with CD56 and CD57 antigens in 49 tissue samples taken from patients with squamous cell carcinoma originating from the palatine tonsils and in 20 tissue samples derived from patients with chronic tonsillitis (the reference group). MT immunoreactivity levels were statistically significantly higher in the tissue samples from squamous cell carcinoma than in those of the reference group and also higher in the squamous cell carcinoma samples compared with the stromal samples. Moreover, stromal fibroblasts exhibited high vimentin and MT immunoreactivity levels. Statistically significantly higher MT immunoreactivity levels within the tumor cells were identified in patients with the presence of lymph node metastases in contrast to those patients without such metastases. Vimentin was detected in both the tumor and the stromal tissue samples and presented an interesting pattern of staining strongly expressed within the stroma and the septal architecture of the tumor. The number of CD56- and CD57-positive lymphocytes identified in tissue samples both from squamous cell carcinoma and from the stroma was statistically significantly lower than that in the reference group. MT expression by tumor cells is thus associated with an aggressive phenotype of the tumor and the ability to create metastases.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Squamous Cell; Female; Fibroblasts; Head and Neck Neoplasms; Humans; Male; Metallothionein; Middle Aged; Pharyngeal Neoplasms; Squamous Cell Carcinoma of Head and Neck; Vimentin

An accumulation of genetic alterations forming the field of cancerization is an important event for the transformation from normal to cancer cell in multistep carcinogenesis. Histopathologically healthy tumor adjacent tissue might be considered as a cancerization field which is typified by genetic changes required for the development of cancer. Metallothionein (MT) is considered to be a protective and anti-apoptotic protein. The aim of our study was to evaluate the MT expression in head and neck squamous cells carcinoma and breast adenocarcinoma and their histologically healthy adjacent tissue.. We have sampled 29 tissue samples in total derived from head and neck cancers and 29 samples of their clear surgical margins, 33 breast adenocarcinomas and 33 clear surgical margins. Antibody recognizing MT-1 was used for immunohistochemical analysis.. MT expression was revealed in 85,7% of head and neck cancers and 94% of breast adenocarcinomas. It was found in all tumor adjacent tissue. MT expression was statistically significantly higher in tumor adjacent tissue than in cancer tissue in cases with the presence of lymph node metastases in both, breast adenocarcinoma and head and neck squamous cell carcinoma. Generally stroma seems to respond to the presence of cancer by the expression of MT, even in tissues which normally do not express MT.. MT might be a normal or protective reaction of healthy adjacent tissue to the presence of tumor.

Topics: Adenocarcinoma; Adult; Aged; Breast Neoplasms; Carcinoma, Squamous Cell; Female; Head and Neck Neoplasms; Humans; Immunohistochemistry; Lymphatic Metastasis; Male; Metallothionein; Middle Aged; Stromal Cells

Cells with acquired anticancer drug resistance frequently exhibited broad cross-resistance to other anticancer agents. Increased human metallothionein (hMT) IIa transcription has been found in some cells with acquired resistance to cisplatin (CP). A panel of 5'hMT-IIa promoter deletions linked to the chloramphenicol acetyl transferase ((5'-hMT-IIaCAT) were used to demonstrate that certain cis-elements are important for the increased hMT-IIa transcription in CP-resistant cells (SCC25/CP) compared to CP-sensitive cells (SCC25). We further identified trans-acting factor differences between SCC25 and SCC25/CP cells using gel mobility shift assays. Significant increases in binding of specific factors to the -286 to -160 and -96 to -51 region were seen in CP-resistant SCC25/CP cells compared to sensitive SCC25 cells. Using cross-competition and super gel shift analyses, we identified enhanced Spl and AP-2 binding activity in SCC25/CP cells. By Western blot analysis and immunoprecipitation, we demonstrated that the level of Spl was unchanged between the two cells types whereas AP-2 was elevated twofold in SCC25/CP cells. Our results indicated that the selection of CP-resistant phenotype in SCC25/CP was accompanied by increased Spl and AP-2 DNA binding activities, which are likely not only to enhance hMT-IIa transcription but could also alter expression of other genes responsible for a broader anticancer drug cross-resistance. Thus, altered trans-acting factors could account for the complex cross-resistant phenotype found in some anticancer drug-resistant cells.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Nucleus; Chloramphenicol O-Acetyltransferase; Cisplatin; Drug Resistance, Neoplasm; Electrophoresis, Agar Gel; Genes, Reporter; Genetic Vectors; Head and Neck Neoplasms; Humans; Metallothionein; Neoplasm Proteins; Promoter Regions, Genetic; Transcription, Genetic; Transcriptional Activation; Transfection; Tumor Cells, Cultured