One of the main characteristics of oral squamous cell carcinoma (OSCC) is that it metastasizes to cervical lymph nodes frequently with a high degree of local invasiveness. A primary feature of malignant tumors is their penetration of neighboring tissues, such as lymphatic and blood arteries, due to the tumor cells' capacity to break down the extracellular matrix (ECM). Matrix metalloproteinases (MMPs) constitute a family of proteolytic enzymes that facilitate tissue remodeling and the degradation of the ECM. MMP-9 and MMP-13 belong to the group of extracellular matrix degrading enzymes and their expression has been studied in OSCC because of their specific functions. MMP-13, a collagenase family member, is thought to play an essential role in the MMP activation cascade by breaking down the fibrillar collagens, whereas MMP-9 is thought to accelerate the growth of tumors. Elevated MMP-13 expression has been associated with tumor behavior and patient prognosis in a number of malignant cases.

To assess the immunohistochemical expression of MMP-9 and MMP-13 in OSCC.

A total of 40 cases with histologically confirmed OSCC by incisional biopsy were included in this cross-sectional retrospective study. The protocols for both MMP-9 and MMP-13 immunohistochemical staining were performed according to the manufacturer’s recommendations along with the normal gingival epithelium as a positive control. All the observations were recorded and Pearson’s χ² test with Fisher exact test was used for statistical analysis.

Our study showed no significant correlation between MMP-9 and MMP-13 staining intensity and tumor size. The majority of the patients were in advanced TNM stages (III and IV), and showed intense expression of MMP-9 and MMP-13.

The present study suggests that both MMP-9 and MMP-13 play an important and independent role in OSCC progression and invasiveness. Intense expression of MMP-9 and MMP-13, irrespective of histological grade of OSCC, correlates well with TNM stage. Consequently, it is evident that MMP-9 and MMP-13 are important for the invasiveness and progression of tumors. The findings may facilitate the development of new approaches for evaluating lymph node metastases and interventional therapy techniques, hence enhancing the prognosis of patients diagnosed with OSCC.

• Matrix metalloproteinases
• Oral squamous cell carcinoma
• Tumor staging
• Immunohistochemistry
• Invasion
• Lymph node metastasis
• TNM stage

• Humans
• Carcinoma, Squamous Cell
• Squamous Cell Carcinoma of Head and Neck
• Epithelial Cell Adhesion Molecule
• Matrix Metalloproteinase 9
• Mouth Neoplasms
• Head and Neck Neoplasms

• NLRP3
• lung
• lymph node
• metastasis
• oral cancer
• spleen

• Carcinoma, Squamous Cell/genetics
• Carcinoma, Squamous Cell/pathology
• Cell Transformation, Neoplastic/genetics
• Cell Transformation, Neoplastic/pathology
• Genomics
• Head and Neck Neoplasms
• Humans
• Lichen Planus, Oral/diagnosis
• Meta-Analysis as Topic
• Mouth Neoplasms/genetics
• Proteomics
• Squamous Cell Carcinoma of Head and Neck

• British Association of Dermatologists Geoffrey Dowling Fellowship
• The Appignani Lichen Planus Benefactor Fund

• MMP2
• MicroRNA-149-3p
• Oral squamous cell carcinoma
• Prognosis
• Progression

Head and neck cancer (HNC) usually arises from squamous cells of the upper aerodigestive tract that line the mucosal surface in the head and neck region. In India, HNC is common in males, and it is the sixth most common cancer globally. Conventionally, HNC attributes to the use of alcohol or chewing tobacco. Over the past four decades, portions of human papillomavirus (HPV)-positive HNC are increasing at an alarming rate. Identification based on the etiological factors and molecular signatures demonstrates that these neoplastic lesions belong to a distinct category that differs in pathological characteristics and therapeutic response. Slow development in HNC therapeutics has resulted in a low 5-year survival rate in the last two decades. Interestingly, HPV-positive HNC has shown better outcomes following conservative treatments and immunotherapies. This raises demand to have a pre-therapy assessment of HPV status to decide the treatment strategy. Moreover, there is no HPV-specific treatment for HPV-positive HNC patients. Accumulating evidence suggests that phytochemicals are promising leads against HNC and show potential as adjuvants to chemoradiotherapy in HNC. However, only a few of these phytochemicals target HPV. The aim of the present article was to collate data on various leading phytochemicals that have shown promising results in the prevention and treatment of HNC in general and HPV-driven HNC. The review explores the possibility of using these leads against HPV-positive tumors as some of the signaling pathways are common. The review also addresses various challenges in the field that prevent their use in clinical settings.

• head and neck cancer
• human pappillomavirus
• phytochemicals
• prevention
• smoking
• therapeutics
• tobacco

Telomerase activity contributes to cell immortalization by avoiding telomere shortening at each cell division; indeed, its catalytic subunit telomerase reverse transcriptase (TERT) is overexpressed in many tumors, including human oral squamous cell carcinoma (hOSCC). In these tumors, matrix metalloproteinases (MMPs), a group of zinc-dependent endopeptidases involved in cell migration, contribute to invasive potential of cancer cells. A proportion of hOSCC is associated with infection by high-risk human papillomavirus (HR-HPVs), whose E6 oncogene enhances TERT and MMPs expression, thus promoting cancer progression. Feline oral squamous cell carcinoma (FOSCC) is a malignant tumor with highly invasive phenotype; however, studies on telomerase activity, TERT, and MMPs expression are scarce. In this study, we demonstrate telomerase activity, expression of TERT, and its transcriptional activator cMyc along with expression of MMP-1, -2, and -9 in FOSCC-derived cell lines SCCF2 and SCCF3, suggesting a contribution by these pathways in cell immortalization and invasion in these tumors. Recent studies suggest that a sub-group of FOSCC as well as SCCF2 and SCCF3 are associated with Felis catus PV type-2 (FcaPV-2) infection. However, in this work, FcaPV-2 E6 gene knock-down caused no shift in either TERT, cMyc, or MMPs levels, suggesting that, unlike its human counterpart, the viral oncogene plays no role in their regulation.

• cat
• infection
• matrix metalloproteinases
• oncogenes
• oral squamous cell carcinoma
• telomerase

Tumor markers are the substances produced in response to the presence of cancer either by the body itself or by the cancer cells. These markers mostly are the proteins that are produced at a greater rate by the cancer cells. Increased levels of these substances can be detected in urine, blood, or body tissues of the patients with certain types of cancer. These markers are useful in differentiating primary or secondary tumors. In few noncancerous conditions, these markers are often found to be elevated. For these reasons, the knowledge regarding these biomarkers has increased tremendously. This article classifies the different types of tumor markers and implicates their role in some diseases.

• Biomarkers
• cancer
• tumor

Podoplanin (PDPN) is a mucin-type transmembrane glycoprotein specific to the lymphatic system. PDPN expression has been found in various human tumors and is considered to be a marker of cancer. We had previously shown that PDPN expression contributes to carcinogenesis in the TPC1 papillary thyroid cancer-derived cell line by enhancing cell migration and invasiveness. The aim of this study was to determine the effect of PDPN down-regulation in another thyroid cancer-derived cell line: BcPAP.

In order to determine the effects of PDPN on malignant features of BcPAP cells (harboring the BRAFV600E mutated allele) and TPC1 cells (carrying the RET/PTC1 rearrangement), we silenced PDPN in these cells using small interfering RNA (siRNA). The efficacy of PDPN silencing was confirmed by qRT-PCR and Western blotting. Then, we tested the motility and invasiveness of these cells (using scratch test and Transwell assay), their growth capacities F(cell cycle analysis, viability, clonogenic activity) and apoptosis assays), adhesion-independent colony-formation capacities, as well as the effect of PDPN silencing on MMPs expression and activity (zymography).

We found that PDPN-induced cell phenotype depended on the genetic background of thyroid tumor cells. PDPN down-regulation in BcPAP cells was negatively correlated with the migration and invasion, in contrast to TPC1 cells in which PDPN depletion resulted in enhanced migration and invasiveness. Moreover, our results suggest that in BcPAP cells, PDPN may be involved in the epithelial-mesenchymal transition (EMT) through regulating the expression of the ezrin, radixin and moesin (E/R/M) proteins, MMPs 9 and MMP2, remodeling of actin cytoskeleton and cellular protrusions. We also demonstrated that PDPN expression is associated with the MAPK signaling pathway. The inhibition of the MAPK pathway resulted in a decreased PDPN expression, increased E/R/M phosphorylation and reduced cell migration. Additionally, PDPN depleted BcPAP cells treated with inhibitors of MEK1/2 kinases (U0126) or of the BRAF V600E protein (PLX4720) had reduced motility, similar to that previously observed in TPC1 cells after PDPN knock-down.

Altogether, our data suggest that PDPN may play an important role in the control of invasion and migration of papillary thyroid carcinoma cells in association with the E/R/M, MMPs and MAPK kinases.

The online version of this article (10.1186/s12885-018-5239-z) contains supplementary material, which is available to authorized users.

• BcPAP
• Ezrin/radixin/moesin
• Invasiveness
• Metalloproteinases
• Motility
• Podoplanin
• TPC1

• HBP1
• MMP-13
• invasion
• oral cancer

• SIBLING-MMP interaction
• SIBLINGs
• dentin sialophosphoprotein
• matrix metalloproteinases
• prostate cancer

• cell proliferation
• oral squamous cell carcinoma
• signaling pathways
• tumor invasion

• Leukoplakia
• matrix metalloproteinase-9
• oral lichen planus
• oral potentially malignant disorders
• oral submucous fibrosis

• Head and neck cancer
• Human papillomavirus
• Kaplan-Meier analysis
• Tumor markers

• Adult
• Aged
• Aged, 80 and over
• Biomarkers, Tumor/genetics
• Carcinoma, Squamous Cell/etiology
• Carcinoma, Squamous Cell/pathology
• Case-Control Studies
• DNA, Viral/genetics
• Female
• Follow-Up Studies
• Gene Expression Profiling
• Head and Neck Neoplasms/etiology
• Head and Neck Neoplasms/pathology
• Humans
• Male
• Middle Aged
• Neoplasm Grading
• Neoplasm Staging
• Papillomaviridae/genetics
• Papillomavirus Infections/complications
• Papillomavirus Infections/virology
• Prognosis
• RNA, Messenger/genetics
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Survival Rate

• Biological markers
• Gene expression
• Head and neck neoplasms
• Matrix metalloproteinase 9
• Metallothionein
• Prognosis
• Tumour microenvironment

• Adult
• Aged
• Aged, 80 and over
• Biomarkers, Tumor/biosynthesis
• Biomarkers, Tumor/genetics
• Female
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Head and Neck Neoplasms/genetics
• Head and Neck Neoplasms/pathology
• Humans
• Male
• Middle Aged
• Neoplasm Proteins/biosynthesis
• Neoplasm Proteins/genetics
• Neoplasm Staging
• Prognosis
• Tumor Microenvironment

Matrix metalloproteinase (MMP)-1 degrades type I collagen of the extracellular matrix and also activates protease activated receptor (PAR)-1 to induce angiogenesis. The aims of this study were to evaluate microvessel density (MVD) and the expression of PAR-1 and MMP-1 in oral squamous cell carcinoma (SCC) specimens with different patterns of invasion (POI) and to evaluate their association with clinical outcomes.

Seventy-four surgically obtained oral SCC samples were classified by POI according to hematoxylin-eosin staining. MVD and the localization and intensity of PAR-1 and MMP-1 expression were detected by immunohistochemistry.

Of the 74 oral SCC samples, 18, 5, 34, and 17 showed type I, II, III, and IV POI, respectively. MVD and expression levels of MMP-1 and PAR-1 differed between POI types I–II and POI types III–IV. Patients with low tumor expression of MMP-1 and PAR-1 and low MVD had a longer survival time than those with high tumor expression of MMP-1 and PAR-1. Moreover, the survival time of patients with POI types III–IV was shorter than that of patients with POI types I–II.

POI combined with expression levels of MMP-1 and PAR-1 may be a valuable tool for assessing the clinical prognosis of patients with oral SCC.

• clinical outcomes
• immunohistochemistry
• oral squamous cell carcinoma
• pattern of invasion

• MMP-20
• colocalization
• dentin sialophosphoprotein (DSPP)
• immunofluorescence
• immunohistochemistry
• proximity ligation assay
• salivary glands

The aim of this study was to investigate whether there is a correlation between the expressions of four matrix metalloproteinases (MMPs): MMP-2, MMP-7, MMP-9 and MMP-13, and the TNM (tumour–node–metastasis) stages of oral squamous cell carcinoma (OSCC); and to explore the implication of these MMPs in OSCC dissemination. Samples from 61 patients diagnosed with oropharyngeal tumour were studied by immunohistochemistry against MMP-2, MMP-7, MMP-9 and MMP-13. The assessment of immunoreactivity was semi-quantitative. The results showed that MMP-2 and MMP-9 had similar expression patterns in the tumour cells with no changes in the immunoreactivity during tumour progression. MMP-9 always had the highest expression, whereas that of MMP-2 was moderate. MMP-7 showed a significant decrease in expression levels during tumour evolution. MMP-13 had constant expression levels within stage T2 and T3, but showed a remarkable decline in immunoreactivity in stage T4. No significant differences in the MMPs immunoreactivity between tumour cells and stroma were observed. Although strong evidence for the application of MMPs as reliable predictive markers for node metastasis was not acquired, we believe that combining patients’ MMPs expression intensity and clinical features may improve the diagnosis and prognosis. Strong evidence for the application of MMPs as reliable predictive markers for node metastasis was not acquired. Application of MMPs as prognostic indicators for the malignancy potential of OSCC might be considered in every case of tumour examination. We believe that combining patients’ MMPs expression intensity and clinical features may improve the process of making diagnosis and prognosis.

• matrix metalloproteinase
• oropharyngeal squamous cell carcinoma
• tumour progression

• matrix metalloproteinases
• periodontal diseases
• tissue inhibitors of metalloproteinases

• Collagenases/metabolism
• Gelatinases/metabolism
• Humans
• Matrix Metalloproteinase Inhibitors/therapeutic use
• Matrix Metalloproteinases/metabolism
• Periodontal Diseases/drug therapy
• Periodontal Diseases/enzymology
• Tissue Inhibitor of Metalloproteinases/metabolism

Pleomorphic adenoma is the most common salivary gland neoplasm, and it can be locally invasive, despite its slow growth. This study aimed to establish a novel cell line (AP-1) derived from a human pleomorphic adenoma sample to better understand local invasiveness of this tumor. AP-1 cell line was characterized by cell growth analysis, expression of epithelial and myoepithelial markers by immunofluorescence, electron microscopy, 3D cell culture assays, cytogenetic features and transcriptomic study. Expression of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) was also analyzed by immunofluorescence and zymography. Furthermore, epithelial and myoepithelial markers, MMPs and TIMPs were studied in the tumor that originated the cell line. AP-1 cells showed neoplastic epithelial and myoepithelial markers, such as cytokeratins, vimentin, S100 protein and smooth-muscle actin. These molecules were also found in vivo, in the tumor that originated the cell line. MMPs and TIMPs were observed in vivo and in AP-1 cells. Growth curve showed that AP-1 exhibited a doubling time of 3.342 days. AP-1 cells grown inside Matrigel recapitulated tumor architecture. Different numerical and structural chromosomal anomalies were visualized in cytogenetic analysis. Transcriptomic analysis addressed expression of 7 target genes (VIM, TIMP2, MMP2, MMP9, TIMP1, ACTA2 e PLAG1). Results were compared to transcriptomic profile of non-neoplastic salivary gland cells (HSG). Only MMP9 was not expressed in both libraries, and VIM was expressed solely in AP-1 library. The major difference regarding gene expression level between AP-1 and HSG samples occurred for MMP2. This gene was 184 times more expressed in AP-1 cells. Our findings suggest that AP-1 cell line could be a useful model for further studies on pleomorphic adenoma biology.

Treatment planning for oral squamous cell carcinoma (OSCC) is based on the clinical TNM (Tumor, Node and Metastasis) classification. This system operates on the assumption that small tumours without clinical spread have a better prognosis than larger tumours with metastases. However, it is a well-known fact that some tumours with the same clinical staging show different growth patterns and clinical behaviour. This makes the prognosis for patients with OSCC difficult to predict on the basis of clinical staging alone. Although many histopathological characteristics of OSCC have been identified as prognostic factors, none is believed to be completely infallible. Therefore, a great need exists for more reliable prognostic markers, which will assist in treatment decisions. It is now well documented that several molecular events of significance for tumour spread, such as gain and loss of adhesion molecules, secretion of proteolytic enzymes, increased cell proliferation and initiation of angiogenesis occur at the tumour–host interface or invasive front, where the deepest and presumably most aggressive cells reside. This review describes the various molecular events and interactions, which take place in the invasive front of the OSCC, and elucidates their role as prognostic markers.

• Head and neck
• invasive front
• molecular markers
• squamous cell carcinoma

Papilloma frequently develops as a benign tumor of the head and neck area, but its potential for malignant transformation has yet to be studied. This study aims to provide basic information for papillomas using the immunohistochemical staining of matrix metalloproteinase 2 (MMP-2) and human papilloma virus (HPV) 16 and 18.

To evaluate the malignant transformation of papillomas, the selected tissue samples were serially diagnosed with pre-cancerous papilloma (with epithelial dysplasia, pseudo-epitheliomatous hyperplasia) or malignant lesion (squamous cell carcinoma, SCC) after the first diagnosis (squamous papilloma, inverted papilloma). The selected tissues were stained with an antibody to MMP-2 and HPV 16-E7, HPV 18-L1. A statistical analysis was performed according to each transformation step.

The epithelial layer of papilloma and pre-cancerous papilloma lesions had a similar MMP-2 expression, but that of the malignant lesion had a significantly increased MMP-2 expression. HPV 16 and 18 infection rates were 28.6%, 33.3% and 63.6% in papillomas, pre-cancerous papilloma lesions, and SCC.

A relatively high MMP-2 expression and HPV 16 or 18 infection of papillomas may be associated with early events in the multistep processes of malignant transformation of papillomas.

• Human papilloma virus
• Immunohistochemistry
• Matrix metalloproteinase 2
• Papilloma
• Squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is a complex tissue that contains tumor cells and the surrounding stroma, which is populated by different types of mesenchymal cells and the extracellular matrix (ECM). Collectively, they are referred to as the tumor microenvironment (TME). Recent studies have shown that TME has a more profound influence on the growth and metastasis of HNSCC than was previously appreciated. Because carcinoma-associated fibroblasts (CAFs) are frequently observed in the stroma of the tumor, this review focuses on the potential role of tumor-CAFs interactions in progression of HNSCC. Tumor-CAFs crosstalk enhances the production of growth factors, cytokines, chemokines, matrix metalloproteinases (MMPs), and inflammatory mediators, which eventually facilitates tumor growth. In fact, factors and cells that do not support tumor growth are usually down regulated or mitigated in TME. Therefore TME may determine the fate of the tumors at the site of invasion and metastasis. For tumor cells that survive at these sites, stromal activation may serve to establish a supportive tumor stroma, fostering the outgrowth of the metastatic cells. The concept of tumor-stromal interactions and microenvironmental niche has profound consequences in tumor growth and metastasis and therefore, it's understanding will open up new strategies for the diagnosis, prognosis and therapy of HNSCC.

• CCL12.
• CXCR4
• Cancer associated fibroblasts (CAFs)
• Cycloxygenase-2 (COX-2)
• Head and neck cancer
• Matrix metalloproteinases (MMPs)

• Adult
• Aged
• Alternative Splicing
• Carcinoma, Squamous Cell/genetics
• Carcinoma, Squamous Cell/metabolism
• Carcinoma, Squamous Cell/pathology
• Cell Growth Processes/physiology
• Cell Line, Tumor
• Cell Movement/physiology
• Female
• Growth Hormone-Releasing Hormone/genetics
• Growth Hormone-Releasing Hormone/metabolism
• Humans
• Immunohistochemistry
• Male
• Middle Aged
• Mouth Neoplasms/genetics
• Mouth Neoplasms/metabolism
• Mouth Neoplasms/pathology

• Biomedical Technology
• Carcinoma, Squamous Cell/diagnosis
• Carcinoma, Squamous Cell/prevention & control
• Coloring Agents
• Diagnostic Imaging/methods
• Fluorescence
• Humans
• Image Processing, Computer-Assisted/methods
• Mass Screening
• Mouth Neoplasms/diagnosis
• Mouth Neoplasms/prevention & control
• Optical Devices
• Precancerous Conditions/diagnosis
• Precancerous Conditions/prevention & control
• Technology Assessment, Biomedical/standards

• CIHR
• R01 DE013124 NIDCR NIH HHS
• R01 DE017013 NIDCR NIH HHS
• R01DE13124 NIDCR NIH HHS
• R01 DE017013-04 NIDCR NIH HHS