World Journal of Surgical Medical and Radiation Oncology Volume No 8

Review Open Access

Matrix Metalloproteinases in Head and Neck Cancer

*Pol Specenier *Anja Brouwer

  • *Department of Oncology, Antwerp University Hospital, University of Antwerp, Wilrijkstraat 10, 2650 Edegem, 32 3 8214014, Belgium.
  • Submitted: Monday, December 22, 2014
  • Accepted: Friday, March 13, 2015
  • Published: Thursday, March 26, 2015

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited


Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases, which degrade all kinds of extracellular matrix proteins. MMPs play an important role in cell behaviors such as proliferation, migration, differentiation, apoptosis, and host defense. Polymorphisms in the promoter regions of multiple MMPs and overexpression of MMPs and tissue inhibitors of metalloproteinases (TIMPs) are associated with head and neck cancer risk and a worse prognosis. Serum and plasma levels of MMP and TIMP might be useful in diagnostics and follow-up. However, their use as therapeutic target should be further investigated, since the antitumor activity of matrix metalloproteinase inhibitors has been disappointing thus far.

Key words

Head and neck cancer, HNSCC, Matrix metalloproteinases, MMP, Prognostic marker, Matrix metalloproteinase inhibitor


Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases, which degrade most extracellular matrix proteins [1, 4]. Dissolution of the extracellular matrix is a key event of invasion and metastasis of malignant lesions of the head and neck [1, 5]. Matrix metalloproteinase substrates also include cytokines, chemokines, growth factors, receptors, and factors associated with angiogenesis, cell adhesion, cell motility, blood clothing cascade, and complement cascade [7]. Therefore, MMPs play an important role in cell behaviors such as proliferation, migration, differentiation, apoptosis, and host defense [7]. Matrix metalloproteinases facilitate tissue remodeling associated with various physiological and pathological processes such as morphogenesis, angiogenesis, tissue repair, and metastasis [3]. Currently, more than 20 different types of MMPs have been identified among vertebrates, and most of them are conserved in humans [2, 8]. Based on their substrate specificity, MMPs have been divided into distinct subclasses: collagenases (MMP-1, MMP-8, MMP-13, and MMP-18), gelatinases (MMP-2, MMP-9), stromelysins (MMP-3, MMP-10 and MMP-11) and matrilysins (MMP-7, MMP-26) and other MMPs [2, 9]. Most of the MMPs are inhibited by specific endogenous tissue inhibitors which are known as tissue inhibitors of matrix metalloproteinases (TIMPs).

Head and neck squamous cell carcinoma (HNSCC) is characterized by the upregulation of a large number of proteolytic enzymes, including urokinase plasminogen activator (uPA) and also multiple MMPs [10].

The incidence of head and neck cancer is approximately 14/100,000, accounting for 16 % to 40 % of all malignancies [11]. In several countries, the incidence is increasing probably due to the increased use of tobacco and alcohol, which are well documented risk factors for HNSCC [12].

Matrix metalloproteinase expression and head and neck cancer risk

Polymorphisms in the promoter regions of multiple MMPs are associated with an increased HNSCC risk [13- 17]. According to meta-analyses, MMP-2-1306 C>T polymorphism is associated with head and neck cancer risk, as is the MMP-1-1607 1G>2G polymorphism, and the MMP-3-1171 5A>6A polymorphism in some subgroups of patients [16, 17]. The single nucleotide +7096 and +6767 polymorphic genotypes and haplotypes +6727 C: +6767 G: +7096 T: +8153 G of the MMP-14 gene are associated with oral cancer risk [18]. Matrix metalloproteinase-2, MMP-7, and MMP-9 expression is upregulated in supraglottic carcinoma tissues as compared with the adjacent non-neoplastic tissues [19], and MMP-2, MMP-9, MMP-20, and tissue inhibitor of metalloproteinase-1 (TIMP-1) are overexpresssed in laryngeal squamous cell carcinoma (SCC) as compared with the adjacent normal laryngeal epithelium [20, 21].

Furthermore, overexpression of MMP-1 and MMP-9 mRNA is associated with progression of oral dysplasia to cancer [22]. Peschos et al., demonstrated that the tissue expression of MMP-9 is upregulated in a stepwise fashion, with two main steps. The first one, when a dysplastic lesion evolves and the next one, when the dysplasia progresses to invasive carcinoma of the larynx [23].

According to a cohort study by Vairaktaris et al., MMP-7 gene expression is associated with increased risk only for early stages of oral cancer [24]. Cytotoxicity of natural killer (NK) cells against an oral (O) SCC cell line is significantly reduced after pretreatment with either MMP-2 or MMP-9, suggesting a potential role of MMP-2 and MMP-9 in an immune escape mechanism of OSCC [25].

Matrix metalloproteinases as tumor markers

Serum and plasma levels of both MMP and TIMP might be useful markers in diagnostics and follow-up after treatment. Multiple MMPs, including MMP-3 [26], MMP-8 [27], and MMP-9 [28] can be elevated in the serum of patients with HNSCC as compared to healthy controls and therefore might be useful as tumor markers for clinical monitoring. Tumor and salivary MMPs are robust diagnostic biomarkers of OSCC. Particularly, salivary concentrations of MMP-1 and MMP-3 were significantly higher in OSCC patients compared to healthy controls [29].

MMP-9, TIMP-1, and TIMP-2 are significantly elevated in plasma of patients with oral cancer. Matrix metalloproteinase-9 emerged as the best statistically significant, single marker in plasma for oral cancer detection and it showed an increase in diagnostic performance when tested in combination with MMP-2 and TIMP-2 [30]. Tsiropoulos et al., collected pre-and post-treatment serum from 49 patients with laryngeal cancer and identified the latent forms of MMP-2 and MMP-9. Both gelatinases were increased in the serum of these patients as compared to healthy individuals. In addition, both patients with supraglottic tumors and active smokers had significantly higher pre-treatment levels of proMMP-2 than patients with glottic tumors or ex-smokers [31]. During the follow-up period the proMMP-2 serum levels increased significantly in the first ten to fifteen days after treatment, gradually decreasing over the following months. The proMMP-9 serum levels showed a gradual decrease after treatment [31].

Matrix metalloproteinase expression and stage and prognosis

Prognosis of HNSCC and MMP expression is correlated for MMP-2 and MMP-9. The first was found to be associated with a worse overall and disease-free survival in laryngeal cancer [32]. Increased MMP-9 expression is a predictor of worse prognosis in laryngeal cancer [33- 35], hypopharyngeal cancer [33], OSCC [36-48], nasopharyngeal cancer, and oropharyngeal cancer [39, 40]. Matrix metalloproteinase-9 expression is also correlated with invasion depth in head and neck cancer lesions [41], and at histologically-negative surgical margins, MMP-9 expression is a predictor for recurrence in OSCC [42]. Moreover, MMP-9 is correlated with blood vessel density in laryngeal SCC [43]. Expression of MMP-2 and MMP-9 is associated with the presence of lymph node metastases in HNSCC [35, 40, 44, 47]. Matrix metalloproteinase-7 expression is also significantly correlated with lymph node metastasis in OSCC [48]. Görögh et al., found MMP-2 expression to be positively correlated, and TIMP-1 and TIMP-2 expression to be negatively correlated with lymph node metastases in laryngeal SCC [49]. TIMP-2 expression and tumor size were also negatively correlated [50]. Moreover, plasma TIMP-1 levels predict survival in HNSCC [49] and high TIMP-2 expression is an independent factor for worse prognosis in early-stage OSCC [51].

Burduk et al., [52] searched for correlations between expressions of MMPs, such as MMP-2 and MMP-9 and their tissue inhibitors TIMP-1 and TIMP-2 and treatment outcome in 41 SCC of the oropharynx patients who underwent surgical treatment.

Cytoplasmic expression of analyzed proteins was found both in cancer cells and tumor stroma. The expression of analyzed antigens was higher in patients with lymph node metastases comparing patients without lymph node involvement, suggesting that microenvironment changes are one of key factors in tumor progression. Divergent expression of MMPs and their inhibitors might be used as prognostic factor of oropharyngeal carcinoma progression [52]

High expression of MMP-10 is frequently observed and is significantly correlated with invasiveness and metastasis in patients with HNSCC. Knockdown of MMP-10 suppressed the invasion of HNSCC cells in vitro [53]. Some polymorphisms in MMP-13 are associated with tumor stage and prognosis [54], and high nuclear MMP-13 expression is predictive of poor outcome in tongue cancer [55].

High level of MMP-14 expression is closely related to the invasion and metastasis of laryngeal carcinoma, and indicates poorer prognosis [56]. Moreover, patients with supraglottic cancer with high MMP-14 protein expression have a poorer prognosis than patients with weak or negative expression of MMP-14 protein [57].

miR-34a is an important tumor suppressor gene in various cancer types. miR-34a expression in primary tumor tissues from patients with tongue (T) SCC with lymph node metastases is significantly lower than the expression level in patients with negative lymph nodes. Overexpression of miR-34a significantly suppresses migration and invasion in TSCC cells in vitro and simultaneously inhibits the expression of MMP-9 and MMP-14. Moreover, miR-34a expression in TSCC is inversely correlated with protein expression of MMP-9 and MMP-14 in the TSCC samples [58].

Serum, plasma, and salivary levels of MMP and TIMP might be also be useful prognostic markers. Concomitantly elevated MMP-3 and MMP-9 serum levels can predict survival of SCC of the upper aero-digestive tract and might even serve as a better predictor of prognosis than TNM staging, in case of synchronous esophageal SCC and HNSCC [59]. Pre-treatment serum levels of MMP-9 might also serve as a prognostic factor in HNSCC [60, 61]. In patients with oral cancer, post-treatment plasma levels of MMP-9 were significantly lower in responders as compared to their pre-treatment levels [62]. Furthermore, MMP-7 and MMP-13 expression is associated with resistance to cisplatin in HNSCC cell lines [63]. Salivary concentrations of MMP-1 and MMP-3 in OSCC patients displayed an increasing trend with higher stage disease [29].

Matrix metalloproteinases as targets for treatment

A number of MMP inhibitors (MMPIs) have been developed for cancer treatment. The most extensively studied classes of MMPIs include Batimastat, Marimastat, Salimatat, Prinomastat and Tanomastat. However, the despite the strong rational for the use of MMPIs, their clinical efficacy has been disappointing thus far [1, 64, 66]

Marimastat (BB-2516) is an orally active broad-spectrum MMPI with collagenase- and angiogenesis-inhibiting properties [67], which reduces the growth of some HNSCC cell lines in vitro. The combination of chemoradiation and Marimastat delayed tumor growth as compared to chemoradiation alone in athymic nude mice bearing SCC-1 xenografts [68]. However, clinical development of Marimastat was halted after disappointing results in phase III trials [69].

Carboxyamidotriazole, a calcium influx inhibitor, also blocks MMP production, cellular proliferation, migration, and chemo-invasion of HNSCC cells in vitro [70].

Although various synthetic broad-spectrum MMPIs had little success in cancer treatment thus far, preclinical data strongly support the use of MMPIs. Nafamostat mesilate (FUT-175), a synthetic serine protease inhibitor, which down-regulates expression of both MMP-2 and MMP-9, has shown anti-tumor activity towards adenocarcinoma and reduces the production of VEGF and transforming growth factor β1 (TGF-β1) by HNSCC cell lines [71]. Treatment with alpha-mangostin also decreased MMP-2 and MMP-9 expression, and reduced cell proliferation in various human HNSCC cell lines [72].

MMPs can be targeted via inhibition of their processing molecule furin. Transfection of HNSCC cell lines with the selective furin inhibitor, alpha 1-PDX, resulted in a significant decrease or absence of tumorigenicity, invasion, and penetration after subcutaneous inoculation of mice. Furthermore, these HNSCC cells showed a remarkable decrease in MMP-2 processing and activity [73]. Schafer et al., explored the use of an intercomplementing anthrax toxin that requires combined cell surface uPA and MMP activities for cellular intoxication and specifically targets the ERK/MAPK pathway for the treatment of HNSCC [10]. They found that this toxin displayed strong systemic anti-tumor activity towards a variety of xenografted human HNSCC cell lines by inducing apoptotic and necrotic tumor cell death, and by impairing tumor cell proliferation and angiogenesis [10].

Overexpression of epidermal growth factor receptor (EGFR) in human HNSCC cell lines is correlated with MMP-9 expression and invasion in vitro [74]. Ligands for EGFR differentially upregulate MMP-9 in these cells [75]. Besides inhibition of invasion, MMPIs could also prevent tumor progression by their ability to inhibit HNSCC proliferation via interferance with EGFR autocrine loops [76].GACFSIAHECGA is a selective MMP-14 peptide-inhibitor, which prevents the migration and invasion both in vitro, and in xenograft models of tongue carcinoma , and prolonged the survival of tumor bearing mice [77]. Also the orally active MMP-2 and MMP-9 specific inhibitor MMI-166 has shown activity in HNSCC xenografs in mice [78].

A growing body of evidence suggests that components of the tumor micro-environment, including cancer-associated fibroblasts (CAF), may modulate the treatment sensitivity of tumor cells. Johansson et al., investigated the possible influence of CAFs on the sensitivity of HNSCC cell lines to cetuximab [79]. Cetuximab treatment caused a reduction in the proliferation rate of these cells, whereas the growth of HNSCC-derived CAF cultures was unaffected. When tumor cells were co-cultured with CAFs, the cetuximab-induced growth inhibition was reduced, and a complete protection from growth inhibition was observed in one of the tumor cell lines investigated. This co-culture resulted in an elevated expression of MMP-1 in both the tumor cells and CAFs. Moreover, the CAF-induced resistance was partly abolished by the presence of an MMPI. However, CAFs treated with siRNA targeting MMP-1 still protected tumor cells from cetuximab treatment, suggesting that several MMPs may cooperate to facilitate resistance or that the protective effect is mediated by another member of the MMP family. These results suggest that inhibiting MMPs may improve the effects of EGFR-targeted therapy [79]. Extracellular matrix metalloproteinase inducer (EMMPRIN) expression in HNSCC is upregulated by the EGF [80]. Epidermal growth factor receptor stimulation induces HNSCC cell invasion and MMP-9 expression which can be abrogated by down-modulation of EMMPRIN. Treatment of HNSCC cells with a combination of an EMMPRIN function-blocking antibody and the EGFR inhibitor AG1478, results in a stronger inhibition of cell proliferation and migration than with either one of the individual agents alone [80]. McNally et al., evaluated treatment of a replicating adenovirus armed with TIMP-2, radiation, and cisplatin in several combinations in vitro and in vivo in HNSCC xenografts [81]. Treatment with the Ad-TIMP-2 virus and radiation decreased cell viability in vitro and resulted in an additional anti-angiogenic response in vivo. The combination of Ad-TIMP-2 virus, radiation, and cisplatin in the SCC1 nude mice demonstrated the greatest response rates on tumor growth and angiogenesis, underscoring the potential benefits of combining chemoradiation and MMPIs.

Multiple anti-cancer agents, who are currently developed or already used, act at least partially through interaction with MMPs. The metastatic ability of CAL-27 cells was suppressed by epigallocatechin gallate (EGCG) and gefitinib via attenuation of the enzymatic activity and protein expression of MMP-2 by mediation through MAPK signaling [82]. Imatinib is a tyrosine-kinase inhibitor (TKI) used in the treatment of several forms of cancers. Via blockage of the signal transduction of protein-tyrosine kinases receptors, MMP-2 and MMP-14 expression was suppressed and an inhibitory effect on malignant cell growth in HNSCC cell lines was observed [83, 84]. Schulz et al., incubated different HNSCC cell lines with rising concentrations of imatinib and/or carboplatin [85]. The combination of carboplatin with imatinib resulted in a significant decrease in MMP-2 expression and an increase in apoptosis in all cell lines. The EFGR TKI gefitinib decreased both MMP-2 and MMP-9 enzyme activity by approximately 25-30% in the highly invasive human OSCC YD-10B cell line in vitro [86]. Icotinib is also an EGFR TKI, which has been shown to inhibit proliferation in tumour cells. Icotinib reduces cell invasion, suppresses the protein levels of MMP-2 and MMP-9, and increases the expression of TIMP-1 in Tca8113 TSCC cells in vitro [87]. Inhibition of cyclooxygenase-2 suppresses the invasiveness of OSCC cell lines via down-regulation of MMP-2 production and activation [88]. Docetaxel exposure significantly decreased MMP-14 expression in the HPV-negative 11A and 14C HNSCC cell lines but not in the HPV-positive CERV196 HNSCC cell line [89, 90]. 5-FU had no significant effect on MMP-14 expression independent of the HPV-status. Significant alterations of MMP-2 could be detected in 11A only [89, 90].


Matrix metalloproteinases play an important role in cell behaviors such as proliferation, migration, differentiation, apoptosis, and host defense. Polymorphisms in the promoter regions of multiple MMPs and overexpression of MMPs and TIMPs are associated with head and neck cancer risk, stage and prognosis. Serum and plasma levels of both MMP and TIMP might be useful both as prognostic markers as well as predictive markers in diagnostics and follow-up. Matrix metalloproteinases are appealing targets for treatment but none of the tested MMPIs has shown meaningful clinical activity thus far.

Conflict of Interest

The authors declare that there are no conflict of interests

Authors’ Contribution

PS: searching and preparing the draft manuscript, and editing the final manuscript.

AB: searching and preparing the draft manuscript, and editing the final manuscript.

Both authors read and approved the final manuscript for publication.


[1].Chaudhary AK, Pandya S, Ghosh K, Nadkarni A: Matrix metalloproteinase and its drug targets therapy in solid and hematological malignancies: an overview. Mutat Res 2013;753:7-23.[Pubmed]

[2].Fanjul-Fernandez M, Folgueras AR, Cabrera S, and Lopez-Otin C: Matrix metalloproteinases: evolution, gene regulation and functional analysis in mouse models. Biochim Biophys Acta 2010; 1803:3-19 [Pubmed]

[3].Hadler-Olsen E, Winberg JO, Uhlin-Hansen L: Matrix metalloproteinases in cancer: their value as diagnostic and prognostic markers and therapeutic targets. Tumour Biol 2013; 34:2041-2051 [Pubmed]

[4].Galliera E, Tacchini L, Corsi Romanelli MM: Matrix metalloproteinases as biomarkers of disease: updates and new insights. Clin Chem Lab Med 2015;53:349-355 [Pubmed]

[5].Chaudhary AK, Singh M, Bharti AC, Asotra K, Sundaram S, Mehrotra R: Genetic polymorphisms of matrix metalloproteinases and their inhibitors in potentially malignant and malignant lesions of the head and neck. J Biomed Sci 2010;17:10 [Pubmed]

[6].Morrison CJ, Butler GS, Rodriguez D, Overall CM: Matrix metalloproteinase proteomics: substrates, targets, and therapy. Curr Opin Cell Biol 2009;21:645-653 [Pubmed]

[7].Van LP, Libert C: Chemokine and cytokine processing by matrix metalloproteinases and its effect on leukocyte migration and inflammation. J Leukoc Biol 2007; 82:1375-1381 [Pubmed]

[8].Yadav L, Puri N, Rastogi V, Satpute P, Ahmad R, Kaur G: Matrix metalloproteinases and cancer - roles in threat and therapy. Asian Pac J Cancer Prev 2014;15:1085-1091 [Pubmed]

[9].Hadler-Olsen E, Winberg JO, Uhlin-Hansen L: Matrix metalloproteinases in cancer: their value as diagnostic and prognostic markers and therapeutic targets. Tumour Biol 2013; 34:2041-2051 [Pubmed]

[10].Schafer JM, Peters DE, Morley T, Liu S, Molinolo AA, Leppla SH, Bugge TH: Efficient targeting of head and neck squamous cell carcinoma by systemic administration of a dual uPA and MMP-activated engineered anthrax toxin. PLoS One 2011;6:e20532 [Pubmed]

[11].Wang B, Zhang S, Yue K, Wang XD: The recurrence and survival of oral squamous cell carcinoma: a report of 275 cases. Chin J Cancer 2013;32:614-618 [Pubmed]

[12].Sanderson RJ, Ironside JA: Squamous cell carcinomas of the head and neck. BMJ 2002;325:822-827 [Pubmed]

[13].Zinzindohoue F, Blons H, Hans S, Loriot MA, Houllier AM, Brasnu D, Laccourreye O, Tregouet DA, Stucker I, Laurent-Puig P: Single nucleotide polymorphisms in MMP1 and MMP3 gene promoters as risk factor in head and neck squamous cell carcinoma. Anticancer Res 2004;24:2021-2026 [Pubmed]

[14].[Peng B, Cao L, Ma X, Wang W, Wang D, Yu L: Meta-analysis of association between matrix metalloproteinases 2, 7 and 9 promoter polymorphisms and cancer risk. Mutagenesis 2010;25:371-379 [pubmed]

[15].Peng B, Cao L, Wang W, Xian L, Jiang D, Zhao J, Zhang Z, Wang X, Yu L: Polymorphisms in the promoter regions of matrix metalloproteinases 1 and 3 and cancer risk: a meta-analysis of 50 case-control studies. Mutagenesis 2010;25:41-48 [Pubmed]

[16].Zhang C, Li C, Zhu M, Zhang Q, Xie Z, Niu G, Song X, Jin L, Li G, Zheng H: Meta-Analysis of MMP2, MMP3, and MMP9 Promoter Polymorphisms and Head and Neck Cancer Risk. PLoS One 2013;8:e62023 [Pubmed]

[17].Zhang C, Song X, Zhu M, Shi S, Li M, Jin L, Lang J, Li G, Zheng H: Association between MMP1 -1607 1G>2G polymorphism and head and neck cancer risk: a meta-analysis. PLoS One 2013;8:e56294 [Pubmed]

[18].Weng CJ, Chen MK, Lin CW, Chung TT, Yang SF: Single nucleotide polymorphisms and haplotypes of MMP-14 are associated with the risk and pathological development of oral cancer. Ann Surg Oncol 2012;19 Suppl 3:S319-S327.[Pubmed]

[19]. Xie M, Sun Y, Li Y: Expression of matrix metalloproteinases in supraglottic carcinoma and its clinical implication for estimating lymph node metastases. Laryngoscope 2004;114:2243-2248. [Pubmed]

[20].Cao XL, Xu RJ, Zheng YY, Liu J, Teng YS, Li Y, Zhu J: Expression of type IV collagen, metalloproteinase-2, metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in laryngeal squamous cell carcinomas. Asian Pac J Cancer Prev 2011;12:3245-3249 [Pubmed]

[21].Liu Y, Li Y, Liu Z, Zhang L, Anniko M, Duan M: Prognostic significance of matrix metalloproteinase-20 overexpression in laryngeal squamous cell carcinoma. Acta Otolaryngol 2011;131:769-773 [Pubmed]

[22].Jordan RC, Macabeo-Ong M, Shiboski CH, Dekker N, Ginzinger DG, Wong DT, Schmidt BL: Overexpression of matrix metalloproteinase-1 and -9 mRNA is associated with progression of oral dysplasia to cancer. Clin Cancer Res 2004;10:6460-6465 [Pubmed]

[23].Peschos D, Damala C, Stefanou D, Tsanou E, Assimakopoulos D, Vougiouklakis T, Charalabopoulos K, Agnantis NJ: Expression of matrix metalloproteinase-9 (gelatinase B) in benign, premalignant and malignant laryngeal lesions. Histol Histopathol 2006;21:603-608.

[24].Vairaktaris E, Serefoglou Z, Yapijakis C, Vylliotis A, Nkenke E, Derka S, Vassiliou S, Avgoustidis D, Neukam FW, Patsouris E: High gene expression of matrix metalloproteinase-7 is associated with early stages of oral cancer. Anticancer Res 2007;27:2493-2498 [Pubmed]

[25].Lee BK, Kim MJ, Jang HS, Lee HR, Ahn KM, Lee JH, Choung PH, Kim MJ: A high concentration of MMP-2/gelatinase A and MMP-9/gelatinase B reduce NK cell-mediated cytotoxicity against an oral squamous cell carcinoma cell line. In Vivo 2008;22:593-597 [Pubmed]

[26].Tadbir AA, Purshahidi S, Ebrahimi H, Khademi B, Malekzadeh M, Mardani M, Taghva M, Sardari Y: Serum level of MMP-3 in patients with oral squamous cell carcinoma--lack of association with clinico-pathological features. Asian Pac J Cancer Prev 2012;13:4545-4548 [Pubmed]

[27].[Kuropkat C, Plehn S, Herz U, Dunne AA, Renz H, Werner JA: Tumor marker potential of serum matrix metalloproteinases in patients with head and neck cancer. Anticancer Res 2002;22:2221-2227 [Pubmed]

[28].Riedel F, Gotte K, Schwalb J, Hormann K: Serum levels of matrix metalloproteinase-2 and -9 in patients with head and neck squamous cell carcinoma. Anticancer Res 2000;20:3045-3049 [Pubmed]

[29].Stott-Miller M, Houck JR, Lohavanichbutr P, Mendez E, Upton MP, Futran ND, Schwartz SM, Chen C: Tumor and salivary matrix metalloproteinase levels are strong diagnostic markers of oral squamous cell carcinoma. Cancer Epidemiol Biomarkers Prev 2011;20:2628-2636.

[30].Singh RD, Nilayangode H, Patel JB, Shah FD, Shukla SN, Shah PM, Patel PS: Combined evaluation of matrix metalloproteinases and their inhibitors has better clinical utility in oral cancer. Int J Biol Markers 2011;26:27-36.

[31].Tsiropoulos G, Papadas T, Triantaphyllidou I, Naxakis S, Markou K, Triaridis S, Vital I, Goumas P, Vynios D: Pre-treatment gelatinases' serum levels and post-treatment changes in laryngeal cancer patients. Hippokratia 2013;17:220-227.

[32].Mallis A, Teymoortash A, Mastronikolis NS, Werner JA, Papadas TA: MMP-2 expression in 102 patients with glottic laryngeal cancer. Eur Arch Otorhinolaryngol 2012;269:639-642.

[33].Saussez S, Cludts S, Capouillez A, Mortuaire G, Smetana K, Jr., Kaltner H, Andre S, Leroy X, Gabius HJ, Decaestecker C: Identification of matrix metalloproteinase-9 as an independent prognostic marker in laryngeal and hypopharyngeal cancer with opposite correlations to adhesion/growth-regulatory galectins-1 and -7. Int J Oncol 2009;34:433-439.

[34].Colovic Z, Pesutic-Pisac V, Poljak NK, Racic G, Cikojevic D, Kontic M: Expression of matrix metalloproteinase-9 in patients with squamous cell carcinoma of the larynx. Coll Antropol 2013;37:151-155.{pubmed]

[35].Cao XL, Xu RJ, Zheng YY, Liu J, Teng YS, Li Y, Zhu J: Expression of type IV collagen, metalloproteinase-2, metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in laryngeal squamous cell carcinomas. Asian Pac J Cancer Prev 2011;12:3245-3249.[Pubmed]

[36].de Vicente JC, Fresno MF, Villalain L, Vega JA, Hernandez VG: Expression and clinical significance of matrix metalloproteinase-2 and matrix metalloproteinase-9 in oral squamous cell carcinoma. Oral Oncol 2005;41:283-293.

[37].Ogbureke KU, Nikitakis NG, Warburton G, Ord RA, Sauk JJ, Waller JL, Fisher LW: Up-regulation of SIBLING proteins and correlation with cognate MMP expression in oral cancer. Oral Oncol 2007;43:920-932 [Pubmed]

[38].Vilen ST, Salo T, Sorsa T, Nyberg P: Fluctuating roles of matrix metalloproteinase-9 in oral squamous cell carcinoma. ScientificWorldJournal 2013;2013:920595.{pubmed]

[39].Dunne AA, Grobe A, Sesterhenn AM, Barth P, Dalchow C, Werner JA: Influence of matrix metalloproteinase 9 (MMP-9) on the metastatic behavior of oropharyngeal cancer. Anticancer Res 2005;25:4129-4134 [Pubmed]

[40].[Liu Z, Li L, Yang Z, Luo W, Li X, Yang H, Yao K, Wu B, Fang W: Increased expression of MMP9 is correlated with poor prognosis of nasopharyngeal carcinoma. BMC Cancer 2010;10:270 [pubmed]

[41].You TK, Kim KM, Noh SJ, Bae JS, Jang KY, Chung MJ, Moon WS, Kang MJ, Lee DG, Park HS: Expressions of E-cadherin, Cortactin and MMP-9 in Pseudoepitheliomatous Hyperplasia and Squamous Cell Carcinoma of the Head and Neck: Their Relationships with Clinicopathologic Factors and Prognostic Implication. Korean J Pathol 2012;46:331-340.

[42].Ogbureke KU, Weinberger PM, Looney SW, Li L, Fisher LW: Expressions of matrix metalloproteinase-9 (MMP-9), dentin sialophosphoprotein (DSPP), and osteopontin (OPN) at histologically negative surgical margins may predict recurrence of oral squamous cell carcinoma. Oncotarget 2012;3:286-298.

[43].Wittekindt C, Jovanovic N, Guntinas-Lichius O: Expression of matrix metalloproteinase-9 (MMP-9) and blood vessel density in laryngeal squamous cell carcinomas. Acta Otolaryngol 2011;131:101-106 [Pubmed]

[44].charoenrat P, Wongkajornsilp A, Rhys-Evans PH, Eccles SA: Signaling pathways required for matrix metalloproteinase-9 induction by betacellulin in head-and-neck squamous carcinoma cells. Int J Cancer 2004;111:174-183.[Pubmed]

[45].charoenrat P, Rhys-Evans PH, Eccles SA: Expression of matrix metalloproteinases and their inhibitors correlates with invasion and metastasis in squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg 2001;127:813-820 [Pubmed]

[46].Zhou CX, Gao Y, Johnson NW, Gao J: Immunoexpression of matrix metalloproteinase-2 and matrix metalloproteinase-9 in the metastasis of squamous cell carcinoma of the human tongue. Aust Dent J 2010;55:385-389.[Pubmed]

[47].Yuce I, Bayram A, Cagli S, Canoz O, Bayram S, Guney E: The role of CD44 and matrix metalloproteinase-9 expression in predicting neck metastasis of supraglottic laryngeal carcinoma. Am J Otolaryngol 2011;32:141-146 [Pubmed]

[48].de Vicente JC, Lequerica-Fernandez P, Santamaria J, Fresno MF: Expression of MMP-7 and MT1-MMP in oral squamous cell carcinoma as predictive indicator for tumor invasion and prognosis. J Oral Pathol Med 2007;36:415-424.[Pubmed]

[49].Pradhan-Palikhe P, Vesterinen T, Tarkkanen J, Leivo I, Sorsa T, Salo T, Mattila PS: Plasma level of tissue inhibitor of matrix metalloproteinase-1 but not that of matrix metalloproteinase-8 predicts survival in head and neck squamous cell cancer. Oral Oncol 2010;46:514-518[Pubmed]

[50].Gorogh T, Beier UH, Baumken J, Meyer JE, Hoffmann M, Gottschlich S, Maune S: Metalloproteinases and their inhibitors: influence on tumor invasiveness and metastasis formation in head and neck squamous cell carcinomas. Head Neck 2006;28:31-39 [Pubmed]

[51].Katayama A, Bandoh N, Kishibe K, Takahara M, Ogino T, Nonaka S, Harabuchi Y: Expressions of matrix metalloproteinases in early-stage oral squamous cell carcinoma as predictive indicators for tumor metastases and prognosis. Clin Cancer Res 2004;10:634-640.[Pubmed]

[52].Burduk PK, Bodnar M, Sawicki P, Szylberg L, Wisniewska E, Kazmierczak W, Martynska M, Marszalek A: Expression of metalloproteinases 2 and 9 and tissue inhibitors 1 and 2 as predictors of lymph node metastases in oropharyngeal squamous cell carcinoma. Head Neck 2014 [Pubmed]

[53].Deraz EM, Kudo Y, Yoshida M, Obayashi M, Tsunematsu T, Tani H, Siriwardena SB, Keikhaee MR, Qi G, Iizuka S, Ogawa I, Campisi G, Lo ML, Abiko Y, Kikuchi A, Takata T: MMP-10/stromelysin-2 promotes invasion of head and neck cancer. PLoS One 2011;6:e25438 [Pubmed]

[54].airaktaris E, Yapijakis C, Derka S, Serefoglou Z, Vassiliou S, Nkenke E, Ragos V, Vylliotis A, Spyridonidou S, Tsigris C, Yannopoulos A, Tesseromatis C, Neukam FW, Patsouris E: Association of matrix metalloproteinase-1 (-1607 1G/2G) polymorphism with increased risk for oral squamous cell carcinoma. Anticancer Res 2007;27:459-464 [Pubmed]

[55].Makinen LK, Hayry V, Atula T, Haglund C, Keski-Santti H, Leivo I, Makitie A, Passador-Santos F, Bockelman C, Salo T, Sorsa T, Hagstrom J: Prognostic significance of matrix metalloproteinase-2, -8, -9, and -13 in oral tongue cancer. J Oral Pathol Med 2012;41:394-399 [Pubmed]

[56].Du B, Wang P, Guo X, Du B: Expression of membrane type 1-matrix metalloproteinase in laryngeal carcinoma. Pathol Oncol Res 1999;5:214-217 [Pubmed]

[57].[Zhang H, Liu M, Sun Y, Lu J: MMP-14 can serve as a prognostic marker in patients with supraglottic cancer. Eur Arch Otorhinolaryngol 2009;266:1427-1434 [Pubmed]

[58].Jia LF, Wei SB, Mitchelson K, Gao Y, Zheng YF, Meng Z, Gan YH, Yu GY: miR-34a Inhibits Migration and Invasion of Tongue Squamous Cell Carcinoma via Targeting MMP9 and MMP14. PLoS One 2014;9:e108435 [Pubmed]

[59]. Wang WL, Chang WL, Yeh YC, Lee CT, Chang CY, Lin JT, Sheu BS: Concomitantly elevated serum matrix metalloproteinases 3 and 9 can predict survival of synchronous squamous cell carcinoma of the upper aero-digestive tract. Mol Carcinog 2013;52:438-445.[Pubmed]

[60].El Houda AN, Badoual C, Hans S, Gey A, Vingert B, Peyrard S, Quintin-Colonna F, Ravel P, Bruneval P, Roncelin S, Lelongt B, Bertoglio J, Fridman WH, Brasnu D, Tartour E: Soluble interleukin-2 receptor and metalloproteinase-9 expression in head and neck cancer: prognostic value and analysis of their relationships. Clin Exp Immunol 2007;150:114-123.

[61].Ruokolainen H, Paakko P, Turpeenniemi-Hujanen T: Serum matrix metalloproteinase-9 in head and neck squamous cell carcinoma is a prognostic marker. Int J Cancer 2005;116:422-427 [Pubmed]

[62].Patel BP, Shah SV, Shukla SN, Shah PM, Patel PS: Clinical significance of MMP-2 and MMP-9 in patients with oral cancer. Head Neck 2007;29:564-572 [Pubmed]

[63].Ansell A, Jerhammar F, Ceder R, Grafstrom R, Grenman R, Roberg K: Matrix metalloproteinase-7 and -13 expression associate to cisplatin resistance in head and neck cancer cell lines. Oral Oncol 2009;45:866-871 [Pubmed]

[64].Chien MH, Lin CW, Cheng CW, Wen YC, Yang SF: Matrix metalloproteinase-2 as a target for head and neck cancer therapy. Expert Opin Ther Targets 2013;17:203-216 [Pubmed]

[65].Hidalgo M, Eckhardt SG: Development of matrix metalloproteinase inhibitors in cancer therapy. J Natl Cancer Inst 2001;93:178-193 [Pubmed]

[66].Perez-Sayans GM, Suarez-Penaranda JM, Gayoso-Diz P, Barros-Angueira F, Gandara-Rey JM, Garcia-Garcia A: Tissue inhibitor of metalloproteinases in oral squamous cell carcinomas - a therapeutic target? Cancer Lett 2012;323:11-19.[Pubmed]

[67].Marimastat: BB 2516, TA 2516: Drugs R D 2003; 4:198-203.[Pubmed[

[68].Skipper JB, McNally LR, Rosenthal EL, Wang W, Buchsbaum DJ: In vivo efficacy of marimastat and chemoradiation in head and neck cancer xenografts. ORL J Otorhinolaryngol Relat Spec 2009;71:1-5 [Pubmed]

[69].Yoshizaki T, Sato H, Furukawa M: Recent advances in the regulation of matrix metalloproteinase 2 activation: from basic research to clinical implication (Review). Oncol Rep 2002;9:607-611 [Pubmed]

[70].70Wu Y, Palad AJ, Wasilenko WJ, Blackmore PF, Pincus WA, Schechter GL, Spoonster JR, Kohn EC, Somers KD: Inhibition of head and neck squamous cell carcinoma growth and invasion by the calcium influx inhibitor carboxyamido-triazole. Clin Cancer Res 1997;3:1915-1921.[Pubmed]

[71].Yamashita Y, Ishiguro Y, Sano D, Kimura M, Fujita K, Yoshida T, Horiuchi C, Taguchi T, Matsuda H, Mikami Y, Tsukuda M: Antitumor effects of Nafamostat mesilate on head and neck squamous cell carcinoma. Auris Nasus Larynx 2007;34:487-491 [Pubmed]

[72].Kaomongkolgit R: Alpha-mangostin suppresses MMP-2 and MMP-9 expression in head and neck squamous carcinoma cells. Odontology 2012.[Pubmed]

[73].Bassi DE, Lopez De CR, Mahloogi H, Zucker S, Thomas G, Klein-Szanto AJ: Furin inhibition results in absent or decreased invasiveness and tumorigenicity of human cancer cells. Proc Natl Acad Sci U S A 2001; 98:10326-10331 [Pubmed]

[74].charoenrat P, Rhys-Evans P, Modjtahedi H, Court W, Box G, Eccles S: Overexpression of epidermal growth factor receptor in human head and neck squamous carcinoma cell lines correlates with matrix metalloproteinase-9 expression and in vitro invasion. Int J Cancer 2000;86:307-317.

[75].charoenrat P, Modjtahedi H, Rhys-Evans P, Court WJ, Box GM, Eccles SA: Epidermal growth factor-like ligands differentially up-regulate matrix metalloproteinase 9 in head and neck squamous carcinoma cells. Cancer Res 2000;60:1121-1128 [Pubmed]

[76].charoenrat P, Rhys-Evans P, Eccles S: A synthetic matrix metalloproteinase inhibitor prevents squamous carcinoma cell proliferation by interfering with epidermal growth factor receptor autocrine loops. Int J Cancer 2002;100:527-533.

[77].Suojanen J, Salo T, Koivunen E, Sorsa T, Pirila E: A novel and selective membrane type-1 matrix metalloproteinase (MT1-MMP) inhibitor reduces cancer cell motility and tumor growth. Cancer Biol Ther 2009;8:2362-2370.[Pubmed]

[78]. Katori H, Baba Y, Imagawa Y, Nishimura G, Kagesato Y, Takagi E, Ishii A, Yanoma S, Maekawa R, Yoshioka T, Nagashima Y, Kato Y, Tsukuda M: Reduction of in vivo tumor growth by MMI-166, a selective matrix metalloproteinase inhibitor, through inhibition of tumor angiogenesis in squamous cell carcinoma cell lines of head and neck. Cancer Lett 2002;178:151-159.

[79].Johansson AC, Ansell A, Jerhammar F, Lindh MB, Grenman R, Munck-Wikland E, Ostman A, Roberg K: Cancer-associated fibroblasts induce matrix metalloproteinase-mediated cetuximab resistance in head and neck squamous cell carcinoma cells. Mol Cancer Res 2012;10:1158-1168.

[80].Suzuki S, Ishikawa K: Combined inhibition of EMMPRIN and epidermal growth factor receptor prevents the growth and migration of head and neck squamous cell carcinoma cells. Int J Oncol 2014;44:912-917 [Pubmed]

[81].McNally LR, Rosenthal EL, Zhang W, Buchsbaum DJ: Therapy of head and neck squamous cell carcinoma with replicative adenovirus expressing tissue inhibitor of metalloproteinase-2 and chemoradiation. Cancer Gene Ther 2009;16:246-255 [Pubmed]

[82].Chang CM, Chang PY, Tu MG, Lu CC, Kuo SC, Amagaya S, Lee CY, Jao HY, Chen MY, Yang JS: Epigallocatechin gallate sensitizes CAL-27 human oral squamous cell carcinoma cells to the anti-metastatic effects of gefitinib (Iressa) via synergistic suppression of epidermal growth factor receptor and matrix metalloproteinase-2. Oncol Rep 2012;28:1799-1807.

[83].Faber A, Sauter A, Hoedt S, Hoermann K, Erben P, Hofheinz RD, Sommer U, Stern-Straeter J, Schultz DJ: Alteration of MMP-2 and -14 expression by imatinib in HPV-positive and -negative squamous cell carcinoma. Oncol Rep 2012;28:172-178.

[84].Schultz JD, Rotunno S, Erben P, Sommer JU, Anders C, Stern-Straeter J, Hofheinz RD, Hormann K, Sauter A: Down-regulation of MMP-2 expression due to inhibition of receptor tyrosine kinases by imatinib and carboplatin in HNSCC. Oncol Rep 2011;25:1145-1151 [Pubmed]

[85]. Schultz JD, Rotunno S, Erben P, Sommer JU, Anders C, Stern-Straeter J, Hofheinz RD, Hormann K, Sauter A: Down-regulation of MMP-2 expression due to inhibition of receptor tyrosine kinases by imatinib and carboplatin in HNSCC. Oncol Rep 2011;25:1145-1151 [Pubmed]

[86].Lee EJ, Whang JH, Jeon NK, Kim J: The epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 (Iressa) suppresses proliferation and invasion of human oral squamous carcinoma cells via p53 independent and MMP, uPAR dependent mechanism. Ann N Y Acad Sci 2007;1095:113-128.

[87].Yang C, Yan J, Yuan G, Zhang Y, Lu D, Ren M, Cui W: Icotinib inhibits the invasion of Tca8113 cells via downregulation of nuclear factor kappaB-mediated matrix metalloproteinase expression. Oncol Lett 2014;8:1295-1298.

[88].Kurihara Y, Hatori M, Ando Y, Ito D, Toyoshima T, Tanaka M, Shintani S: Inhibition of cyclooxygenase-2 suppresses the invasiveness of oral squamous cell carcinoma cell lines via down-regulation of matrix metalloproteinase-2 production and activation. Clin Exp Metastasis 2009;26:425-432 [Pubmed]

[89].Aderhold C, Umbreit C, Faber A, Birk R, Sommer JU, Hormann K, Schultz JD: Matrix metalloproteinase-2 and -14 in p16-positive and -negative HNSCC after exposure To 5-FU and docetaxel In Vitro. Anticancer Res 2014;34:4929-4937.

[90].Umbreit C, Aderhold C, Faber A, Sauter A, Hofheinz RD, Stern-Straeter J, Hoermann K, Schultz JD: Imatinib-associated matrix metalloproteinase suppression in p16-positive squamous cell carcinoma compared to HPV-negative HNSCC cells in vitro. Oncol Rep 2014;32:668-676.