Identification of potential biomarkers of lymph node metastasis in oral squamous cell carcinoma by cDNA microarray analysis

Nakagawa, Masaki; Fujita, Hideaki; Ida, Hiroko; Hoshina, Hideyuki; Inoue, Takamitsu; Seki, Yukie; Ohnishi, Makoto; Ohyama, Tokio; Shingaki, Susumu; Kaji, Masataka; Saku, Takashi; Takagi, Ritsuo

doi:10.1002/ijc.11283

Cited by 146 publications

(123 citation statements)

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“…In addition, microarray gene expression studies on whole HNSCC tumour samples have identified the overexpression of several MMPs including MMP-2 (Nagata et al, 2003;Chung et al, 2004). Lastly, MMP-2 is among the recently identified predictive genes that show a positive correlation with lymph node metastasis (Roepman et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Involvement of focal adhesion kinase in cellular invasion of head and neck squamous cell carcinomas via regulation of MMP-2 expression

et al. 2008

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Focal adhesion kinase (FAK) is considered intimately involved in cancer progression. Our previous research has demonstrated that overexpression of FAK is an early and frequent event in squamous cell carcinomas of the supraglottic larynx, and it is associated with the presence of metastases in cervical lymph nodes. The purpose of this study was to examine the functional role of FAK in the progression of head and neck squamous cell carcinomas (HNSCC). To this end, expression of FAK-related nonkinase (FRNK) or small interfering RNA (siRNA) against FAK was used to disrupt the FAK-induced signal transduction pathways in the HNSCC-derived SCC40 and SCC38 cell lines. Similar phenotypic effects were observed with the two methodological approaches in both cell lines. Decreased cell attachment, motility and invasion were induced by FRNK and FAK siRNA, whereas cell proliferation was not impaired. In addition, increased cell invasion was observed upon FAK overexpression in SCC cells. FRNK expression resulted in a downregulation of MMP-2 and MMP-9 expression. Interestingly, MMP-2 overexpression in FRNK-expressing cells rescued FRNK inhibition of cell invasion. This is the first demonstration of a direct rescue of impaired cell invasion by the re-expression of MMP-2 in a tumour cell type with decreased expression of functional FAK. Collectively, these data reported here support the conclusion that FAK enhances invasion of HNSCC by promoting both increased cell motility and MMP-2 production, thus providing new insights into possible therapeutic intervention strategies. Head and neck squamous cell carcinoma (HNSCC) is one of the most common types of human cancer, comprising B50% of all malignancies in some developing nations. HNSCC is associated with severe disease-and treatment-related morbidity and has a 5-year survival rate of B50%. This survival rate has remained largely unchanged in the past three decades (Sankaranarayanan et al, 1998;Gonzalez-Botas and Vazquez Barro, 2006). A major determinant of the lethal progression of HNSCC is the spreading of the malignant cells to regional lymph nodes which represents a major prognostic indicator (Forastiere et al, 2001). Thus, attempts to identify the genes involved in metastasis are pivotal for the early prediction of HNSCC behaviour and development of novel molecular therapies. However, the identities of molecular alterations that endow cancer cells with these metastatic functions are largely unknown.The process of metastasis consists of sequential and selective steps including proliferation, motility, invasion, loss of cell -cell and cell -matrix adhesion, and remodelling of the extracellular matrix. A key factor involved in the control of cellextracellular matrix interactions is focal adhesion kinase (FAK), an intracellular tyrosine kinase protein that is localised to cellular focal contact sites (Schaller et al, 1992). Initially, phosphorylation of FAK occurs on its major autophosphorylation site, Tyr 397 . Phosphorylation of this tyrosine initiates a cascade of signal transdu...

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Section: Discussionmentioning

confidence: 99%

Involvement of focal adhesion kinase in cellular invasion of head and neck squamous cell carcinomas via regulation of MMP-2 expression

et al. 2008

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“…These findings argue for some common alterations, but also obvious differences in the pathogenesis of oesophageal SCC and carcinogenesis of the skin. Altered expression of integrins and MMPs is also a hallmark for other SCCs derived from oral (Mendez et al, 2002;Nagata et al, 2003;Tsai et al, 2004), hypopharyngeal (Cromer et al, 2004), lung (Gogali et al, 2004;Kettunen et al, 2004) and cervical epithelium (Chen et al, 2003). Future confirmation at the protein level and functional analysis of the identified genes in tissue culture Tumour-associated genes in cutaneous SCC development L Hummerich et al and animal model systems will be required to define the individual roles that the identified genes play in tumour initiation, promotion and progression.…”

Section: Discussionmentioning

confidence: 99%

Identification of novel tumour-associated genes differentially expressed in the process of squamous cell cancer development

et al. 2005

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Chemically induced mouse skin carcinogenesis represents the most extensively utilized animal model to unravel the multistage nature of tumour development and to design novel therapeutic concepts of human epithelial neoplasia. We combined this tumour model with comprehensive gene expression analysis and could identify a large set of novel tumour-associated genes that have not been associated with epithelial skin cancer development yet. Expression data of selected genes were confirmed by semiquantitative and quantitative RT-PCR as well as in situ hybridization and immunofluorescence analysis on mouse tumour sections. Enhanced expression of genes identified in our screen was also demonstrated in mouse keratinocyte cell lines that form tumours in vivo. Self-organizing map clustering was performed to identify different kinetics of gene expression and coregulation during skin cancer progression. Detailed analysis of differential expressed genes according to their functional annotation confirmed the involvement of several biological processes, such as regulation of cell cycle, apoptosis, extracellular proteolysis and cell adhesion, during skin malignancy. Finally, we detected high transcript levels of ANXA1, LCN2 and S100A8 as well as reduced levels for NDR2 protein in human skin tumour specimens demonstrating that tumourassociated genes identified in the chemically induced tumour model might be of great relevance for the understanding of human epithelial malignancies as well.

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“…[45][46][47] Although most studies evaluate MMP mRNA or immunohistochemical reactivity, which may not correspond to in vivo enzymatic activity, increased active MMP-2 and MMP-9 has prognostic importance in laryngeal SCC 48,49 and oral cavity SCC. 13,50-52 Although MT1-MMP can degrade type I collagen and other matrix components, 29 MT1-MMP also activates MMP-2 and is, therefore, considered a critical enzyme controlling proteolytic activity.…”

Section: Assessment Of Matrix Metalloproteases In Head and Neck Cancermentioning

confidence: 99%

Matrix metalloproteases in head and neck cancer

Rosenthal¹,

2006

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Matrix metalloproteases (MMPs) are a collection of enzymes capable of cleaving extracellular matrix components, growth factors, and cell-surface receptors. MMPs modulate most aspects of tumorigenesis and are highly expressed in cancer compared with normal tissues. Preclinical studies have demonstrated that head and neck squamous cell carcinomas (HNSCCs) express high levels of MMPs in vivo and that inhibition of these enzymes in vitro and in mouse models decreases invasion and metastasis. However, the clinical trials for MMP inhibitors have failed to demonstrate a significant survival advantage in most cancers. The disparity between preclinical and clinical studies has led to the reevaluation of how MMP functions in cancer and the design of clinical trials for molecularly targeted agents. Mouse model data and analysis of HNSCC tumor specimens suggests that membrane type-1 MMP (MT1-MMP) may be a critical enzyme in tumor cell invasion and survival in vivo. This accumulated data provide evidence for development of selective MT1-MMP inhibitors as therapy in HNSCC.Keywords matrix metalloprotease inhibitor; MMP; extracellular matrix; head and neck cancer; squamous cell carcinoma; membrane type-1 MMP; drug development; proteases The hallmark of cancer remains regional and distant metastases. Regional metastasis in head and neck squamous cell carcinoma (HNSCC) decreases survival by almost 50%, and invasion beyond the lymph node capsule further decreases survival. 1 For tumor cells to invade and metastasize they must: (1) develop motility, (2) alter cell-cell and cell-matrix adhesion, and (3) remodel the extracellular matrix. 2 It was recognized in the 1980s that matrix metalloprotease (MMP) could degrade extracellular matrix (ECM) components and that this could potentiate local tumor invasion and metastasis. 3 A significant amount of effort has been funneled into the development of MMP inhibitors (MPIs) promote tumor angiogenesis by mobilizing or activating factors such as basic fibroblast growth factor, vascular endothelial growth factor, or transforming growth factor-beta. 15,16,18 Second, the complexity of cell types expressing MMPs in the tumor mass was appreciated ( Figure 1 ASSESSMENT OF MATRIX METALLOPROTEASES IN HEAD AND NECK CANCERMMPs consistently found overexpressed in head and neck cancer include MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11, MMP-13, and MMP-14 (Table 1). However, MMP-1, MMP-2, MMP-9, and MT-1 MMP are most commonly identified in HNSCC and associated with disease progression. With the understanding that conflicting reports are abundant and negative studies unlikely to be published, it is possible to summarize the extensive MMP findings in HNSCC. Although most studies evaluate only one or two MMPs within a given head and neck site, studies have examined expression of multiple TIMPs and MMPs in oral cavity SCC. 12,22 Interestingly, these studies commonly identify upregulation of TIMP-1, which is associated with a poor survival. Levels of TIMP-2 are often unchanged between t...

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Identification of potential biomarkers of lymph node metastasis in oral squamous cell carcinoma by cDNA microarray analysis

Cited by 146 publications

References 37 publications

Involvement of focal adhesion kinase in cellular invasion of head and neck squamous cell carcinomas via regulation of MMP-2 expression

Involvement of focal adhesion kinase in cellular invasion of head and neck squamous cell carcinomas via regulation of MMP-2 expression

Identification of novel tumour-associated genes differentially expressed in the process of squamous cell cancer development

Matrix metalloproteases in head and neck cancer

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