Expression of Proteolytic Enzymes in Head and Neck Cancer–Associated Fibroblasts

Rosenthal, Eben L.; McCrory, Allison; Talbert, Melissa; Carroll, William R.; Magnuson, J. Scott; Peters, Glenn E.

doi:10.1001/archotol.130.8.943

Cited by 49 publications

(39 citation statements)

References 19 publications

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“…These enzymes are capable of cleaving most ECM components, as well as other biologically important proteins such as growth factors, other proteases, adhesion molecules, and cell surface receptors (Table 1). [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] With a widening understanding of MMP substrates, a more complex role for these enzymes in tumor growth and metastasis has been appreciated.…”

Section: Matrix Metalloproteasesmentioning

confidence: 99%

“…However, most peritumoral MMPs are synthesized by host cells such as endothelial cells, fibroblasts, and inflammatory cells rather than tumor cells themselves. 24,30 In fact, elegant mouse models of tumor progression in mice have demonstrated that MMP-9 expression by bone marrow-derived cells contributes to an aggressive phenotype in squa-mous cell carcinoma. 21,31 Last, MMPs have both tumor promoting and inhibitory effects.…”

Section: Matrix Metalloproteases In Cancermentioning

confidence: 99%

Section: Assessment Of Matrix Metalloproteases In Head and Neck Cancermentioning

confidence: 99%

“…Although HNSCC tumor cells do express some MMP-2, MMP-9, and MT1-MMP, these enzymes are primarily expressed by the surrounding fibroblasts and inflammatory cells. 20,24 Also of note, tumors are continually exposed to normal serum, which contains high levels of MMP-2 and MMP-9.Studies in preclinical mouse models of HNSCC have demonstrated that endogenous and synthetic inhibitors of MMPs can inhibit in vivo growth, 11,62 but more dramatic effects are seen in prevention of metastasis. [63][64][65] Multiple studies using orthotopic head and neck cancer models demonstrate an effect with MMP inhibitors; however, these models emphasize an early intervention, the need for tumor selection epidermal growth factor receptor (EGFR) status, and the lack of cellular toxicity.…”

mentioning

confidence: 99%

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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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Section: Matrix Metalloproteasesmentioning

confidence: 99%

Section: Matrix Metalloproteases In Cancermentioning

confidence: 99%

Section: Assessment Of Matrix Metalloproteases In Head and Neck Cancermentioning

confidence: 99%

mentioning

confidence: 99%

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Matrix metalloproteases in head and neck cancer

Rosenthal¹,

2006

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“…Membrane-type I matrix metalloproteinase (MT1-MMP) is a potent collagenase highly expressed in human and mouse breast carcinomas, where it has been localized to both stromal and tumor epithelial cells (Okada et al, 1995;Polette et al, 1996Polette et al, , 1997Ueno et al, 1997;Bisson et al, 2003;Rosenthal et al, 2004;Szabova et al, 2005). To analyse the role of MT1-MMP in an in vivo tumor model directly, we crossed mice deficient for MT1-MMP (Holmbeck et al, 1999) to a mouse strain carrying the polyoma virus middle T-antigen (PyMT) under the control of the mouse mammary tumor virus (MMTV) promoter (Guy et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

MT1-MMP is required for efficient tumor dissemination in experimental metastatic disease

et al. 2007

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Membrane-type I matrix metalloproteinase (MT1-MMP) is associated with multiple forms of cancer including mammary cancer. To directly evaluate the significance of MT1-MMP expression in tumor progression and metastasis using a genetically induced cancer model, we crossed MT1-MMP-deficient mice to MMTV-polyoma virus middle T-antigen (PyMT) mice. Expression of PyMT in the MT1-MMP-deficient background consistently resulted in hyperplasia of the mammary gland as seen in wild-type PyMT littermates. Following orthotopic transplantation of PyMT þ glands into the cleared mammary fat pad of syngeneic recipient mice, MT1-MMP-deficient tumors were palpable earlier than wild-type tumors. Moreover, MT1-MMP-deficient tumors grew to the experimental end point size quicker than control tumors, but demonstrated markedly reduced ability to metastasize to the lungs of recipient mice. Accordingly, MT1-MMPdeficient mice displayed an overall reduction in metastasis count of 50%. MT1-MMP was expressed solely in the stroma of PyMT-induced tumors and those metastatic nodules that formed in the lungs were devoid of MT1-MMP expression. Stromal fibroblasts isolated from MT1-MMP-deficient tumors did not degrade type I collagen suggesting that efficient dissemination of tumor cells is dependent on stromal cell remodeling of the tumor environment. The data demonstrate directly that MT1-MMP-mediated proteolysis by stromal cells is important in the metastatic process.

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Examination of Oral Cancer Biomarkers by Tissue Microarray Analysis

Choi¹,

Jordan²,

Méndez³

et al. 2008

Arch Otolaryngol Head Neck Surg

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Background. Oral squamous cell carcinoma (OSCC) is a major healthcare problem worldwide. 30 Efforts in our laboratory and others focusing on the molecular characterization of OSCC tumors 31 with the use of DNA microarrays have yielded heterogeneous results. To validate the DNA microarray results on a subset of genes from these studies that could potentially serve as biomarkers of OSCC, we elected to examine their expression by an alternate quantitative method and by assessing their protein levels. Design.Based on DNA microarray data from our lab and data reported in the literature, we identified six potential biomarkers of OSCC to investigate further. We employed quantitative, real-time polymerase chain reaction (qRT-PCR) to examine expression changes of CDH11, MMP3, SPARC, POSTN, TNC, TGM3 in OSCC and normal control tissues. We further examined validated markers on the protein level by immunohistochemistry (IHC) analysis of OSCC tissue microarray (TMA) sections.Results. qRT-PCR analysis revealed up-regulation of CDH11, SPARC, POSTN, and TNC gene expression, and decreased TGM3 expression in OSCC compared to normal controls. MMP3 was not found to be differentially expressed. In TMA IHC analyses, SPARC, periostin, and tenascin C exhibited increased protein expression in cancer compared to normal tissues, and their expression was primarily localized within tumor-associated stroma rather than tumor epithelium.Conversely, transglutaminase-3 protein expression was found only within keratinocytes in normal controls, and was significantly down-regulated in cancer cells. Conclusions. Of six potential gene markers of OSCC, initially identified by DNA microarray analyses, differential expression of CDH11, SPARC, POSTN, TNC, and TGM3 were validated by TMA paper Choi P, et al. 3 qRT-PCR. Differential expression and localization of proteins encoded by SPARC, POSTN, TNC, and TGM3 were clearly shown by TMA IHC.

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Expression of Proteolytic Enzymes in Head and Neck Cancer–Associated Fibroblasts

Cited by 49 publications

References 19 publications

Matrix metalloproteases in head and neck cancer

Matrix metalloproteases in head and neck cancer

MT1-MMP is required for efficient tumor dissemination in experimental metastatic disease

Examination of Oral Cancer Biomarkers by Tissue Microarray Analysis

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