Differential expression of matrix metalloproteinases and their inhibitors in non-small cell lung cancer

Thomas, P.; Khokha, Rama; Shepherd, Frances A.; Feld, Ronald; Tsao, Ming‐Sound

doi:10.1002/(sici)1096-9896(200002)190:2<150::aid-path510>3.0.co;2-w

Cited by 116 publications

(67 citation statements)

References 22 publications

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“…We also found an up-regulation of host-derived MMP-13 in tumors from the orthotopic model compared with control lung. MMP-13 has shown to be expressed in the stroma of 87% of human NSCLC samples (21). The functional significance of the overexpression of MMP-13 in lung tumors remains unknown.…”

Section: Discussioncontrasting

confidence: 99%

Analysis of Host- and Tumor-Derived Proteinases Using a Custom Dual Species Microarray Reveals a Protective Role for Stromal Matrix Metalloproteinase-12 in Non–Small Cell Lung Cancer

et al. 2006

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We used a customized Affymetrix protease microarray (Hu/Mu ProtIn chip) designed to distinguish human and mouse genes to analyze the expression of proteases and protease inhibitors in lung cancer. Using an orthotopic lung cancer model, we showed that murine matrix metalloproteinase (MMP)-12, MMP-13, and cathepsin K were up-regulated in tumor tissue compared with normal mouse lung. To determine the relevance of stromal proteases detected using this model system, we compared the results to an analysis of human lung adenocarcinoma specimens using the U133 Plus 2.0 Affymetrix microarray. MMP-12, MMP-13, and cathepsin K showed an increase in expression in human tumors compared with normal lung similar to that seen in the orthotopic model. Immunohistochemical analysis confirmed MMP-12 expression in the stroma of human lung tumor samples. To determine the biological relevance of stromal MMP-12, murine Lewis lung carcinoma cells were injected into the tail vein of syngeneic wild-type (WT) and MMP-12-null mice. MMP-12-null and WT mice developed equivalent numbers of lung tumors; however, there was a 2-fold increase in the number of tumors that reached >2 mm in diameter in MMP-12-null mice compared with WT controls. The increase in tumor size correlated with an increase in CD31-positive blood vessels and a decrease in circulating levels of the K1-K4 species of angiostatin. These results show a protective role for stromal MMP-12 in lung tumor growth. The use of the Hu/Mu ProtIn chip allows us to distinguish tumor-and host-derived proteases and guides the further analysis of the significance of these genes in tumor progression. (Cancer Res 2006; 66(16): 7968-75)

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Section: Discussioncontrasting

confidence: 99%

Analysis of Host- and Tumor-Derived Proteinases Using a Custom Dual Species Microarray Reveals a Protective Role for Stromal Matrix Metalloproteinase-12 in Non–Small Cell Lung Cancer

et al. 2006

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“…Metastatic dissemination was hampered in MMP-9-deficient mice when compared to wild-type control mice in a mouse model of cancer dissemination (Itoh et al, 1999). The expression of TIMPs (particularly TIMP-1 and TIMP-2) was correlated with the cancer stage (Thomas et al, 2000) and their levels have been proposed to be used as prognosis markers of lung adenocarcinoma progression (Ylisirnio et al, 2000).…”

Section: Role Of Mmps In Lung Cancercontrasting

confidence: 87%

Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs in the respiratory tract: Potential implications in asthma and other lung diseases

Guéders

Foidart

Noël

et al. 2006

European Journal of Pharmacology

279

224

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In healthy lung, Matrix Metalloproteinases (MMPs) and their physiological inhibitors, tissue inhibitors of matrix metalloproteinases (TIMPs), are produced in the respiratory tract by a panel of different structural cells. These activities are mandatory for many physiological processes including development, wound healing and cell trafficking. Deregulation of proteolytic-antiproteolytic network and inappropriate secretion of various MMPs by stimulated structural or inflammatory cells is thought to take part to pathophysiology of numerous lung diseases including asthma, chronic obstructive pulmonary disease (COPD), lung fibrosis and lung cancer. Cytokines and growth factors are involved in these inflammatory processes and some of those mediators interact directly with MMPs and TIMPs leading either to a regulation of their expression or changes in their biological activities by proteolytic cleavage. In turn, cytokines and growth factors modulate secretion of MMPs establishing a complex network of reciprocal interactions. Every MMP seem to play a rather specific role and some variations of their expression are observed in different lung diseases. The precise role of these enzymes and their inhibitors is now studied in depth as they could represent relevant therapeutic targets for many diseases. Indeed, MMP inhibition can lead either to a decrease of the intensity of a pathological process or, in the contrary for some of them, to an increase of disease severity. In this review, we focus on the role played by MMPs and TIMPs in asthma and we provide an overview of their potential roles in COPD, lung fibrosis and lung cancer, with a special emphasis on loops including MMPs and cytokines and growth factors relevant in these diseases.Keywords: Matrix metalloproteinase; Tissue inhibitor of MMP; Asthma; Cytokine; Growth factors Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs)Matrix metalloproteinases (MMPs), or matrixins, belong to the metzincin superfamily of metalloproteinases, also including astacins, ADAMs (a protein with a disintegrin and metallopro-tease domain) and ADAM-TS proteases (ADAM with a thrombospondin-like motif) (Sternlicht and Werb, 2001;Folgueras et al., 2004;Handsley and Edwards, 2005;Noel et al., 2004). MMPs are proteolytic enzymes believed to be implicated in many physiological and pathological processes including embryonic development, morphogenesis, reproductive processes, bone remodeling, wound healing, cancer, arthritis, atherosclerosis, MMPs are zinc and calciumdependent enzymes being able to degrade virtually all extracellular matrix components. This can modulate cell behaviour by creating influential cellular environment (Shapiro, 1998). The extracellular matrix is a complex network of molecules including collagens, fibronectin, laminin, entactin/ nidogen and heparan sulfate proteoglycans (Mott and Werb, 2004). The extracellular matrix is a mechanical support for cells but also acts as a reservoir for cytokines and growth factors (vascular endothelial ...

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“…6 Furthermore, these 2 previous studies observed MMP-9 expression in 65 or 52% of the patients, respectively. In view of a recent histopathological study of differential expression of MMPs in NSCLC, 14 which reported MMP-9 expression in 36.5% and MMP-9 homogeneous expression in 2.6% of tissue sections, immunohistochemical finding of MMP-9 in 52-65% of specimens might rather be assessed as detection of MMP-9 expression, but may not be considered as detection of homogeneous expression of MMP-9. The high rates of positive immunostaining could result from the cut point of 20% stained cancer cells in both studies 10,11 mentioned above.…”

Section: Discussionmentioning

confidence: 99%

Prognostic impact of matrix metalloproteinase‐9 in operable non‐small cell lung cancer

Sienel¹,

Hellers²,

Morresi‐Hauf³

et al. 2002

Intl Journal of Cancer

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We assessed the clinical impact of MMP-9 expression on long-term survival in patients with operable non-small cell lung cancer (NSCLC). Primary tumors of 143 consecutive patients with NSCLC resected completely and without overt distant metastases (pT1-4, pN0-2, M0, R0) were examined for MMP-9 expression using immunohistochemistry with a polyclonal, affinity-purified rabbit antibody that recognizes both latent and active MMP-9. Immunohistochemical staining of tumor cells was evaluated in comparison to normal bronchiolar epithelium that served as an internal positive control. MMP-9 expression was categorized into negative, <5% tumor cells stained; heterogeneous, >5% and <95% tumor cells stained; and homogeneous, >95% The standard treatment for early stage NSCLC is surgery resulting in a 5-year survival rate of only 50 -60% in Stage I and II. 5,6 A better understanding of the molecular mechanisms of lung cancer progression might help to identify patients at risk for an unfavorable outcome with potential consequences for adjuvant therapy.Penetration of basement membranes and degradation of extracellular matrix are essential steps in the dissemination of tumor cells from primary tumors to distant organs. 7 One group of proteolytic enzymes that has been associated with these abilities is the matrix metalloproteinase family (MMP). Matrix metalloproteinase 9 (MMP-9) (92 kDa Type IV collagenase or gelatinase B) has the potency to degrade gelatin and Type IV collagen, 8 which is a major component of basement membranes. The clinical relevance of MMP 9 in NSCLC remains in discussion. First clinical trials investigating the efficacy of MMP-inhibitors in advanced cancer were rather disappointing. 9 Furthermore, previous studies examining the prognostic impact of immunohistochemical detection of MMP-9 in NSCLC 10,11 are discussed controversially because they did not demonstrate an independent prognostic impact of MMP-9 considering all standard prognostic factors included in the international system for staging lung cancer. 6 To clarify the prognostic impact of MMP 9 in operable NSCLC, we applied a new immunohistochemical evaluation system, focusing on homogeneous expression of MMP-9. The prognostic value was analyzed in relation to established prognostic factors of the TNM-system. Our study shows that the prognostic impact of homogeneous MMP-9 expression remains independent from possible prognostic joint effects of pT-status, pN-status, tumor histology and tumor grading. Because of this independence, MMP-9 may be considered as an interesting target for adjuvant anticancer therapy in operable NSCLC using selective MMP-inhibitors with high specificity for MMP-9. MATERIAL AND METHODS PatientsAfter approval by the ethical committee of the University of Munich and after written informed consent, tissue specimens of 147 consecutive patients with completely resected NSCLC were collected. The tumors were classified according to the international union against cancer (UICC) TNM-classification. 6 The preoperative staging of all patient...

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Differential expression of matrix metalloproteinases and their inhibitors in non-small cell lung cancer

Cited by 116 publications

References 22 publications

Analysis of Host- and Tumor-Derived Proteinases Using a Custom Dual Species Microarray Reveals a Protective Role for Stromal Matrix Metalloproteinase-12 in Non–Small Cell Lung Cancer

Analysis of Host- and Tumor-Derived Proteinases Using a Custom Dual Species Microarray Reveals a Protective Role for Stromal Matrix Metalloproteinase-12 in Non–Small Cell Lung Cancer

Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs in the respiratory tract: Potential implications in asthma and other lung diseases

Prognostic impact of matrix metalloproteinase‐9 in operable non‐small cell lung cancer

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