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

Abstract

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...

Serum matrix metalloproteinase‐9 in head and neck squamous cell carcinomais a prognostic marker

“…[4][5][6][7][8] Some immunohistochemical studies have shown that MMP-9 could have prognostic value in predicting long-term outcome in different types of tumors. 14,22,31,32 In our previous study, we reported that overexpression of MMP-9 immunoreactive protein in tissue section from primary tumors of head and neck carcinoma correlated with cause-specific and relapsefree survival. 22 There are, however, few previous publications report that serum MMP-9 would have any prognostic role in cancer patients.…”

“…9,10 Increased expression of MMP-2 and MMP-9 immunoreactive protein in various cancer tissues has been found to be associated with shortened survival and shortened relapse-free times in patients suffering from these cancers. [11][12][13][14] Recently, increased serum MMP-9 and MMP-2 levels have been reported to be practical in predicting disease prognosis in some types of tumors. [15][16][17][18] Several studies have shown that gelatinases are expressed in head and neck carcinoma cells, and gelatinases may take part in the progression and invasion of these tumors.…”

Simultaneous measurement of MMP9 and TIMP1 mRNA in human non small cell lung cancers by multiplex real time RT-PCR

“…As recently stated by Bonomi [28], a combined therapy with MMP-inhibitors agents should be limited to patients with MMP overexpression and pharmacological treatments should be tailored accordingly. For this type of treatment, the measurement of expression of the target MMP in tumor, in comparison to the adjacent non cancer tissue, may identify patients eligible for a specific MMP inhibitor therapy [19]. Even if an increased MMP mRNA expression may not be associated to an increased enzymatic activity, because of the necessity of the activation of MMP latent forms, an alteration of MMPs and TIMPs expression in cancer tissues could reflect an altered balance in the control of ECM, which is always a feature of malignant disease [5].…”

“…Among them, TIMP-1 has a selective binding with the pro-MMP-9 and is considered the main inhibitor for MMP-9 [13,15]. The detection of MMP9 expression has been performed in lung cancer by immunohistochemistry [1,7,[15][16][17][18][19], zymography [9,10,18,20], immunoenzymatic assays [21] and Northern analysis [8,15]. Increased plasma levels of MMP-9 protein were also detected in lung cancer patients [22,23].…”

Characteristics of primary care physicians and their practices associated with mammography rates for older women

“…There were some discrepancies in the correlations between MMP-9 expression and tumor invasiveness in some tumor types. 33,[35][36][37][38] We noted a small number of instances of TIMP-1 expression among thymic epithelial tumors. The current study demonstrated that neither MMP-9 nor TIMP-1 plays a large role in the invasiveness of thymic epithelial tumors.…”