Expression of Matrix Metalloproteinases and Tissue Inhibitor of Matrix Metalloproteinases in Non-Small-Cell Lung Cancer

Suzuki, Makoto; Iwamoto, Toshihiko; Fujisawa, Takehiko; Baba, Masayuki; Yamaguchi, Yutaka; Kimura, Hideki; Suzuki, Hiroto

doi:10.1159/000024506

Cited by 37 publications

(20 citation statements)

References 19 publications

(21 reference statements)

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“…Thus, in the present study, we measured the activities of MMPs. Several studies have shown that MMP-2 activity may be associated with a poor prognosis in lung cancer and other cancers [10]. We found that MMP-2 activity was significantly increased in tumor tissue of NSCLC.…”

Section: Discussionmentioning

confidence: 48%

Matrix Metalloproteinase Activity in Early-Stage Lung Cancer

et al. 2013

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Background: The matrix metalloproteinases (MMPs)-2, -9 and -7 are thought to be associated with tumor invasion, metastasis, and angiogenesis. However, their possible roles in early-stage lung cancer are not clear. We measured the activity of MMP-2, -7 and -9 in early-stage lung cancer tissues. Material and Methods: Normal lung tissues and cancer tissues were collected from 60 consecutive stage-I non-small cell lung cancer (NSCLC) patients. The activities of MMP-2 and MMP-9 were determined by gelatin zymography, and the activity of MMP-7 was determined by casein zymography. Furthermore, the ratio of the active form of MMP-2 in tumor tissue (T) compared with normal tissue (N) was determined, and the survival in the groups with different MMP-2 T:N ratio was compared. Results: The activity of both MMP-2 and MMP-9 was detected in all cancer and normal tissues. Interestingly, MMP-9 activity was significantly reduced, whereas MMP-2 activity was significantly increased, in cancer tissues compared to normal tissues. The survival rate of the MMP-2 T:N ratio > 2.5 group was 57.45%, which was significantly reduced compared with that of the T:N ratio ≤ 2.5 group (86.78%). Conclusion: Our findings suggest that MMP-2, but not MMP-9 and MMP-7, may be implicated in early-stage tumor invasion, metastasis, and angiogenesis in NSCLC.

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Section: Discussionmentioning

confidence: 48%

Matrix Metalloproteinase Activity in Early-Stage Lung Cancer

et al. 2013

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“…MMP-2 and MMP-9 degrade collagen type IV, a major component of ECM, whereas MMP-13 mainly degrades fibrillar collagen and is not expected to contribute greatly to cell invasion through basement membrane. By studying the expression of MMP-2 and MMP-9 in 11 NSCLC cell lines and 43 NSCLC clinical specimens using PCR and immunohistochemistry, Suzuki et al 39 concluded that MMP-2 plays a more important role in invasion of NSCLC than MMP-9. Using immunocytochemistry, Bodey et al 40 reported high-intensity staining of MMPs 2, 9 and 13 in human lung adenocarcinomas, which is consistent with our results obtained from human lung squamous carcinoma.…”

Section: Discussionmentioning

confidence: 99%

Enhanced in vitro invasiveness and drug resistance with altered gene expression patterns in a human lung carcinoma cell line after pulse selection with anticancer drugs

Liang

O’Driscoll

McDonnell

et al. 2004

Intl Journal of Cancer

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The human lung carcinoma cell line DLKP was exposed to sequential pulses of 10 commonly used chemotherapeutic drugs (VP-16, vincristine, taxotere, mitoxantrone, 5-fluorouracil, methotrexate, CCNU, BCNU, cisplatin and chlorambucil); resulting cell lines exhibited resistance to the selecting agents (ranging approx. 1.5-to 36-fold) and, in some cases, cross-resistance to methotrexate (approx. 1.4-to 22-fold), vincristine (1.6-to 262-fold), doxorubicin (Adriamycin, approx. 1.1-to 33-fold) and taxotere (approx. 1.1-to 36-fold). Several of the variants displayed collateral sensitivity to cisplatin. A marked increase in in vitro invasiveness and motility was observed with variants pulsed with mitoxantrone, 5-fluorouracil, methotrexate, BCNU, cisplatin and chlorambucil. There was no significant change in invasiveness of cells pulsed with VP-16, vincristine, taxotere or CCNU. All of the pulseselected variants showed elevated levels of MDR-1/P-gp protein by Western blot analysis, although mdr-1 mRNA levels were not increased (except for DLKP-taxotere). In DLKPtaxotere, MRP1 protein levels were also greatly elevated, but mrp1 mRNA levels remained unchanged. BCRP was upregulated in DLKP-mitoxantrone at both the mRNA and protein levels. Gelatin zymography, Western blot and RT-PCR showed that DLKP and its variants secreted MMPs 2, 9 and 13. MMP inhibition assays suggested that MMP-2 plays a more important role than MMPs 9 and 13 in cell invasion of these DLKP drug-resistant variants in vitro. Reducing intracellular drug levels, often associated with overexpression of P-gp, 3 members of the MRP family 4 and the BCRP/ MXR protein, 5 is an important and frequent mechanism of MDR.Invasion through basement membrane is believed to be a critical step in metastasis. There are 4 main classes of proteases involved in proteolytic degradation of the ECM: serine-, cysteine-and aspartyl-proteases as well as MMPs. 6 The MMPs are a family of more than 20 members produced by tumour cells, connective tissue cells and inflammatory cells. MMPs are secreted as latent proenzymes and activated by proteolytic removal of an aminoterminal domain. 7 A large body of evidence shows that MMPs play a crucial role in cancer invasion and metastasis. Based on sequence homology and substrate specificity, MMP-2 and MMP-9 are classified as type IV collagenases that degrade the major component (type IV collagen) of basement membrane; 8 MMP-13, also called "collagenase-3", belongs to a group known as interstitial collagenases, which degrade collagen types I, II, III, VII, VIII and X. 9 The possibility of a relationship between drug resistance and invasion/metastasis phenotypes has been raised by 2 types of observation: 10 firstly, some tumour cells selected for resistance to drugs are invasive/metastatic relative to nonresistant parental cells; secondly, in some cases, secondary (more metastatic) tumours are more resistant to chemotherapeutic drugs than their primary counterparts. In support of this, Osmak et al. 11 reported a study of drug-resistant cervical and ...

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“…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].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2004

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Summary Extracellular matrix (ECM) homeostasis is strictly maintained by a coordinated balance between the expression of matrix metalloproteinases (MMPs) and their specific inhibitors (TIMPs). Our study was focused on the simultaneous measurement of the expression profile of MMP9 mRNA and its principal inhibitor, TIMP-1, in 100 non small cell lung cancers (NSCLC) and in corresponding adjacent non malignant tissues. The measurement was performed with a multiplex quantitative RT-PCR assay based on TaqMan assay, using two probes labelled with different fluorocromes. We found that both MMP9 and TIMP-1 mRNAs were significantly higher in NSCLC (P < 0.0001) in comparison to corresponding controls as well as the MMP9/TIMP-1 ratio (P = 0.014). MMP9 and TIMP-1 mRNA expression was highly correlated in cancer samples (r = 0.73, P < 0.0001). The analysis in the two main histotypes revealed a significant increase of MMP9 mRNA in adenocarcinomas in comparison to normal tissues (P = 0.006) but not in squamous cell carcinomas, while TIMP-1 mRNA showed a significative increase both in adenocarcinomas and in squamous cell carcinoma samples (P = 0.02 and 0.01, respectively). Both MMP9 and TIMP-1 mRNAs were significantly correlated to lymphnode invasion and cancer stage. Survival analysis revealed that high levels of expression of MMP9 mRNA, but not of TIMP-1, were significantly associated to an unfavourable outcome in NSCLC patients in toto (P = 0.017). In addition our results showed that high levels of MMP9 expression are of independent prognostic impact in operable NSCLC.Our data seem to demonstrate a simultaneous and coordinated up-regulation of MMP9 and TIMP-1 expression at the mRNA level in NSCLC, even if this phenomenon seems variable according to the histotype. In addition, the increase of MMP9/TIMP-1 ratio may reflect an unbalance of their production in affected tissues. The increased expression of the two mRNAs, even not necessarily equate their enzymatic activities, seems to parallel a major cancer aggressiveness.

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Expression of Matrix Metalloproteinases and Tissue Inhibitor of Matrix Metalloproteinases in Non-Small-Cell Lung Cancer

Cited by 37 publications

References 19 publications

Matrix Metalloproteinase Activity in Early-Stage Lung Cancer

Matrix Metalloproteinase Activity in Early-Stage Lung Cancer

Enhanced in vitro invasiveness and drug resistance with altered gene expression patterns in a human lung carcinoma cell line after pulse selection with anticancer drugs

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

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