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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Matrix metalloproteinases (MMPs) have been shown to have a significant role in determining cancer cell behaviour. The present study was undertaken to analyze the expression and prognostic value of MMP-7 and MMP-9 in non-small cell lung cancer (NSCLC). The relationship of MMP-7 with beta-catenin was also evaluated. The study consists of 212 patients with resected NSCLC. Tumour samples were stained immunohistochemically, and the expression of MMP-7 and MMP-9 was evaluated in both tumour cells and peritumoural stromal tissue. The results were compared to clinicopathological factors of the patients. A high staining of MMP-7 and MMP-9 in tumour cells was noted in 62 (30%) and 113 (57%) cases, respectively. Expression of MMP-7 was noted more often in adenocarcinomas than in other histological types (p=0.022). High cancer cell associated MMP-7 was related to lower T-factor (p=0.037), better tumour differentiation (p=0.005) and normal beta-catenin expression in tumour cells (p=0.001). A high MMP-9 expression in tumour cells was related to poor tumour differentiation (p=0.016). The stromal signal for MMP-9 was observed in 58 (32%) cases and was linked with higher tumour grade (p=0.031). In survival analyses the significant predictors of survival were histological type of tumour and tumour stage (p=0.0009 and 0.0012, respectively). MMP-7 or MMP-9 signals were not related to patient's outcome. The results show that high MMP-9 expression indicates aggressive, and high MMP-7 less aggressive tumour behaviour in NSCLC. However, MMP-7 and MMP-9 expressions had no prognostic value in NSCLC.
Lung Cancer 2006 Mar
PMID:Expression of matrix metalloproteinases 7 and 9 in non-small cell lung cancer. Relation to clinicopathological factors, beta-catenin and prognosis. 1642 26

Exposure to arsenic in drinking water is associated with an increased rate of lung cancer. The objective of this study was to determine whether arsenic exposure at relatively low concentrations (approximately 20 microg/L) is associated with changes in biomarkers of lung inflammation, as measured by the ratio of sputum metalloproteinase and antiproteinase activity. A total of 73 subjects residing in Ajo and Tucson, Arizona were recruited for this cross-sectional study. Tap water and first morning void urine were analyzed for arsenic. Matrix metalloproteinase 2 (MMP-2), 9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1) were measured in induced sputum. Household tap water arsenic levels in Ajo (20.3+/-3.7 microg/L) were higher than in those Tucson (4.0+/-2.3 microg/L), as were mean urinary total inorganic arsenic levels (29.1+/-20.4 and 11.0+/-12.0 microg/L, respectively). Log-normalized MMP-2, MMP-9, and TIMP-1 concentrations in sputum were not significantly different between towns. However, after adjusting for town, asthma, diabetes, urinary monomethylarsonic acid/inorganic arsenic, and smoking history, total urinary arsenic was negatively associated with MMP-2 and TIMP-1 levels in sputum and positively associated with the ratio of MMP-2/TIMP-1 and MMP-9/TIMP-1 in sputum. Increased sputum proteinase/antiproteinase activity suggests a potential toxic mechanism for low-level arsenic exposure.
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PMID:Environmental arsenic exposure and sputum metalloproteinase concentrations. 1648 58

Hypoxia is associated with malignant progression and poor outcome in human cancers. The effects of hypoxia are mediated by a series of genomic changes that enable tumor cells to survive or escape their oxygen deficient environment. Recent studies indicated that carbonic anhydrase IX (CA IX) is an intrinsic marker of hypoxia. In the present study we investigated with quantitative RT-PCR the expression of CA IX mRNA in 93 non-small cell lung carcinomas (NSCLC) and in their paired not affected tissues. CA IX mRNA was expressed in 100% NSCLC and in 76% of paired not affected tissues, even if tumoral CA IX expression was found constantly higher (p < 0.02) than that found in normal tissues. The increase of CA IX mRNA expression in cancer tissues was significantly correlated to the increase of corresponding protein, as determined with conventional immunoblotting (p = 0.027). In addition the expression of CA IX mRNA in NSCLC samples was significantly correlated to VEGF (p = 0.002) and MMP-9 (p = 0.002) mRNAs. Whereas CA IX mRNA expression was not associated to any clinical-pathological parameters in our patients, global survival analysis of cancer-related death revealed that high expression of CA IX mRNA predicted unfavorable outcome (p = 0.001) and shorter disease free survival interval (p = 0.004). A multivariate analysis showed that CA IX expression was the strongest prognostic parameter (p = 0.000) in comparison to other conventional predictive markers. In addition, differences emerged on the basis of clinical-pathological parameters: in fact separate Kaplan-Meyer analyses of patients indicated that whereas high levels of CA IX mRNA expression were not predictive of worse prognosis in early NSCLC (G1, T1, Stage 1 and pN- patients), this parameter appeared highly significant in advanced NSCLC (G2-G3, T2-T3, Stage 2-3 and pN+ patients). Finally we demonstrated that CA IX expression was not able to discriminate different survival probability in adenocarcinomas, whereas the same parameter was highly predictive in squamous (p = 0.03) and adenosquamous cell carcinomas (p = 0.001).
Lung Cancer 2006 Apr
PMID:Quantitative analysis of carbonic anhydrase IX mRNA in human non-small cell lung cancer. 1651 6

To analyze mechanisms for cancer metastasis, we established high metastatic sublines from mouse Lewis lung cancer (P29) by repeated injection. Sublines established from the two subclones H7 and C4 commonly exhibited increased proliferation and invasion activity and reduced expression of ganglioside GM1, although they showed different preferences in their target organs of metastasis. The high metastatic sublines secreted higher levels of activated matrix metalloprotease (MMP)-9 as well as pro-MMP-9 in the culture medium than the parent lines. Furthermore, they contained MMP-9 at the glycolipid-enriched microdomain (GEM)/rafts fractionated by the sucrose density gradient ultracentrifugation of Triton X-100 extracts, whereas the parent cells showed faint bands at the fraction. When high metastatic sublines were treated with methyl-beta-cyclodextrin, their invasion activities were dramatically suppressed, and the MMP-9 secretion was also suppressed. All these results indicated that GEM/rafts play crucial roles in the increased invasion and high metastatic potential. To clarify the implication of reduced GM1 expression, low GM1-expressing cell lines were established using an RNA interference-expression vector of the GM1 synthase. Low GM1-expressing cell lines showed increased proliferation and invasion, enrichment in the GEM/rafts, and increased secretion of MMP-9. Among adhesion molecules, only integrin beta1 was detected in GEM/rafts with stronger intensity in high metastatic lines and low GM1-expressing cells. Taken together, integrins seemed to be enriched in the GEM/rafts by reduced GM1 levels, and subsequently MMP-9 was recruited to the GEM/rafts, resulting in its efficient secretion and activation, and eventually in the increased invasion and metastatic potentials.
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PMID:Metastatic potential of mouse Lewis lung cancer cells is regulated via ganglioside GM1 by modulating the matrix metalloprotease-9 localization in lipid rafts. 1663 68

Oncostatin M (OSM) is a multifunctional regulator of cell growth and differentiation. It inhibits the growth of many types of tumor cells, but its role in metastasis is unknown. We studied the human OSM expressed and purified from reconstructed E. Coli on its activity of inhibiting metastasis of tumor cells by a series of assays in vitro and in vivo. Clone formation assay in soft agar was used to measure the inhibition activity of OSM on the proliferation of high metastatic human lung cancer cells 95-D. Cell attachment assay, cell migration assay and cell invasion assay were used to evaluate inhibition by OSM on 95-D cells of the adhesion ability, the migration ability, and the ability of cells to cross tissue barriers, respectively. Inhibition of OSM on secretion of MMP-2 and -9 secretion in 95-D cells was determined by Western blot. The in vivo inhibitory effect of OSM on metastasis of murine melanoma cells B16BL6 was examined in the pulmonary metastasis model. In vitro studies showed that OSM inhibited the proliferation of 95-D cells at low concentration. OSM also reduced the adhesion and invasion ability of 95-D cells and inhibited the secretion of MMP-2 and MMP-9 in OSM treated cells. In vivo results showed that OSM (20 microg/kg/d for 7 days) inhibited pulmonary metastasis at a rate of 20.7%. There were no differences in animal weights among the groups. These results suggest that OSM has the potential of being a clinical inhibitor on metastasis of some cancer cells.
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PMID:Inhibition effect of Oncostatin M on metastatic human lung cancer cells 95-D in vitro and on murine melanoma cells B16BL6 in vivo. 1697 73

Matrix metalloproteinases (MMP) are a group of proteinases that have normal physiologic roles degrading and remodeling the extracellular matrix. They also have multiple roles in different stages of tumor progression. Elevated levels of MMPs have been observed in many tumors; these increases have a strong association with the invasive phenotype. MMP-2 and MMP-9 are particularly involved in cancer invasion and metastasis. MMP inhibitors are currently being tested as therapeutic agents for a number of cancers in both preclinical models and in clinical trials. To date, clinical trials using this strategy have had limited efficacy. A major concern is the lack of specificity of commercially available MMP inhibitors. An adenoviral vector expressing small interfering RNA against the MMP-2 gene (Ad-MMP-2) was constructed to specifically inhibit MMP-2 expression. The effect of Ad-MMP-2 on invasion, angiogenesis, tumor growth, and metastasis of A549 lung cancer cell was evaluated. Ad-MMP-2 infection of lung cancer cells showed specific down-regulation of MMP-2 protein, activity, and transcription as determined by Western blotting, gelatin zymography, and reverse transcription-PCR. Ad-MMP-2 inhibition also mitigated lung cancer invasion and migration, and reduced tumor cell-induced angiogenesis in vitro. In an experimental metastatic lung tumor model, treatment of established tumors by Ad-MMP-2 inhibited s.c. tumor growth and formation of lung nodules in mice. Adenoviral-mediated RNA interference against MMP-2 has significant therapeutic potential for lung cancer and exerts some of this effect by inhibiting angiogenesis.
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PMID:Adenovirus-mediated small interfering RNA against matrix metalloproteinase-2 suppresses tumor growth and lung metastasis in mice. 1698 63

Snail, Slug and Sip1 regulate cadherin and protease expression and mediate epithelial-mesenchymal transition in cancer. We analyzed the expression of cadherins and matrix metalloproteinases (MMP) and their transcriptional regulators in malignant mesothelioma (MM). One hundred and ten MM specimens (86 solid, 24 effusions) and 10 non-malignant effusions with reactive mesothelial cells (RMC) were analyzed for E-cadherin, N-cadherin and P-cadherin protein expression using immunhistochemistry. MM effusions were further analyzed for expression of Snail, Slug, Sip1, E-cadherin, MMP-2, MMP-9, MT1-MMP (MMP-14) and the MMP inhibitor TIMP-2, and for MMP-2 and MMP-9 activity using RT-PCR, Western blotting, immunhistochemistry and zymography. Results were analyzed for relationship with specimen type (biopsy versus effusion) and anatomic site (pleural versus peritoneal). E-cadherin, N-cadherin and P-cadherin expression was found in 69/110 (63%), 87/110 (79%) and 84/110 (76%) MM cases, respectively. Pleural and peritoneal MM showed comparable expression, but all three cadherins were upregulated in effusions compared to solid tumors (p<0.001). RMC were uniformly negative for E-cadherin and N-cadherin, and showed P-cadherin expression in 7/10 specimens. Immunohistochemistry localized MMP-2, MMP-9 and TIMP-2 to MM cells in 11/15, 14/15 and 8/15 effusions, respectively. RT-PCR showed direct association between MMP-2 mRNA expression level and the levels of MT1-MMP (p=0.027) and TIMP-2 (p=0.011). Snail protein expression showed positive association with MT1-MMP (p=0.016) and TIMP-2 (p=0.02) mRNA expression, but its expression was unrelated to MMP-2 and MMP-9 expression or activity. Snail, Slug and Sip1 levels did not show inverse association with E-cadherin levels. Our data show that E-cadherin and N-cadherin are selectively expressed in malignant mesothelial cells, and that P-cadherin and N-cadherin are expressed with similar frequency in MM. In agreement with our earlier data for ovarian carcinoma, cadherin expression is upregulated in effusions compared to solid lesions. The increased E-cadherin expression in effusions may be related to lack of negative regulation at the epigenetic level. The relationship between Snail and MMP in MM is uncertain at present.
Lung Cancer 2006 Dec
PMID:Expression of Snail, Slug and Sip1 in malignant mesothelioma effusions is associated with matrix metalloproteinase, but not with cadherin expression. 1699 43

Matrix metalloproteinases (MMP) including MMP-2 and MMP-9 play a major role in tumour invasion by proteolysing the extracellular matrix. Their activation, particularly that of MMP-9, is partly dependent on plasmin that is inhibited by TFPI-2 (tissue factor pathway inhibitor-2), a serine protease inhibitor whose gene expression is decreased in about one-third of non-small cell lung cancers (NSCLC). In addition, MMP-2 and MMP-9 are essential in the development of NSCLC and can be regulated by functional promoter polymorphisms. In this study, the -1306C/T MMP-2, -735C/T MMP-2 and -1562C/T MMP-9 polymorphisms were analysed in 90 NSCLC patients and 90 controls. In addition, the promoter region of the TFPI-2 gene was screened for sequence variations in both groups by DHPLC. A -167G/A polymorphism was identified in 3% of controls whereas none of the 90 patients exhibited this genetic variation in the TFPI-2 promoter region. Moreover, no difference in -1306C/T MMP-2, -735C/T MMP-2 and -1562C/T MMP-9 genotypes was found between cases and controls. However, the homozygous -1562CC MMP-9 genotype was more frequent in patients with squamous cell carcinoma than in controls (p=0.018). When genotype distributions were compared to MMP-2 and MMP-9 gene expression in tumours, no relationship was found with the -1306 MMP-2 and -1562 MMP-9 polymorphisms. In contrast, tumour MMP-2 gene expression was lower in homozygous -735CC patients than in those with CT or TT genotypes. In addition, the survival time was longer in patients with the MMP-2 -735T allele than in those with the CC genotype (p=0.02). The relative risk of death was increased 2.6-fold in -735CC patients (p=0.045; 95% CI=1.0-6.7). The results of this study suggest that the -735C/T MMP-2 polymorphism might be an independent prognostic marker in NSCLC, but this should be confirmed in a larger cohort of patients.
Lung Cancer 2007 May
PMID:Influence of MMP-2 and MMP-9 promoter polymorphisms on gene expression and clinical outcome of non-small cell lung cancer. 1720 28

Cancer invasion and metastasis, involving a variety of pathological processes and cytophysiological changes, contribute to the high mortality of lung cancer. The type 1 insulin-like growth factor receptor (IGF-1R), associated with cancer progression and invasion, is a potential anti-invasion and anti-metastasis target in lung cancer. To inhibit the invasive properties of lung cancer cells, we successfully down-regulated IGF-1R gene expression in A549 human lung cancer cells by small interfering RNA (siRNA) technology, and evaluated its effects on invasion-related gene expression, tumor cell in vitro invasion, and metastasis in xenograft nude mice. A549 cells transfected with a plasmid expressing hairpin siRNA for IGF-1R showed a significantly decreased IGF-1R expression at the mRNA level as well as the protein level. In biological assays, transfected A549 cells showed a significant reduction of cell-matrix adhesion, migration and invasion. Consistent with these results, we found that down-regulation of IGR-1R concomitantly accompanied by a large reduction in invasion-related gene expressions, including MMP-2, MMP-9, u-PA, and IGF-1R specific downstream p-Akt. Direct tail vein injections of plasmid expressing hairpin siRNA for IGF-1R significantly inhibited the formation of lung metastases in nude mice. Our results showed the therapeutic potential of siRNA as a method for gene therapy in inhibiting lung cancer invasion and metastasis.
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PMID:Suppression of type 1 Insulin-like growth factor receptor expression by small interfering RNA inhibits A549 human lung cancer cell invasion in vitro and metastasis in xenograft nude mice. 1727 89

The brain is frequently affected by the spread of lung cancer, and haematogenous metastasis is a common route to brain metastasis. We therefore developed an isogenic brain metastasis model of lung cancer to use the Lewis lung carcinoma cell line and analysed dynamics of neoplastic cells after extravasation. Histological analysis revealed two characteristic patterns: metastatic foci exhibiting an angiocentric pattern were designated 'perivascular proliferations'; neoplastic cells infiltrating the brain parenchyma were designated 'invasive proliferations'. Electron microscopic observation of perivascular proliferations showed that neoplastic cells were confined to the perivascular space. In invasive proliferations, however, fragments of collagen fibre were observed in the gaps between neoplastic cells, indicating that the neoplastic cells had disintegrated the pia-glial membrane. We analysed the expressions of matrix metalloproteinase-2 (MMP-2) and MMP-9 by using both immunohistochemical analysis and real-time polymerase chain reaction analysis. MMP-2 expression was significantly higher in invasive proliferations. MMP-9 expression was significantly higher in day 7, but there was no significant difference in day 11. The pia-glial membrane and perivascular space are the barriers that neoplastic cells must overcome to infiltrate the brain. In conclusion, our findings suggest that brain metastasis requires two distinct processes.
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PMID:A double three-step theory of brain metastasis in mice: the role of the pia mater and matrix metalloproteinases. 1749 10


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