Clinical Cancer Research CTRC-AACR San Antonio Breast Cancer Symposium
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Delebecq, T. J.
Right arrow Articles by Huet, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Delebecq, T. J.
Right arrow Articles by Huet, G.
Clinical Cancer Research Vol. 6, 1086-1092, March 2000
© 2000 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Overexpression Level of Stromelysin 3 Is Related to the Lymph Node Involvement in Non-small Cell Lung Cancer1

Thérèse Janecki Delebecq, Henri Porte, Farid Zerimech, Marie-Christine Copin, Valérie Gouyer, Evelyne Dacquembronne, Malika Balduyck, Alain Wurtz and Guillemette Huet2

Laboratoire de Biochimie, Hôpital Claude Huriez [T. J. D., F. Z., V. G., E. D., M. B., G. H.], Service de Chirurgie Thoracique et Générale, Hôpital Calmette [T. J. D., H. P., A. W.], and Laboratoire d’Anatomie Pathologique [M. C. C.], Hôpital Claude Huriez, 59037 Lille Cedex, France


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 RESULTS
 DISCUSSION
 REFERENCES
 
Proteases contribute to tumor invasion and metastasis via their potential to degrade basement membranes and extracellular matrix. Our aim was to compare the level of several proteases: urokinase-type plasminogen activator (u-PA), matrix metalloproteinase 2 (MMP-2; 72-kDa type IV collagenase, also known as gelatinase A), MMP-11 [also known as stromelysin 3 (STR3)], and cathepsins B and L in resected non-small cell lung cancer. Between June 1996 and March 1998, samples of lung tumor tissues were taken from 119 surgically treated patients. Thirty out of the 119 tumor samples were matched with corresponding adjacent normal tissue. u-PA was measured by a commercially available immunoluminometric assay. Metalloproteinases and cathepsins have been evaluated at the RNA level by Northern blot and quantified with a PhosphorImager. Expression of these proteases was compared to the following clinicopathological parameters: pathological diagnosis, tumor size, exposure to asbestos, radiotherapy, neo-adjuvant chemotherapy, tumor-node-metastasis stage, lymph node involvement, presence of metastasis. u-PA, MMP-2, MMP-11/STR3, and cathepsin B were significantly increased in tumor (the tumor:normal ratio was on average increased by 5.4-, 2.2-, 83.5-, and 2.2-fold, respectively). The tumor:normal ratio of MMP-11/STR3 was found to be significantly linked to the lymph node involvement (P < 0.05). Our results suggest that several proteases are involved in the invasive potential of non-small cell lung cancer and that the quantification of MMP-11/STR3 could represent an useful prognostic marker.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
RESULTS
 DISCUSSION
 REFERENCES
 
NSCLC3 represents a heterogeneous group of cancers both biologically and histopathologically. In patients with NSCLC, the clinicopathological parameters, i.e., size of the primary tumor, involvement of regional lymph nodes, and presence of distant metastases, have been thus far the most important prognostic factors. Accordingly, they largely determine treatment that relies on surgery when the primary lesion is completely resectable in the absence of distant metastases. Nevertheless, the aggressiveness of lung carcinoma is not always related to the tumor-node-metastasis staging, and molecular markers of tumor aggressiveness are necessary to improve therapeutic planning. Angiogenesis and metastasis highly contribute to the development and progression of lung cancer. As a consequence, the determination and/or validation of markers of metastatic propensity turn out to be essential in the therapeutic management.

The metastatic propensity is linked to the cell capacity of degrading basement membranes and extracellular matrix. Many proteases, including u-PA, MMPs, and the cathepsins, have been thus far described as potentially involved in angiogenesis and metastasis (1 , 2) .

In comparison to other tumors, in particular breast cancer, the potential role of proteases in dissemination of lung tumors has not been as much studied. u-PA antigen level has been reported as not statistically associated with the prognosis of squamous and large cell lung carcinoma (3) or of adenocarcinoma (4) . At the mRNA level, u-PA has been found expressed in stromal and/or cancer cells of lung carcinomas (5) . Both epithelial and stromal u-PA expression were linked to the tumor size, and stromal u-PA expression was furthermore linked to the lymph node involvement (6) . The MMP gelatinase A (MMP-2) has been described to be expressed in many lung tumors (7 , 8) . MMP-11 (STR3) has been studied in non-small cell lung carcinomas by in situ hybridization, immunohistochemical staining, and semiquantitative reverse PCR (6 , 9 , 10) . STR3 was overexpressed in stromal cells in non-small cell lung carcinomas and was also expressed in epithelial cells in squamous and basaloid carcinomas (6 , 9 , 10) . Stromal STR3 expression was linked to the tumor size and lymph node involvement in most lung carcinomas (6) . Cathepsin L and, moreover, cathepsin B were shown at a higher level in NSCLC tissues than in surrounding nonmalignant tissues (11 , 12) . Cathepsin B immunostaining was associated with poor prognosis (13) .

In an attempt to deal with proteases as molecular markers in lung carcinomas, we have quantified the expression of the above mentioned proteases in a series of non-small cell lung tissues and then studied the relationships with the prognostic clinicopathological factors.

PATIENTS AND METHODS
Patients.
From June 1996 to March 1998, 119 patients (93% men; mean age, 59 years; range, 29–76 years) who underwent surgery for NSCLC in the Department of Surgery (Centre Hospitalier Régional Universitaire de Lille) were included in this study (Table 1)Citation . Only patients completely resected in a potentially curative way for adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and neuroendocrine non-small cell lung carcinoma were enrolled in the study. Patients with localized metastatic spread in only one site treated by surgery with a curative aim (brain or adrenals) after or before lung resection were also included in the study. Patients who had a metastatic spread in more than one site were excluded from the study. Patients who died of surgical complications during the postoperative course were excluded from the study. We also excluded patients with an extrapulmonary cancer history and patients with a synchronous lung lesion histologically different from the resected NSLC.


View this table:
[in this window]
[in a new window]
  		Table 1 Tumor characteristics in patients with lung cancer

 
Tissue Samples.
Tumor specimens of NSLC were taken from 119 patients. Thirty tumor samples were matched with corresponding adjacent normal tissue, which was taken at a minimal distance of 5 cm from the tumor margin. At the time of collection, tissue samples were divided into three parts: one part was submitted to pathological study, and the two others were snap frozen in liquid nitrogen and stored at –80°C until respective treatment for protein or RNA extraction. In some cases, the tissue sample could only be divided into two parts.

Immunoassay of u-PA.
Tissue extracts were prepared by homogenization in 10 mM Tris-HCl, pH 7.4, 1.5 mM EDTA, 5 mM Na2MoO4, 1 mM monothioglycerol buffer. Supernatants were collected after centrifugation at 15,000 x g for 3 h. u-PA was evaluated by an immunoluminometric assay using LIA kits provided by Byk-France (LIA-mat u-PA, AB Sangtec Medical, Bromma, Sweden). This assay is a monoclonal two-site incubation immunoluminometric assay (sandwich principle), which evaluates free u-PA, and also receptor and PAI-1-bound u-PA. The immunological reaction is detected by a light reaction through the oxidation of the isoluminol bound to antibodies.

Protein content of the cytosolic extracts was determined by the BCA protein kit test from Pierce using BSA as a control. The results were expressed in ng of protease per mg of protein.

mRNA Levels of MMP-2, MMP-11 (STR3), Cathepsin B, and Cathepsin L.
Total cellular RNA was isolated after homogeneization of lung tissue in guanidinium isothiocyanate and centrifugation through cesium chloride gradients.

Fifteen µg of total cellular RNA were electrophoresed on 0.9% agarose-2.2 M formaldehyde gels and subsequently transferred onto nylon membrane (Hybond N+, Amersham Pharmacia Biotech, Rainham, United Kingdom). The membranes were hybridized overnight with the 32P-labeled probes (Random primed DNA labeling kit; Roche Molecular Biochemicals, Meylan, France). The MMP-2 probe was obtained from the ATCC. The STR3, cathepsin B, and cathepsin L probes spanned nucleotides 346-2105 (14) , 147-1011 (15) , and 604–999 (16) , respectively. After hybridization, the blots were exposed to a PhosphorImager screen (Molecular Dynamics). For normalization, the membrane was hybridized with the human actin cDNA probe. The results were expressed as the ratio between the labeling obtained after hybridization with the proteinase cDNA probe and the labeling obtained after hybridization with the actin cDNA probe.

Statistical Analysis.
Two groups of patients were considered: a first group included the 30 patients for whom matched tumor and normal tissues were available, and a second group included all 119 patients. In the first group, we have calculated for each patient the tumor:normal ratio of expression for the different proteases.

The expression of proteases was compared with the following clinicopathological parameters: histological type, tumor size, exposure to asbestos, preoperative radiotherapy, neoadjuvant chemotherapy, histopronostic grading, lymph node involvement, and presence of metastasis.

Statistical analyses were carried out using StatView statistical software on a personal computer. The differences between tumoral tissue and normal adjacent tissue were examined using the Wilcoxon signed rank test. The difference between two independent groups was determined by the Mann-Whitney U test, and the significance of differences among more than two groups was determined by Kruskal-Wallis one-way analysis. Values of P less than 0.05 in two-tailed analyses were considered significant.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 RESULTS
DISCUSSION
 REFERENCES
 
Concentration of u-PA Antigen.
The distribution of u-PA in lung carcinoma and their control lung tissue is illustrated in Fig. 1Citation . In the 30 tumor samples, the concentration of u-PA was found to be statistically higher than in the corresponding control lung tissue (P < 0.0001, Table 2Citation ). The mean fold increase was 5.4 (Table 2)Citation .



View larger version (20K):
[in this window]
[in a new window]
  		Fig. 1. Distribution of protease levels in matched pairs of tumor and control lung tissue samples.

 

View this table:
[in this window]
[in a new window]
  		Table 2 Comparison of u-PA antigen, MMP-11/STR3, MMP-2, cathepsin B and L mRNA levels in the 30 matched pairs of tumor and normal lung tissues

 
Expression of MMP-2, MMP-11/STR3, Cathepsin B, and Cathepsin L Genes.
As shown in Fig. 2Citation , MMP-2, MMP-11/STR3, and cathepsin L transcripts were respectively identified as single autoradiographic bands of 3.1, 2.4, and 1.2 kb. Cathepsin B transcripts appeared as two autoradiographic bands of 4 and 2.3 kb. The level of protease transcripts in lung carcinoma and their control lung tissue was quantified by direct measurement of radioactivity on the membranes and then normalized to actin expression. The degree of variation in MMP-2, MMP-11/STR3, cathepsin B, and cathepsin L gene expression in neoplastic and control tissues is illustrated in Fig. 1Citation . In the 30 tumor samples, the expression of MMP-2, MMP-11/STR3, and cathepsin B genes was found to be statistically higher than in the corresponding control lung tissue (P < 0.005, Table 2Citation ). The mean fold increase was of 2.2 for MMP-2, 83.8 for MMP-11/STR3, and 2.2 for cathepsin B (Table 2)Citation . In contrast, no statistically significant difference was found for cathepsin L between the expression in tumor and nontumor tissue (Table 2)Citation .



View larger version (90K):
[in this window]
[in a new window]
  		Fig. 2. Northern blot analysis of MMP-2, MMP-11, cathepsin B, and cathepsin L in some paired lung carcinomas and control mucosas. Total RNAs (15 µg) extracted from pathological and control nontumoral lung tissue were migrated on 0.9% agarose-formaldehyde gels and hybridized with the MMP-2, MMP-11/STR3, cathepsin B, and cathepsin L probes. Hybridization of the blot with the cDNA actin probe served as a control for RNA loading and was used to normalize the relative accumulation of MMP-2, MMP-11/STR3, cathepsin B, and cathepsin L transcripts.

 
Level of u-PA, MMP-2, MMP-11, Cathepsin B, and Cathepsin L in Relation to Clinicopathological Parameters.
The relationships between the tumor:normal ratio of protease expression and the conventional clinicopathological parameters with prognostic significance in lung cancer were analyzed (Table 3)Citation .


View this table:
[in this window]
[in a new window]
  		Table 3 Relationships between the tumor:normal ratio of protease expression and clinicopathological features in matched pairs of tumor and normal lung tissues

 
u-PA, MMP-2, cathepsin B, and cathepsin L were not related to any of these clinicopathological parameters. In contrast, the tumor:normal ratio of MMP-11/STR3 was found significantly linked to the lymph node involvement (P = 0.0433 for the lymph node status and P = 0.0373 for the capsular rupture; Table 3Citation and Fig. 3Citation ).



View larger version (15K):
[in this window]
[in a new window]
  		Fig. 3. Comparison between the median tumor:normal ratio of MMP-11/STR-3 expression according to the lymph node status in matched pairs of tumor and control lung tissues.

 
We then analyzed the correlation between the levels of protease expression in the 119 tumor samples and the clinicopathological parameters (Table 4)Citation . Although not statistically significant, a trend (P = 0.0866) was particularly observed between the MMP-11/STR3 expression and the lymph node status.


View this table:
[in this window]
[in a new window]
  		Table 4 Relationships between the levels of protease expression in the 119 tumor samples and clinicopathological parameters

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
REFERENCES
 
Much research, including studies on human tumor tissue samples and in vitro or in vivo experiments on cell cultures or animal models, has demonstrated the key role of proteases in tumor spread and metastasis. In particular, investigation by immunohistochemistry and in situ hybridization on human tumors has shown overexpression of proteases by the stromal cells at the periphery of tumors, suggesting the involvement of proteases in the extension of the malignant process. The aim of this study was to quantify the expression of several proteases and to study their relationship with the recognized clinicopathological prognostic variables, in an attempt to determine whether overexpression of some proteases could be particularly relevant to the malignancy of lung cancer.

Among the proteases studied here, our results show that u-PA, MMP-2, MMP-11/STR3, and cathepsin B levels are significantly increased in lung carcinoma in comparison with adjacent normal tissue (the tumor:normal ratio was on average increased by 5.4-, 2.2-, 83.5-, and 2.2-fold, respectively). For cathepsin L, no statistically significant difference was observed. In situ hybridization and immunohistochemistry studies in lung cancer showed that most proteases, including u-PA and MMP-11/STR3, were found to be predominantly expressed in stromal cells, suggesting an active role in the local peritumoral region (6 , 9 , 10) . Besides, the enzymatic activity of protease in the extracellular space is also regulated by specific protease inhibitors. The proteolysis of extracellular matrix components in the processes of tumor invasion and metastasis is finally controlled by the balance between proteases and protease inhibitors (17) .

For MMP-2 and cathepsin B, which were only slightly increased in lung tumor tissue (by 2.2-fold), no correlation appeared with any of the clinicopathological prognostic variables. Although u-PA level was found to be more increased (by 5.4-fold), no relationship could be found between u-PA level and any of the clinicopathological prognostic variable in both statistical studies. Pedersen et al. (3 , 4) also reported the absence of a statistically significant association of u-PA level with age, sex, tumor size, stage, extent of surgery, and number of tumor-positive mediastinal lymph nodes in squamous carcinomas, large cell carcinomas, and adenocarcinomas of the lung. These observations contrast with findings in other types of cancer, in particular breast cancer, in which u-PA level is an independent prognostic factor of relapse-free survival (18, 19, 20, 21) . However, stromal u-PA expression assessed in non-small cell lung carcinomas by in situ hybridization was correlated to the tumor size and lymph node involvement (6) .

The mean increase in MMP-11/STR3 level in lung carcinoma was much higher (by 83.5-fold). A previous semiquantitative analysis of STR3 expression in 58 paired tumor and normal tissue from NSCLCs has been investigated by reverse PCR, and an overexpression of STR3 was also observed (9) . By in situ hybridization and immunohistochemistry, STR-3 was primarily localized in stromal cells adjacent to tumor cells (6 , 9 , 10) , and the stromal expression was linked to the tumor size and lymph node involvement in most lung carcinomas (6) . The high increase here quantified for STR3 expression highlights the important role of this metalloproteinase in the malignant progression of lung tumor. Furthermore, the tumor:normal ratio of STR3 expression was found to be statistically correlated with the lymph node involvement, whereas such correlation did not exist for all of the other proteases examined. With regard to the expression level of STR3 in the tumor only, the significance of the relationship with the lymph node involvement was no more reached, although a clear trend was observed (P = 0.0866). This fact can be explained by the increased accuracy of the results when paired malignant and nonmalignant tissues are analyzed on the same Northern blot, with the same cDNA probes respectively for STR3 and for actin. Our data suggest that STR3 could be particularly involved in the metastatic dissemination of lung tumors.

However, surprisingly, STR3 is a MMP devoid of a proteolytic activity toward the matrix components. The unique known substrates for STR3 are the serine proteinase inhibitors {alpha}1-PI and {alpha}2-antiplasmin (22 , 23) . {alpha}1-PI is a predominant inhibitor of neutrophil elastase, which is known to play an important role in the physiopathology of the lung, because severe {alpha}1-PI deficiency leads to the development of pulmonary emphysema. The pathogenesis of the emphysema results from the {alpha}1-PI deficiency in the alveolar structures, which are progressively destroyed by neutrophil elastase (24) . It may be suggested that the role of STR3 in lung metastasis could be mediated through an increased activity of neutrophil elastase. Likewise, the effect of STR3 upon {alpha}2-antiplasmin could act through an increased activity of plasmin, which is able on one hand to degrade most components of the extracellular matrix and on the other hand to promote the activation of other proMMPs (25 , 26) . Indeed, the metastatic process is thought to result from a complex proteolytic cascade involving the sequential activation of several inactive proenzymes into active enzymes (27) .

Overexpression of STR3 has been also found to be associated with other epithelial cancers: breast (14 , 28) , head and neck (29) , colon (30 , 31) , and esophagus (32) . Recently, STR3 has been reported as an independent prognostic factor for relapse-free survival in node-positive breast cancer (33) . Taken together, these observations suggest that STR3 plays an important part in the progression of epithelial malignancies and could represent an important therapeutic target for cancer treatment.

In conclusion, our quantitative study suggests the potential role of u-PA, MMP-2, MMP-11/STR3, and cathepsin B in progression and metastasis of lung NSCLC. Our data particularly show that the quantification of STR3 expression should be of particular interest as a marker of aggressiveness and invasiveness in lung cancer.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by a grant from the Comité du Nord de la Ligue Nationale Contre le Cancer. Back

2 To whom requests for reprints should be addressed, at Laboratoire de Biochimie, Hôpital Claude Huriez, rue Michel Polonovski, 59037 Lille Cedex, France. Phone: 03-20-44-61-54; Fax: 03-20-44-56-93; E-mail: huet{at}lille.inserm.fr Back

3 The abbreviations used are: NSCLC, non-small cell lung cancer; {alpha}1-PI, {alpha}1-proteinase inhibitor; MMP, matrix metalloproteinase; STR3, stromelysin 3; u-PA, urokinase-type plasminogen activator. Back

Received 8/ 4/99; revised 12/ 7/99; accepted 12/ 7/99.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Duffy M. J. Proteases as Prognostic Markers in Cancer. Clin. Cancer Res., 2: 613-618, 1996.[Abstract]
  2. Woodhouse E. C., Chuaqui R. F., Liotta L. A. General mechanisms of metastasis. Cancer (Phila.), 80: 1529-1537, 1997.[CrossRef][Medline]
  3. Pedersen, H., Brünner, N., Francis, D., Osterlind, K., Ronne, E., Hoi Hansen, H., Dano, K., and Grondahl-Hansen, J. Prognostic impact of urokinase, urokinase receptor, and type 1 plasminogen activator inhibitor in squamous and large cell lung cancer tissue. Cancer Res., 54: 4671–4675, 1994.
  4. Pedersen, H., Grondahl-Hansen, J., Francis, D., Osterlind, K., Hoi Hansen, H., Dano, K., and Brünner, N. Urokinase and plasminogen activator inhibitor type 1 in pulmonary adenocarcinoma. Cancer Res., 54: 120–123, 1994.
  5. Bolon I., Gouyer V., Devouassoux M., Vandenbunder B., Wernert N., Moro D., Brambilla C., Brambilla E. Expression of c-ets-1, collagenase 1, and urokinase-type plasminogen activator genes in lung carcinomas. Am. J. Pathol., 147: 1298-1310, 1995.[Abstract]
  6. Bolon I., Devouassoux M., Robert C., Moro D., Brambilla C., Brambilla E. Expression of urokinase-type plasminogen activator, stromelysin 1, stromelysin 3, and matrilysin genes in lung carcinomas. Am. J. Pathol., 150: 1619-1629, 1997.[Abstract]
  7. Urbanski S. J., Edwards D. R., Maitland A., Leco K. J., Watson A., Kossalkowska A. E. Expression of metalloproteinases and their inhibitors in primary pulmonary carcinomas. Br. J. Cancer, 66: 1188-1194, 1992.[Medline]
  8. Kawano N., Osawa H., Ito T., Nagashima Y., Hirahara F., Irayama Y., Nakatani Y., Kimura S., Kitajim H., Koshikawa N., Miyazaki K., Kitamura H. Expression of gelatinase A, tissue inhibitor of metalloproteinases-2, matrilysin and trypsin(ogen) in lung neoplasms: an immunohistochemical study. Hum. Pathol., 28: 613-622, 1997.[CrossRef][Medline]
  9. Anderson I. C., Sugarbaker D. J., Ganju R. K., Tsarwhas D. G., Richards W. G., Sunday M., Kobzik L., Shipp M. A. Stromelysin-3 is overexpressed by stromal elements in primary non-small cell lung cancers and regulated by retinoic acid in pulmonary fibroblasts. Cancer Res., 55: 4120-4126, 1995.[Abstract/Free Full Text]
  10. Bolon I., Brambilla E., Vanderbunder B., Robert C., Lantuejoul S., Brambilla C. Changes in the expression of matrix proteases and of the transcription factor C-Ets-1 during progression of precancerous bronchial lesions. Lab. Invest., 75: 1-13, 1996.[Medline]
  11. Werle B., Ebert W., Klein W., Spiess E. Assessment of cathepsin L activity by use of the inhibitor CA-074 compared to cathepsin B activity in human lung tumor tissue. Biol. Chem. Hoppe-Seyler, 376: 157-164, 1995.[Medline]
  12. Ledakis P., Tester W. T., Rosenberg N., Romero-Fischmann D., Daskal I., Lak T. T. Cathepsins D, B, and L in malignant human lung tissue. Clin. Cancer Res., 2: 561-568, 1996.[Abstract]
  13. Inoue T., Ishida T., Sugio K., Sugimachi K. Cathepsin B expression and laminin degradation as factors influencing prognosis of surgically treated patients with lung adenocarcinoma. Cancer Res., 54: 6133-6136, 1994.[Abstract/Free Full Text]
  14. Basset P., Bellocq J. P., Wolf C., Stoll I., Hutin P., Limacher J. M., Podhajcer C. L., Chenard M. P., Rio M. C., Chambon P. A novel matrix metalloproteinase gene specifically expressed in stromal cells of breast carcinomas. Nature (Lond.), 348: 699-704, 1990.[CrossRef][Medline]
  15. Lemaire R., Huet G., Zerimech F., Grard G., Fontaine C., Duquesnoy B., Flipo R. M. Selective induction of the secretion of cathepsins B and L by cytokines in synovial fibroblast-like cells. Br. J. Rheumatol., 36: 735-743, 1997.[Abstract/Free Full Text]
  16. Lemaire R., Flipo R. M., Monté D., Dupressoir T., Duquesnoy B., Cesbron J. Y., Janin A., Capron A., Lafyatis R. Synovial fibroblast-like cells transfection with the SV40 large T antigen induces a transformed phenotype and permits transient tumor formation in immunodeficient mice. J. Rheumatol., 21: 1409-1419, 1994.[Medline]
  17. Liotta L. A., Steeg P. S., Stetler-Stevenson W. G. Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell, 64: 327-336, 1991.[CrossRef][Medline]
  18. Foekens J., Schmitt M., Van Putten W. L., Peters A. H., Bontenbal M., Janicke F., Klijn J. G. M. Prognostic value of urokinase type plasminogen activator in 671 primary breast cancer patients. Cancer Res., 52: 6101-6105, 1992.[Abstract/Free Full Text]
  19. Janicke F., Schmitt M., Pache L., Ulm K., Harbeck N., Höfler H., Graeff H. Urokinase (u-PA), and its inhibitor PAI-1 are strong and independent prognostic factors in mode-negative breast cancer. Breast Cancer Res. Treat., 24: 195-208, 1993.[CrossRef][Medline]
  20. Fernö, M., Bendahl, PO., Borg, A., Brundell, J., Hirschberg, L., Olsson, H., and Killander, D. Urokinase plasminogen activator, a strong independent prognostic factor in breast cancer, analyzed in steroid receptor cytosols with a luminometric immunoassay. Eur. J. Cancer, 32A: 793–801, 1996.
  21. Peyrat J. P., Vanlemmens L., Fournier J., Huet G., Révillion F., Bonneterre J. Prognostic value of p53 and urokinase-type plasminogen activator in node-negative human breast cancers. Clin. Cancer Res., 4: 189-196, 1998.[Abstract]
  22. Woessner J. F. Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J., 5: 2145-2154, 1991.[Abstract]
  23. Pei D., Majmudar G., Weiss S. J. Hydrolytic inactivation of a breast carcinoma-cell-derived serpin by human stromelysin-3. J. Biol. Chem., 269: 25849-25855, 1994.[Abstract/Free Full Text]
  24. Crystal R. G. {alpha}1-Antitrypsin deficiency, emphysema and liver disease: genetic basis and strategies for therapy. J. Clin. Int., 85: 1343-1352, 1990.
  25. Dano K., Andreasen P. A., Grondahl-Hansen J., Kristensen P., Nielsen L. S., Skriver L. Plasminogen activators, tissue degradation, and cancer. Adv. Cancer Res., 44: 139-266, 1985.[Medline]
  26. Mignatti P., Rifkin D. B. Biology and biochemistry of proteinases in tumor invasion. Physiol. Rev., 73: 161-195, 1993.[Free Full Text]
  27. Birkedal-Hansen H. Proteolytic remodeling of extracellular matrix. Curr. Opin. Cell. Biol., 7: 728-735, 1995.[CrossRef][Medline]
  28. Engel G., Heselmeyer K., Aver G., Backdahl M., Eriksson E., Linder S. Correlation between stromelysin-3 mRNA level and outcome of human breast cancer. Int. J. Cancer, 58: 830-835, 1994.[Medline]
  29. Muller D., Wolf C., Abecassis J., Millon R., Engelmann A., Bronner G., Rouyer N., Rio M. C., Eber M., Methlin G., Chambon P., Basset P. Increased stromelysin-3 gene expression is associated with increased local invasiveness in head and neck squamous cell carcinomas. Cancer Res., 53: 165-169, 1993.[Abstract/Free Full Text]
  30. Newell K. J., Witty J. P., Rodgers W. H., Matrisian L. M. Expression and localization of matrix-degrading metalloproteinases during colorectal tumorigenesis. Mol. Carcinog, 10: 199-206, 1994.[Medline]
  31. Porte H., Chastre E., Prevot S., Nordlinger B., Empereur S., Basset P., Chambon P., Gespach C. Neoplastic progression of human colorectal cancer is associated with overexpression of the stromelysin-3 and BM-40/SPARC genes. Int. J. Cancer, 64: 70-75, 1995.[Medline]
  32. Porte H., Triboulet J. P., Kotelevets L., Carrat F., Prévot S., Nordlinger B., DiGioia Y., Wurtz A., Comoglio P., Gespach C., Chastre E. Overexpression of stromelysin-3, BM-40/SPARC, and MET genes in human esophageal carcinoma: implications for prognosis. Clin. Cancer Res., 4: 1375-1382, 1998.[Abstract]
  33. Ahmad A., Hanby A., Dublin E., Poulsom R., Smith P., Barnes D., Rubens R., Anglard P., Hart I. Stromelysin 3: an independent prognostic factor for relapse-free survival in node positive breast cancer and demonstration of novel breast carcinoma cell expression. Am. J. Pathol., 152: 721-728, 1998.[Abstract]



This article has been cited by other articles:


Home page
 FASEB J.Home page
Y. Pan, L. Zhao, J. Liang, J. Liu, Y. Shi, N. Liu, G. Zhang, H. Jin, J. Gao, H. Xie, et al.
Cellular prion protein promotes invasion and metastasis of gastric cancer
FASEB J, September 1, 2006; 20(11): 1886 - 1888.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
N. B. Leighl, L. Paz-Ares, J.-Y. Douillard, C. Peschel, A. Arnold, A. Depierre, A. Santoro, D. C. Betticher, U. Gatzemeier, J. Jassem, et al.
Randomized Phase III Study of Matrix Metalloproteinase Inhibitor BMS-275291 in Combination With Paclitaxel and Carboplatin in Advanced Non-Small-Cell Lung Cancer: National Cancer Institute of Canada-Clinical Trials Group Study BR.18
J. Clin. Oncol., April 20, 2005; 23(12): 2831 - 2839.
[Abstract] [Full Text] [PDF]

Home page
 CLIN APPL THROMB HEMOSTHome page
E. Cobos, C. Jumper, and C. Lox
Pretreatment Determination of the Serum Urokinase Plasminogen Activator and its Soluble Receptor in Advanced Small-Cell Lung Cancer or Non-Small-Cell Lung Cancer
Clinical and Applied Thrombosis/Hemostasis, July 1, 2003; 9(3): 241 - 246.
[Abstract] [PDF]

Home page
 Clin. Cancer Res.Home page
V.-M. Wasenius, S. Hemmer, E. Kettunen, S. Knuutila, K. Franssila, and H. Joensuu
Hepatocyte Growth Factor Receptor, Matrix Metalloproteinase-11, Tissue Inhibitor of Metalloproteinase-1, and Fibronectin Are Up-Regulated in Papillary Thyroid Carcinoma: A cDNA and Tissue Microarray Study
Clin. Cancer Res., January 1, 2003; 9(1): 68 - 75.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Delebecq, T. J.
Right arrow Articles by Huet, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Delebecq, T. J.
Right arrow Articles by Huet, G.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online