Abstract
Background: The roles of matrix metalloproteinases (MMPs) in cancer metastasis have been studied. Macrophages are considered to release MMPs in the tissues of patients with lung cancer.
Methods: Intracellular collagenase activity was measured in CD14+ CD45+ cells from bronchial lavage fluid to establish a new diagnostic tool for lung cancer. Between August 2000 and November 2001 bronchoscopy and bronchial lavage were performed in 45 patients with abnormal shadows on the chest radiograph; 21 had lung cancer and 24 had non-malignant disease.
Results: Collagenase activity in patients with primary lung cancer (5.54 (0.65)) or non-small cell lung cancer (NSCLC) (5.62 (0.71)) was significantly higher than in those with non-malignant disease (3.63 (0.78), p=0.006 and p=0.008, respectively). Only three of 18 patients in the low activity group were diagnosed as having cancer compared with 18 of 27 in the high activity group (p=0.001). This significance was not seen in non-smokers but it was apparent in smokers/ex-smokers. Excluding non-smokers improved the specificity of collagenase activity in differentiating cancer and non-malignant disease from 62.5% to 80.0%. The sensitivity of the test was 85.7% in all patients and 88.2% in smokers/ex-smokers.
Conclusions: Measurement of intracellular collagenase activity in macrophages in bronchial lavage fluid is a useful diagnostic tool for distinguishing between cancer and non-malignant diseases, especially in smokers and ex-smokers.
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- Arenberg D. A., Keane M. P., DiGiovine B., Kunkel S. L., Strom S. R., Burdick M. D., Iannettoni M. D., Strieter R. M. Macrophage infiltration in human non-small-cell lung cancer: the role of CC chemokines. Cancer Immunol Immunother. 2000 May;49(2):63–70. doi: 10.1007/s002620050603. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bergers G., Javaherian K., Lo K. M., Folkman J., Hanahan D. Effects of angiogenesis inhibitors on multistage carcinogenesis in mice. Science. 1999 Apr 30;284(5415):808–812. doi: 10.1126/science.284.5415.808. [DOI] [PubMed] [Google Scholar]
- Chambers A. F., Matrisian L. M. Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst. 1997 Sep 3;89(17):1260–1270. doi: 10.1093/jnci/89.17.1260. [DOI] [PubMed] [Google Scholar]
- Cox G., Jones J. L., O'Byrne K. J. Matrix metalloproteinase 9 and the epidermal growth factor signal pathway in operable non-small cell lung cancer. Clin Cancer Res. 2000 Jun;6(6):2349–2355. [PubMed] [Google Scholar]
- Finlay G. A., O'Driscoll L. R., Russell K. J., D'Arcy E. M., Masterson J. B., FitzGerald M. X., O'Connor C. M. Matrix metalloproteinase expression and production by alveolar macrophages in emphysema. Am J Respir Crit Care Med. 1997 Jul;156(1):240–247. doi: 10.1164/ajrccm.156.1.9612018. [DOI] [PubMed] [Google Scholar]
- Garbisa S., Scagliotti G., Masiero L., Di Francesco C., Caenazzo C., Onisto M., Micela M., Stetler-Stevenson W. G., Liotta L. A. Correlation of serum metalloproteinase levels with lung cancer metastasis and response to therapy. Cancer Res. 1992 Aug 15;52(16):4548–4549. [PubMed] [Google Scholar]
- González-Avila G., Iturria C., Vadillo F., Terán L., Selman M., Pérez-Tamayo R. 72-kD (MMP-2) and 92-kD (MMP-9) type IV collagenase production and activity in different histologic types of lung cancer cells. Pathobiology. 1998;66(1):5–16. doi: 10.1159/000027989. [DOI] [PubMed] [Google Scholar]
- Goyert S. M., Ferrero E., Rettig W. J., Yenamandra A. K., Obata F., Le Beau M. M. The CD14 monocyte differentiation antigen maps to a region encoding growth factors and receptors. Science. 1988 Jan 29;239(4839):497–500. doi: 10.1126/science.2448876. [DOI] [PubMed] [Google Scholar]
- Halpert I., Sires U. I., Roby J. D., Potter-Perigo S., Wight T. N., Shapiro S. D., Welgus H. G., Wickline S. A., Parks W. C. Matrilysin is expressed by lipid-laden macrophages at sites of potential rupture in atherosclerotic lesions and localizes to areas of versican deposition, a proteoglycan substrate for the enzyme. Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9748–9753. doi: 10.1073/pnas.93.18.9748. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Herbst R. S., Yano S., Kuniyasu H., Khuri F. R., Bucana C. D., Guo F., Liu D., Kemp B., Lee J. J., Hong W. K. Differential expression of E-cadherin and type IV collagenase genes predicts outcome in patients with stage I non-small cell lung carcinoma. Clin Cancer Res. 2000 Mar;6(3):790–797. [PubMed] [Google Scholar]
- Iizasa T., Fujisawa T., Suzuki M., Motohashi S., Yasufuku K., Yasukawa T., Baba M., Shiba M. Elevated levels of circulating plasma matrix metalloproteinase 9 in non-small cell lung cancer patients. Clin Cancer Res. 1999 Jan;5(1):149–153. [PubMed] [Google Scholar]
- Ito Y., Kawanishi Y., Shoji N., Ohyashiki K. Decline in antibiotic enzyme activity of neutrophils is a prognostic factor for infections in patients with myelodysplastic syndrome. Clin Infect Dis. 2000 Nov;31(5):1292–1295. doi: 10.1086/317470. [DOI] [PubMed] [Google Scholar]
- Janssen-Heijnen M. L., Gatta G., Forman D., Capocaccia R., Coebergh J. W. Variation in survival of patients with lung cancer in Europe, 1985-1989. EUROCARE Working Group. Eur J Cancer. 1998 Dec;34(14 Spec No):2191–2196. doi: 10.1016/s0959-8049(98)00312-8. [DOI] [PubMed] [Google Scholar]
- Kumaki F., Matsui K., Kawai T., Ozeki Y., Yu Z. X., Ferrans V. J., Travis W. D. Expression of matrix metalloproteinases in invasive pulmonary adenocarcinoma with bronchioloalveolar component and atypical adenomatous hyperplasia. Am J Pathol. 2001 Dec;159(6):2125–2135. doi: 10.1016/S0002-9440(10)63064-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Labeta M. O., Landmann R., Obrecht J. P., Obrist R. Human B cells express membrane-bound and soluble forms of the CD14 myeloid antigen. Mol Immunol. 1991 Jan-Feb;28(1-2):115–122. doi: 10.1016/0161-5890(91)90094-z. [DOI] [PubMed] [Google Scholar]
- Liotta L. A., Steeg P. S., Stetler-Stevenson W. G. Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell. 1991 Jan 25;64(2):327–336. doi: 10.1016/0092-8674(91)90642-c. [DOI] [PubMed] [Google Scholar]
- Liotta L. A., Tryggvason K., Garbisa S., Hart I., Foltz C. M., Shafie S. Metastatic potential correlates with enzymatic degradation of basement membrane collagen. Nature. 1980 Mar 6;284(5751):67–68. doi: 10.1038/284067a0. [DOI] [PubMed] [Google Scholar]
- Marcus P. M., Bergstralh E. J., Fagerstrom R. M., Williams D. E., Fontana R., Taylor W. F., Prorok P. C. Lung cancer mortality in the Mayo Lung Project: impact of extended follow-up. J Natl Cancer Inst. 2000 Aug 16;92(16):1308–1316. doi: 10.1093/jnci/92.16.1308. [DOI] [PubMed] [Google Scholar]
- Nakamura T., Ebihara I., Shimada N., Koide H. Effect of cigarette smoking on plasma metalloproteinase-9 concentration. Clin Chim Acta. 1998 Aug 28;276(2):173–177. doi: 10.1016/s0009-8981(98)00104-1. [DOI] [PubMed] [Google Scholar]
- Nelson A. R., Fingleton B., Rothenberg M. L., Matrisian L. M. Matrix metalloproteinases: biologic activity and clinical implications. J Clin Oncol. 2000 Mar;18(5):1135–1149. doi: 10.1200/JCO.2000.18.5.1135. [DOI] [PubMed] [Google Scholar]
- Pan M. R., Chuang L. Y., Hung W. C. Non-steroidal anti-inflammatory drugs inhibit matrix metalloproteinase-2 expression via repression of transcription in lung cancer cells. FEBS Lett. 2001 Nov 23;508(3):365–368. doi: 10.1016/s0014-5793(01)03118-0. [DOI] [PubMed] [Google Scholar]
- Passlick B., Sienel W., Seen-Hibler R., Wöckel W., Thetter O., Mutschler W., Pantel K. Overexpression of matrix metalloproteinase 2 predicts unfavorable outcome in early-stage non-small cell lung cancer. Clin Cancer Res. 2000 Oct;6(10):3944–3948. [PubMed] [Google Scholar]
- Penninger J. M., Irie-Sasaki J., Sasaki T., Oliveira-dos-Santos A. J. CD45: new jobs for an old acquaintance. Nat Immunol. 2001 May;2(5):389–396. doi: 10.1038/87687. [DOI] [PubMed] [Google Scholar]
- Rothe G., Klingel S., Assfalg-Machleidt I., Machleidt W., Zirkelbach C., Banati R. B., Mangel W. F., Valet G. Flow cytometric analysis of protease activities in vital cells. Biol Chem Hoppe Seyler. 1992 Jul;373(7):547–554. doi: 10.1515/bchm3.1992.373.2.547. [DOI] [PubMed] [Google Scholar]
- Shapiro S. D. Diverse roles of macrophage matrix metalloproteinases in tissue destruction and tumor growth. Thromb Haemost. 1999 Aug;82(2):846–849. [PubMed] [Google Scholar]
- Shapiro S. D. Elastolytic metalloproteinases produced by human mononuclear phagocytes. Potential roles in destructive lung disease. Am J Respir Crit Care Med. 1994 Dec;150(6 Pt 2):S160–S164. doi: 10.1164/ajrccm/150.6_Pt_2.S160. [DOI] [PubMed] [Google Scholar]
- Weaver Lindell K., Hopkins Ramona O., Chan Karen J., Churchill Susan, Elliott C. Gregory, Clemmer Terry P., Orme James F., Jr, Thomas Frank O., Morris Alan H. Hyperbaric oxygen for acute carbon monoxide poisoning. N Engl J Med. 2002 Oct 3;347(14):1057–1067. doi: 10.1056/NEJMoa013121. [DOI] [PubMed] [Google Scholar]
- Wright S. D., Ramos R. A., Tobias P. S., Ulevitch R. J., Mathison J. C. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science. 1990 Sep 21;249(4975):1431–1433. doi: 10.1126/science.1698311. [DOI] [PubMed] [Google Scholar]
- Yurchenco P. D., Schittny J. C. Molecular architecture of basement membranes. FASEB J. 1990 Apr 1;4(6):1577–1590. doi: 10.1096/fasebj.4.6.2180767. [DOI] [PubMed] [Google Scholar]
- Zucker S., Cao J., Chen W. T. Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatment. Oncogene. 2000 Dec 27;19(56):6642–6650. doi: 10.1038/sj.onc.1204097. [DOI] [PubMed] [Google Scholar]
- Zucker S., Cao J. Imaging metalloproteinase activity in vivo. Nat Med. 2001 Jun;7(6):655–656. doi: 10.1038/89016. [DOI] [PubMed] [Google Scholar]