Annals of Oncology Advance Access published online on January 30, 2008
Annals of Oncology, doi:10.1093/annonc/mdm609
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ADAM-17 predicts adverse outcome in patients with breast cancer
1 Department of Pathology, Laboratory Medicine
2 UCD School of Medicine and Medical Science, Conway Institute, University College Dublin, Dublin 4, Ireland
3 Cancer Prevention Fellowship Program, Office of Preventive Oncology, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
4 Medical Oncology, St Vincent's University Hospital, Dublin 4, Ireland
* Correspondence to: Prof. M. J. Duffy, Nuclear Medicine Laboratory, St Vincent's University Hospital, Dublin 4, Ireland. Tel: +353-1-2094378; Fax: +353-1-2696018; E-mail: michael.j.duffy{at}ucd.ie
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Abstract |
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ADAM-17 is a matrix metalloproteinase-like enzyme involved in the release of several ligands that have been shown to promote both cancer formation and progression. These ligands include transforming growth factor-
, amphiregulin, heparin-binding epidermal growth factor, epiregulin and tumor necrosis factor-. In this investigation, we measured the expression of total ADAM-17 by enzyme-linked immunosorbent assay in 153 invasive breast cancers. We also measured the precursor and active forms by western blotting in 140 invasive breast cancers. Expression of ADAM-17 was significantly increased in high-grade compared with low-grade tumors and was independent of tumor size, lymph node metastasis and estrogen receptor status. Patients with high expression of ADAM-17 had a significantly shorter overall survival compared with those with low expression. Significantly, the prognostic impact of ADAM-17 was independent of conventional prognostic factors for breast cancer. Our results are further evidence that ADAM-17 is involved in breast cancer progression and thus provides further impetus for exploiting ADAM-17 as new target for cancer treatment. ADAM-17, breast cancer, metalloproteinases, prognosis
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introduction |
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The ADAMs (A Disintegrin And Metalloprotease) are multidomain transmembrane proteins. Although ADAMs may contain up to eight distinct domains, the two best characterized are the metalloprotease domain, which is involved in the shedding of several biologically important membrane-bound ligands, and the disintegrin sequence which is involved in cell adhesion (for review, see [1, 2]). One of the first ADAMs implicated in membrane shedding was ADAM-17, which was shown to release the active form of tumor necrosis factor (TNF)-
from its precursor. ADAM-17 is thus sometimes referred to TNF- converting enzyme or TACE. Other growth factors shown to be released by ADAM-17 include the epidermal growth factor-receptor (EGFR) ligands, transforming growth factor (TGF)-, amphiregulin, heparin-binding epidermal growth factor (HB-EGF) and epiregulin [1, 2].
All these factors released by ADAM-17 have been implicated in tumor formation and/or progression. Although high doses of TNF are used to treat certain malignancies [3], several animal studies suggest that this cytokine is involved in cancer formation/progression. Thus, in a mouse model, either a deficiency of TNF- or the administration of a neutralizing antibody directed against the cytokine inhibited the development of chemically induced skin cancer [4]. TNF- was also shown to be involved in the formation/progression of liver [5], intestinal [6] and ovarian cancer [7]. Similarly, TGF-, amphiregulin, HB-EGF and epiregulin have all been reported to mediate tumor formation/progression [8–11].
Consistent with its ability to release tumor-promoting factors such as TNF-, TGF-, amphiregulin, HB-EGF and epiregulin, ADAM-17 has also been implicated in tumor formation/progression. Recently, for example, ADAM-17-catalyzed shedding of TGF- was found to be necessary for murine tumor formation [12], while in a three-dimensional culture of human breast cancer progression, inhibition of ADAM-17 reversed the malignant phenotype [13]. This reversion of the malignant phenotype resulted from the failure to release TGF- and amphiregulin [13].
Using breast cancer cell lines in culture, we previously found that ADAM-17 promoted both proliferation and invasion, while in human breast tumors ADAM-17 expression levels correlated with parameters of proliferation and invasion [14]. The aim of this study was to extend our investigations on ADAM-17 in human breast cancer and, in particular, to test the hypothesis that if ADAM-17 levels correlated with variables of tumor progression, elevated levels would be associated with adverse outcome.
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samples and patients
The breast cancer samples analyzed were sent to our laboratory for the assay of estrogen receptor (ER)-
by enzyme-linked immunosorbent assay (ELISA). Samples from patients with in situ carcinomas were not included in the study. All patients underwent either modified radical mastectomy or local excision combined with external beam radiotherapy. Following histopathological examination, residual tumor tissue was immediately frozen in liquid nitrogen. The characteristics of the carcinomas used and the adjuvant therapies received are summarized in Table 1. Median patient follow-up at the time of analysis was 37 months. The end point investigated was overall survival (OS), defined as the time in months from operation to death from any cause. ER- was measured by ELISA as previously described [15]. The cut-off point was 200 fmol/g wet weight of tissue.
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measurement of ADAM-17 by ELISA
ADAM-17 protein was measured by ELISA in extracts from 153 breast cancers (Quantikine®, R&D Systems, Minneapolis, MN). This ELISA is claimed to detect both the free fraction of ADAM-17 and ADAM-17 bound to recombinant human tissue inhibitors of metalloproteases. The claimed sensitivity of the assay was 0.6 ng/ml. ADAM-17 protein levels were measured according to the manufacturer's instruction.
measurement of ADAM-17 by western blotting
ADAM-17 protein was measured by western blotting in extracts of 140 breast cancers as previously described [14]. In brief, total protein was isolated from tissue samples using 50 mM Tris–HCl (pH 7.4) containing protease inhibitors [1 mM benzamidine-HCl, 1 µM trans-Epoxysuccinyl-L-leucylamido-(4-guanidino)butane (E-64) and 10 mM ethylene diamine tetraacetic acid (Sigma Aldrich, St Louis, MO)] (2 ml/100 mg sample). Immediately before use, samples were diluted in sodium dodecyl sulphate (SDS) sample buffer containing 50 mM Tris–HCl (pH 6.8), 2% SDS, 8% glycerol, 5% 2-mercaptoethanol and 0.01% bromophenol blue, and heated for 10 min at 70°C. One hundred microgram of total protein was separated on 7% Tris–Glycine SDS gels. Following transfer onto nitrocellulose, the filter was blocked in 5% (wt/vol) milk (Marvel® instant dried skimmed milk, Tesco, Ireland) in TBS, 0.05% Triton X-100 (vol/vol) (TBS-T) for 1 h at room temperature. Polyclonal rabbit anti-ADAM-17 (ProSci Incorporated, Poway, CA) was diluted to 5 µg/ml in 5% (wt/vol) milk in TBS-T and incubated with the membrane overnight at 4°C. Following three 10-min washes in TBS-T, the membrane was incubated with 1:1000 HRP-conjugated anti-rabbit immunoglobulin secondary antibody (Sigma Aldrich) for 1 h at room temperature. Excess secondary antibody was removed with three washes in TBS-T. A further wash in TBS was carried out before incubation with 6 ml of chemiluminescence reagent (Luminol, Santa Cruz Biotechnology, CA) for 1 min. Membranes were exposed to X-ray film (Fujifilm) in the dark for 15 min. Analysis of β-actin expression was carried out on the same blot using a mouse monoclonal antibody (Sigma Aldrich), as previously described [14].
statistical analysis
Nonparametric analysis was carried out, as ADAM-17 concentrations were not normally distributed. The Mann–Whitney U-test was used for relating ADAM-17 concentrations to the clinicopathological variables. Both univariate and multivariate analysis of events (death as end point) was carried out using Cox proportional hazards model. Relative risk (RR) values with 95% confidence intervals (CIs) were used to convey the effects. All P values were two sided. In addition, those factors that were significant at the 0.05 level in univariate analysis were included in the multivariate proportional hazards model. Stepwise and backwards regression was used in order to obtain the final model. All statistics were carried out using StatView for Windows Version 5.0.1 (SAS Institute Inc., Cary, NC), except for the survival analysis, which was carried out using SPSS version 11.0 (SPSS Inc., Chicago, IL).
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relationship between ADAM-17 protein levels determined by ELISA and standard prognostic factors for breast cancer
The distribution of ADAM-17 protein as determined by ELISA in the 153 breast cancers analyzed is shown in Figure 1. Concentrations ranged from undetectable to 12.9 ng/mg protein, with a median value of 3.56 ng/mg protein. As ADAM-17 protein concentrations did not exhibit a Gaussian distribution, nonparametric statistical analyses were employed.
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Table 2 shows the relationship between ADAM-17 levels and standard prognostic factors for breast cancer. Significantly higher concentrations were found in high-grade, i.e. grade 3, compared with low-grade carcinomas, i.e. grade 1 and 2 cancers (P = 0.003, Mann–Whitney U-test) and in ductal compared with lobular cancers (P = 0.008, Mann–Whitney U-test). ADAM-17 concentrations, however, were independent of tumor size, nodal status, patient age at diagnosis and hormone receptor status.
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relationship between ADAM-17 expression as determined by ELISA and western blotting
Of the 153 cancers assayed by ELISA, extracts from 118 representative samples were available for western blotting. As previously reported [14], following western blotting, ADAM-17 protein has been found to exist in two main forms in breast tissue, namely a 120-kDa precursor and a 100-kDa active form. A weak but statistically significant relationship was observed between protein levels determined by ELISA and both the 120-kDa (Spearman's rank correlation: P = 0.043, r = 0.193, n = 118) and 100-kDa form (Spearman's rank correlation: P < 0.0001, r = 0.390, n = 118), as measured by western blotting (Figure 2).
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relationship between ADAM-17 protein levels and patient outcome
Initially, ADAM-17, as determined by ELISA, was related to patient outcome as a continuous variable. Increasing concentrations were significantly associated with poor OS (Wald test: P = 0.01; RR = 1.189; 95% CI = 1.041–1.357). In order to establish a cut-off value for separating patients into good and poor prognostic groups, ADAM-17 values were divided into quartiles. As shown in Figure 3, at each of the cut-off points investigated, patients with high levels of ADAM-17 had a significantly worse outcome than those with lower levels. However, as the 75th percentile gave the best stratification, it was therefore used in subsequent investigations relating ADAM-17 to patient outcome.
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25th percentile. Level 2: 25th–50th percentile. Level 3: 50th -75th percentile. Level 4: > 75th percentile. ADAM-17 was determined by ELISA.Table 3 compared the prognostic utility of ADAM-17 levels with that of standard prognostic factors for breast cancer. As might be expected, tumor size, tumor grade and extent of lymph node involvement significantly predicted poor outcome using univariate analysis. Significantly, in multivariate analysis, ADAM-17 correlated with shorter OS. Thus, the prognostic value of ADAM-17 was independent of tumor size, grade and lymph node metastases.
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relationship between precursor and active forms of ADAM-17 and patient outcome
In addition to total ADAM-17, we also related both the precursor and active fractions of ADAM-17 (determined using western blotting) to patient outcome. Using a cut-off at the 75th percentile value, patients with high levels of both the precursor and active form had a significantly shorter OS than those with low levels (P = 0.047; RR = 2.748; 95% CI = 0.996–7.586, and P = 0.021; RR = 3.115; 95% CI = 1.126–8.618, respectively) (Figure 4). Using multivariate analysis, however, neither the active nor the precursor forms of ADAM-17 were independently predictive of outcome.
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discussion |
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In this study, we used two different assays to measure ADAM-17 in extracts of breast cancer, i.e. a new ELISA and western blotting. Each of these assays has specific advantages and disadvantages. The main advantage of the ELISA is that it is quantitative. On the other hand, it measures total ADAM-17 and thus cannot separate the precursor and active fractions of the protein. Conversely, using western blotting, the precursor and active forms can be separated. This method, however, is only semiquantitative.
Although concentrations of ADAM-17 determined by ELISA correlated significantly with both the active and precursor fraction, the associations were relatively weak, especially for the precursor form. The moderately stronger correlation between the ELISA concentrations and the active form may relate to the fact that this is the predominant form of ADAM-17 in breast cancer [14].
In this study, expression levels of ADAM-17 protein, as determined by ELISA, were independent of tumor size, presence or absence of lymph node metastasis, ER status and patient age at diagnosis. Significantly higher concentrations were, however, found in grade 3 compared with grade 1 and 2 tumors. Similarly, higher concentrations of ADAM-17 were found in ductal compared with lobular cancers, suggesting that this ADAM may have a different role in the formation of the two most frequently observed histological types of breast cancer. Previously, we reported that that the active form of ADAM-17 was expressed more frequently in lymph node-positive compared with lymph node-negative breast cancers [14]. In agreement with our findings using ELISA, neither the precursor nor the active forms of ADAM-17 were significantly related to tumor size, ER status or patient age at diagnosis [14].
Using both ELISA and western blotting, we show here that elevated levels of ADAM-17 predict poor outcome in patients with breast cancer. Indeed, using ELISA, ADAM-17 concentrations predicted outcome independent of conventional prognostic factors for breast cancer, such as tumor size, lymph node metastasis and ER status. As might be expected, the active form of ADAM-17 was a stronger predictor of outcome than the precursor form. Indeed, why the enzymatically inactive precursor was associated with outcome is unclear. The finding however, suggests that this form of ADAM-17 may be playing a nonproteolytic role in tumor progression, perhaps by altering adhesion. The apparent stronger prognostic impact of the ELISA-determined concentrations compared with the precursor and active forms measured by western blotting may be due to the fact that the ELISA provides quantitative values while the blotting technique is only semiquantitative. Previously, on the basis of an in silico approach, Kenny and Bissell [13] reported that elevated ADAM-17 mRNA expression was also associated with adverse outcome in patients with breast cancer.
Over the last two decades, although multiple prognostic markers have been proposed for breast cancer, only a few have progressed to regular clinical use [16]. These include ER and HER-2. Both these markers are not only prognostic but also predictive of response to therapy and act as direct targets for therapy, i.e. hormone therapy is directed against ER, while trastuzumab (Herceptin) targets HER-2 [17, 18].
As well as predicting patient outcome, ADAM-17 is also a potential marker of therapy outcome and a target for anticancer therapy. As a therapy predictive marker, ADAM-17 may have a role in identifying patients likely to be resistant to therapies directed against EGFR and HER-2, i.e. tyrosine kinase inhibitors and trastuzmab, respectively. Although multiple mechanisms are likely to be responsible for resistance to trastuzumab [18, 19], one mechanism is excess formation of ligands that activate EGFR and promote heterodimerization with HER-2 [20]. Thus, in a recent study in an animal model, trastuzumab-resistant human breast cancer cells were found to express a number of EGRF ligands such as TGF-, HB-EGF and EGF [20]. One of these factors, i.e. TGF-, was found to completely negate the growth inhibitory effects of trastuzumab. As mentioned in the Introduction, TGF- is known to be released from its inactive precursor by ADAM-17. Similarly, excess production of TGF- as well as amphiregulin, has been shown to confer resistance to gefitinib in lung cancer [21, 22].
ADAM-17 may also be a target for anticancer treatment. Recently, a number of relatively selective inhibitors have been described for this enzyme [23–29]. One of these, known as INCB3619 (Incyte, Wilmington, MA), blocked tumor cell proliferation and was synergistic with existing drugs in inhibiting tumor growth in model systems [25–29]. An ADAM inhibitor related to INCB3619, i.e. INCB7839 (Incyte), is currently in clinical trials against a number of cancers, including breast cancer (http://www.incyte.com/). Significantly, unlike the matrix metalloprotease inhibitors previously used [30], the ADAM-17 inhibitor did not induce musculoskeletal side effects, at least in the experimental animals investigated [29]. ADAM-17 inhibitors would be expected to be particularly useful in tumors that are dependent on EGFR/HER-2 signaling. Indeed, ADAM-17 inhibitors might have efficacy in tumors resistant to tyrosine kinase or trastuzumab because of excess formation of ligands, such as TGF-.
Like most reports on prognostic markers in cancer, this study has a number of limitations. These include its retrospective nature and the fact that the samples investigated were mostly from large tumors. Furthermore, almost all the patients investigated received some form of adjuvant therapy. It was thus not possible to determine whether ADAM-17 was a pure prognostic or predictive factor or indeed both.
In conclusion, our results reported here showing a significant association between increased concentrations of ADAM-17 and poor outcome in patients with breast cancer, provide further evidence that this protein is involved in cancer progression [12–14]. Our findings thus complement previous results from models systems, implicating ADAM-17 in the progression of breast cancer [12–14]. Before being considered as a clinically useful prognostic marker, our results with ADAM-17 should be confirmed in an external validation study which should preferably be carried out as part of a prospective randomized trial. Finally, our results provide an impetus for further work on ADAM-17 inhibitors for the treatment of cancer.
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Health Research Board of Ireland (Role of ADAMS in Breast Cancer, RP/II/2002 and Breast Cancer Metastasis: Biomarkers and Functional Mediators, PRP/2005/35).
Received for publication September 27, 2007. Revision received December 21, 2007. Accepted for publication December 24, 2007.
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1. Blobel CP. ADAMs: key components in EGFR signalling and development. Nat Rev Mol Cell Biol (2005) 6:32–43.[CrossRef][Web of Science][Medline]
2. Duffy MJ, Lynn DJ, Lloyd AT, et al. The ADAMs family of proteins: from basic studies to potential clinical applications. Thromb Haemost (2003) 89:622–631.[Web of Science][Medline]
3. Bongartz T, Sutton AJ, Sweeting MJ, et al. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA (2006) 295:2275–2285.
4. Suganuma O, Okabe S, Marino MW, et al. Essential role of tumour necrosis factor alpha (TNF-alpha) in tumour promotion as revealed by TNF-alpha deficient mice. Cancer Res (1999) 59:4518–5451.
5. Pilarsky E, Porat RM, Stein I, et al. NF-kappaB functions as a tumor promoter in inflammation-associated cancer. Nature (2004) 431:461–466.[CrossRef][Medline]
6. Greten FR, Eckman L, Greten TF, et al. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell (2004) 118:285–296.[CrossRef][Web of Science][Medline]
7. Yang WL, Godwin AK, Xu XX. Tumor necrosis factor-alpha-induced matrix proteolytic enzyme production and basement membrane remodeling by human ovarian surface epithelial cells: molecular basis linking ovulation and cancer risk. Cancer Res (2004) 64:1534–1540.
8. Schroeder JA, Lee DC. Transgenic mice reveal roles for TGF-alpha and EGF receptor in mammary gland development and neoplasia. J Mammary Gland Biol Neoplasia (1997) 2:119–129.[CrossRef][Medline]
9. Lamarca HL, Rosen JM. Estrogen regulation of mammary gland development and breast cancer: amphiregulin takes center stage. Breast Cancer Res (2007) 9:304.[CrossRef][Medline]
10. Miyamoto S, Hirata M, Yamazaki A, et al. Heparin-binding EGF-like growth factor is a promising target for ovarian cancer therapy. Cancer Res (2004) 64:5720–5727.
11. Zhuang S, Yan Y, Daubert RA, et al. Epiregulin promotes proliferation and migration of renal proximal tubular cells. Am J Physiol Renal Physiol (2007) 293:F219–F226.
12. Borrell-Pages M, Rojo F, Albanell J, et al. TACE is required for the activation of the EGFR by TGF-alpha in tumors. EMBO J (2003) 22:1114–1124.[CrossRef][Web of Science][Medline]
13. Kenny PA, Bissell MJ. Targeting TACE-dependent EGFR ligand shedding in breast cancer. J Clin Invest (2007) 117:337–345.[CrossRef][Web of Science][Medline]
14. McGowan PM, Ryan BM, Hill ADK, et al. ADAM-17 expression in breast cancer correlates with variables of tumor progression. Clin Cancer Res (2007) 13(8):2235–2243.
15. Cullen R, Maguire TM, McDermott EW, et al. Studies on oestrogen receptor-alpha and -beta mRNA in breast cancer. Eur J Cancer (2001) 37:1118–1122.[CrossRef][Web of Science][Medline]
16. Soerjomataram I, Louwman MWJ, Ribot JG, et al. An overview of prognostic factors for long term survivors of breast cancer. Breast Cancer Res Treat (2007) In press.
17. Duffy MJ. Estrogen receptors: role in breast cancer. Crit Rev Clin Lab Med (2006) 43:325–347.[CrossRef]
18. Hudis CA. Trastuzumab, mechanism of action and use in clinical practice. N Engl J Med (2007) 357:39–51.
19. Ritter CA, Perez-Torres M, Rinehart C, et al. Human breast cancer cells selected for resistance to trastuzumab in vivo overexpress epidermal growth factor receptor and ErbB ligands and remain dependent on the ErbB receptor network. Clin Cancer Res (2007) 13:4909–4919.
20. Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nature Rev Cancer (2005) 5:341–354.[CrossRef][Web of Science][Medline]
21. Kakiuchi S, Daigo Y, Ishikawa N, et al. Prediction of sensitivity of advanced non-small cell lung cancer to gefitinib. Human Mol Genet (2004) 13:3029–3043.
22. Kakiuchi S, Daigo Y, Takano A, et al. Increases of amphiregulin and transforming growth factor-alpha in serum as predictors of poor response to gefitinib among patients with advanced non-small cell lung cancer. Cancer Res (2005) 65:9176–9184.
23. Moss ML, Bartsch JW. Therapeutic benefits from targeting of ADAM family members. Biochemistry (2004) 43:7227–7235.[CrossRef][Web of Science][Medline]
24. Gilmore JL, King BW, Harris K, et al. Synthesis and structure-activity relationship of a novel achiral series of TNF-alpha converting enzyme inhibitors. Bioorg Med Chem Lett (2006) 16:2699–2704.[CrossRef][Medline]
25. Levin JI, Chen JM, Laakso LM, et al. Acetylenic TACE inhibitors. Part 3: thiomorpholine sulfonamide hydroxamates. Bioorg Med Chem Lett (2006) 16:1605–1609.[CrossRef][Medline]
26. Zhou B-BS, Petyon M, He B, et al. Targeting ADAM-mediated ligand cleavage to inhibit HER2 and EGFR pathways in non-small cell lung cancer. Cancer Cell (2006) 10:39–50.[CrossRef][Web of Science][Medline]
27. Liu X, Fridman JS, Wang Q, et al. Selective inhibition of ADAM metalloproteases blocks HER-2 extracellular domain (ECD) cleavage and potentiates the anti-tumor effects of trastuzumab. Cancer Biol Ther (2006) 5:648–656.[Web of Science][Medline]
28. Liu PC, Liu X, Li Y, et al. Identification of ADAM10 as a major source of HER2 ectodomain sheddase activity in HER2 overexpressing breast cancer cells. Cancer Biol Ther (2006) 5:657–664.[Web of Science][Medline]
29. Fridman JS, Caulder E, Hansbury M, et al. Selective inhibition of ADAM metalloproteases as a novel approach for modulating ErbB pathways in cancer. Clin Cancer Res (2007) 13:1892–1902.
30. Zucker S, Cao J, Chen W-T. Critical appraisal of the use of matrix metalloproteinases inhibitors in cancer treatment. Oncogene (2000) 19:6642–6650.[CrossRef][Web of Science][Medline]
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