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The Biology Behind |
Authors' Affiliations: 1 Veterans Affairs Medical Center, Northport, and 2 Stony Brook University, Stony Brook, New York
Requests for reprints: Stanley Zucker, Veterans Affairs Medical Center (mail code 151), 79 Middleville Road, Northport, NY 11768. Phone: 631-261-4400, ext. 2861; Fax: 631-544-5317; E-mail: s_zucker{at}yahoo.com.
In this issue of Clinical Cancer Research, Nikkola et al. have presented the results of measurement of serum levels of matrix metalloproteinases (MMP) in patients with advanced melanoma who received chemotherapy and IFN-
treatment (1). Scientific investigation of the role of proteases in cancer progression has been on a roller-coaster ride for the past few years. Although there is a little doubt that MMPs are an important compotent of cancer invasion and metastasis, specific details remain elusive. Nonetheless, measurement of plasma/serum levels of MMPs as a means of monitoring disease activity has been a promising development.
Matrix metalloproteinases (MMP) are a large family of zinc-dependent endoproteases that have been implicated in many physiologic and pathologic processes. Beginning with the discovery of tadpole collagenase in 1962 (2), the focus of MMPs for the next four decades has been on the degradation of extracellular matrix components (collagens, laminin, fibronectin, etc.), with more recent emphasis on cell signaling activities (3, 4). Following the identification of increased cancer cell levels of MMP-2 and MMP-9, which digest type IV collagen (the key component of basement membranes; ref. 5), MMPs were implicated in cancer-related processes including invasion, metastasis, angiogenesis, and cell proliferation (3, 6, 7). Although some MMPs (MMP-2, -7, -9, -11, -14) are readily detected in most types of tumors, the pattern of expression of other MMPs (MMP-1, -3, -8, -13) varies considerably. A correlation between high tumor levels of MMPs (MMP-1, -2, -7, -9, -11, -14) and poor clinical outcome has been noted in numerous publications involving almost every type of cancer (3, 8, 9). Not only are MMPs increased in cancer cells, but they are also increased in stromal (fibroblasts and endothelial cells) and inflammatory cells within the tumor. Cross-talk between tumor cells and stromal cells results in enhanced production of MMPs by both cell types (10, 11). It is important to remember that increased tissue levels of MMPs have also been identified in many nonmalignant pathologic and physiologic conditions, e.g., inflammatory diseases (arthritis, colitis, periodontitis), shock, atherosclerosis, cerebrovascular diseases, and pregnancy (12).
In normal physiology, high concentrations of tissue inhibitors of metalloproteinases (TIMP-1, -2, -3, -4) serve to regulate the activity of MMPs, thereby limiting proteolytic activity to the pericellular and cell surface microenvironment (6). The ratio of MMPs to TIMPs in cancer specimens has been proposed to reflect dominant proteolytic activity and poor prognosis. Emphasis has been placed on the importance of active rather than total MMP levels in tumors. However, there are technical limitations to the identification of activated MMPs in tissues. Paradoxically, elevated tumor and blood levels of TIMP-1 and TIMP-2 have been correlated with poor clinical outcome (12).
Based on impressive preclinical studies (animal tumor models) which showed an important role for MMPs in cancer, the pharmaceutical industry successfully developed several synthetic MMP inhibitors that could be readily administered orally to patients with cancer. Initial phase I and II industry-sponsored clinical trials were supportive of the concept that broad-spectrum MMP inhibitors had anticancer activity against several tumor types. Based primarily on pragmatic rather than scientific considerations, clinical trials involving different MMP inhibitors were initiated in patients with advanced cancers. Unfortunately, none of several randomized phase III clinical trials of MMP inhibitors in cancer (lung, pancreas, prostate, stomach, breast) have shown efficacy (3, 6, 7). In retrospect, the failure of MMP inhibitors to alter disease progression in metastatic cancer might have been anticipated because MMPs seem to be more important in early aspects of cancer progression (13). The role of MMPs in early stage cancer versus initiation of metastasis and growth at secondary sites remains to be more clearly defined (14, 15).
In spite of these clinical setbacks, scientific interest in MMPs continues to mount. More recent studies have uncovered numerous diverse activities of MMPs that expand our understanding of their role in disease. MMPs function as modulators of biologically active signaling molecules. Extracellular matrix–localized growth factors, e.g., basic fibroblast growth factor, transforming growth factor-ß, as well as cell surface–bound precursors of growth factors, are released in their active forms following MMP cleavage. Growth factor receptors (e.g., fibroblast growth factor receptor 1) and adhesive proteins (e.g., integrins, cadherin, CD44) can be cleaved at the cell surface by MMPs. Other examples of substrates cleaved by MMPs include proteins involved in apoptosis, angiogenesis, cell migration, and evasion of immune surveillance (3, 4, 7). Exposure of cryptic sites that contain signaling information for responsive cells is another common theme of MMPs (16). Although MMP cleavage would seem to facilitate cancer invasion and metastasis, cleavage of some substrates can interfere with cancer dissemination, i.e., MMP-induced cleavage of plasminogen results in generation of angiostatin, an inhibitor of tumor angiogenesis (17).
Malignant melanoma, a cancer long-renowned for production of proteases and metastatic propensity, provides an example of the complicated interaction between MMPs and cell surface molecules in cancer. Whereas, MMP-2 is not detectable in human melanoma in situ, high levels of the activated protease are present in advanced primary and metastatic melanomas at the tumor-stroma interface (18). Other studies have suggested a dynamic role for MMPs in melanoma. For example, in the early radial growth stage, increased tumor levels of MMP-9 and the inducer of MMPs (EMMPRIN) have been shown; these levels are decreased during the invasive vertical growth phase (19). Of potential clinical relevance, Nikkola et al. (9) have reported that high tissue levels of MMP-1 and MMP-3 in melanoma correlated with shorter patient survival; high expression of MMP-13 correlated with visceral metastasis. In the current issue of Clinical Cancer Research, Nikkola et al. (1) have presented results of measurement of serum levels of MMPs in a similar group of patients with advanced melanoma who underwent treatment with chemotherapy and IFN-. Patients with high serum levels of MMP-9 had significantly poorer overall survival and more extensive metastases than patients with lower serum levels of MMP-9. In contrast, serum levels of MMP-1 were higher in controls than in melanoma patients. Nonetheless, patients with elevated levels of MMP-1 progressed more rapidly after initiating therapy. In multivariate analysis with age and gender, MMP-9 and MMP-1 turned out to be independent prognostic factors for overall survival. The authors concluded that serum MMP-9 could have clinical value in identifying patients at high risk for melanoma progression.
Unfortunately, serious technical flaws in this otherwise well-conceived study undermine confidence in the authors' conclusions. These include: (a) MMP-9 measurements in serum primarily reflect release of proteases by leukocytes during the clotting process in the blood collection tube (8, 20–23); the addition of an anticoagulant to collected blood is necessary to prevent this in vitro artifact. (b) MMP-9 is unstable even on storage at –80°C (24), hence, depending on the technique employed,3 assays may need to be done without long delay; the serum specimens in this study were collected between 1995 and 1998 and presumably assayed an undisclosed number of years later. (c) The control group was limited to 8 healthy individuals; based on the wide population variability of MMP levels in blood (25), this is an inadequate sample size to serve as a comparison with 71 patients with melanoma. (d) The demonstration of activated MMP-13 in serum is unexpected. Further studies will need to be done to determine whether activation of MMP-13 occurred during prolonged storage of blood samples.
In conclusion, similar to previous reports in colon and breast cancer (26, 27), the measurement of circulating blood levels of MMP-9 may be useful in predicting prognosis in advance melanoma. However, these studies need to be repeated with greater attention to the details of plasma specimen collection. Unfortunately, in spite of several definitive articles describing the artifact (7, 20–23), many manuscripts continue to be published on measurements of MMP-9 in serum samples.
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Grant support: Research Enhancement Award Program from the Department of Veterans Affairs (S. Zucker) and a grant from the U.S. Army Materiel Command (J. Cao).
Received 4/ 7/05; revised 5/ 4/05; accepted 5/ 6/05.
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and basic fibroblast growth factor-mediated mechanisms. J Invest Dermatol 2005;124:638–43.[CrossRef][Medline]
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