help button home button Am J Pathol R & D Systems
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS

This Article
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
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 Google Scholar
Google Scholar
Right arrow Articles by Yan, L.
Right arrow Articles by Moses, M. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yan, L.
Right arrow Articles by Moses, M. A.
(American Journal of Pathology. 2001;158:1185-1190.)
© 2001 American Society for Investigative Pathology

Commentaries

A Case of Tumor Betrayal

Biphasic Effects of TIMP-1 on Burkitt’s Lymphoma

Li Yan and Marsha A. Moses

From the Department of Surgery, Children’s Hospital, Harvard Medical School, Boston, Massachusetts

Among a number of different proteinases that are capable of digesting extracellular matrix (ECM) components, the matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, play a major role.1 Collectively, MMPs have been shown to cleave most ECM components either independently or in a collaborative manner. Because excessive digestion of ECM is a hallmark of many pathological conditions including tumor growth and metastasis, it is critical that MMP activity be precisely regulated both spatially and temporally. In addition to the transcriptional and translational control of MMP expression by growth hormones/factors, cytokines, cell-ECM or cell-cell contacts, and oncogene expression, MMP activity is regulated by their endogenous inhibitors, the tissue inhibitors of matrix metalloproteinases (TIMPs). TIMPs not only directly control the activity of active MMPs, but also have substantial influence on the activation process of MMP zymogens.2-5

Given the ability of TIMPs to inhibit the proteolytic activity of MMPs, it is not surprising to find that TIMPs are capable of blocking tumor metastasis, either by inhibiting tumor invasion of basement membrane or by restraining tumor angiogenesis.6 However, recent studies have suggested that the inhibitory effects of TIMPs on tumor progression are not only due to their ability to inhibit MMP activity, but also because of their ability to directly modulate the cell growth and apoptosis of tumor cells, as well as host endothelial cells (ECs).

In an intriguing study published in this issue of The American Journal of Pathology, divergent effects of TIMP-1 on Burkitt’s lymphoma growth in nude mice are reported by Guedez and co-workers.96 When Epstein-Barr virus-negative Burkitt’s lymphoma cells were forced to overexpress TIMP-1 by retroviral transfection, a biphasic tumor growth pattern was observed. After injection into nude mice, these cells showed an initial fast proliferation phase due to the stimulation of tumor cell proliferation and the protection from apoptosis elicited by TIMP-1. However, once these tumors reached a certain size (0.4 mm2), the initial fast growth phase was replaced by a slowdown of tumor progression accompanied by tumor necrosis and regression. The authors provide convincing evidence to show that this late stage inhibition was caused by the suppression of tumor-induced host angiogenesis. These novel in vivo results highlight the importance of MMPs and their endogenous inhibitors during tumor progression and angiogenesis.

TIMPs and Tumor Growth

TIMPs and Cell Proliferation

Since first being discovered as having the ability to stimulate the proliferation of erythroid progenitor cells,7 in addition to inhibiting MMP activity,8 TIMP-1’s growth promoting effects have been extended to a variety of cells, including mammary epithelial cells,9 keratinocytes,10 lymphoid, myeloid, endothelial, fibroblasts, hepatoma, breast carcinoma, and chondrocyte cells.11 Like TIMP-1, TIMP-2 was shown to stimulate cell proliferation in human osteosarcoma cells and cultured rabbit corneal epithelial cells, potentially via a tyrosine kinase-dependent signaling pathway,12,13 and to promote fibroblast or fibrosarcoma cell growth by stimulating cAMP production.14 Unlike TIMP-1,11 TIMP-2 also exhibits inhibitory effects on the proliferation of ECs,15 renal carcinoma cells,16 and several other carcinoma cells.17 Interestingly, TIMP-1 and TIMP-2 exert different effects on EC processes in that TIMP-2 inhibits fibroblast growth factor-driven EC proliferation and TIMP-1 does not.15 In fact, the latter has been shown to exert a stimulatory effect on EC growth in vitro.11 Both inhibitors can, however, suppress capillary EC migration and tube formation in response to angiogenic stimuli.18

These regulatory effects of TIMPs on cell proliferation may not necessarily be a function of their MMP inhibitory activity.15,19 For example, modulation of cell proliferation by TIMPs has been attributed to their interactions with unknown cell surface receptors,10,14 as well as to their potential regulation of DNA synthesis in the nucleus.20,21 Moreover, the divergent and sometimes even contradictory effects of TIMPs on cell growth in vitro are cell type-specific. Although these provocative findings could be taken to presage the divergent effects of tumor growth and angiogenesis that is demonstrated by Guedez and co-workers,96 their study is the first to document these two divergent in vivo effects within the same tumor system. It will be important to learn whether this biphasic effect is observed in other tumor systems and whether all TIMPs are capable of exerting this same effect.

TIMPs and Tumor Cell Apoptosis

In addition to their growth-promoting ability, TIMPs can also affect programmed cell death, or apoptosis, in both normal cells and transformed tumor cells. TIMP-1 expression levels have been shown to correlate with cell apoptosis in a series of B lymphoma cells.22,23 Overexpression of TIMP-1 can rescue mammary epithelial cells from apoptosis induced by uncontrolled ECM degradation.24 Similarly, TIMP-2 expression has inhibitory effects on apoptosis of melanoma cells.25 In contrast, however, it has been reported that TIMP-3, a matrix-associated inhibitor, induces cell apoptosis in melanoma cells,26 colon carcinoma cells,27 and vascular smooth muscle cells.28 The cell-death domain of TIMP-3 has been localized to the amino terminus and its apoptotic effect appears to correlate with the inhibition of metalloproteinase activity.29

According to Guedez and colleagues,96 the initial growth-stimulatory effect of TIMP-1 on Burkitt’s lymphoma in vivo is likely achieved through its inhibition of apoptosis. In fact, the same group has recently reported that TIMP-1 expression in Burkitt’s lymphoma cell lines inhibits induction of apoptosis by Fas-dependent and -independent pathways, and up-regulates BCL-XL expression.22 Based simply on the anti-apoptotic effect of TIMP-1, one would expect that TIMP-1-positive tumors would grow much more aggressively than their TIMP-1-negative counterparts. However in this study, after reaching a certain size (0.4 mm2), the growth rate of TIMP-1-positive tumors decreased significantly. These observations led the authors to invoke the anti-angiogenic activity of TIMP-1 as a potential mechanism for the tumor suppression observed in their model. This anti-angiogenic mechanism is strongly supported by the immunostaining and microvessel counts provided in this study. In addition, their finding that tumor regression after the initial period of increased tumor growth was marked by the presence of only microscopic foci of residual proliferating tumor cells observed only on biopsy of the tumor site is reminiscent of the tumor dormancy elicited by a number of angiogenesis inhibitors30-32 and begs the question as to how long this dormant period might last. Based on recent work demonstrating that MMPs may be required for the acquisition of the angiogenic phenotype during tumor progression,33,34 we would hypothesize that any shift in the proteolytic balance in favor of MMP activity would activate the switch to the angiogenic phenotype, thereby bringing an end to the period of tumor dormancy.

TIMPs and Tumor Metastasis

The inhibitory function of TIMPs during tumor metastasis has been well demonstrated in a variety of tumors. Overexpression of TIMP-1 or TIMP-2 inhibits the invasive behavior of highly invasive and metastatic B16F10 murine melanoma cells,25 fibrosarcoma cells,35 the osteolytic bone metastases of breast carcinoma,36 and the extravasation of pulmonary metastasis of a bladder carcinoma.37 The newly identified TIMP-4 has also been shown to inhibit breast carcinoma cell invasion in vitro and tumor metastasis in vivo.38 Furthermore, targeted disruption of TIMP-1 expression increases the invasive behavior of primitive mesenchymal cells derived from embryonic stem cells.39 Adenovirus-mediated expression of TIMP-3 resulted in a similar, and even more potent, inhibition of cell invasion than that caused by TIMP-1 and TIMP-2, in melanoma, fibrosarcoma, and ovarian carcinoma cells.26,40 In addition, TIMP-3 can also induce apoptosis by preventing cell adhesion to underlying matrix.26

TIMPs and Tumor Angiogenesis

Tumor angiogenesis is required for sustained tumor growth because the new capillaries are conduits for oxygen and nutrients. Without angiogenesis, tumor growth is restricted to the tissue diffusion distance of ~0.2 mm.41 MMPs and TIMPs have been shown to be involved in various stages of the angiogenic process, from EC migration and proliferation, to deposition and remodeling of basement membrane of newly formed blood vessels.18 Furthermore, modulation of MMP or TIMP expression has a profound influence on angiogenesis at various stages in different tumors.33,34,42-44

TIMPs and EC Proliferation and Migration

It is only in recent years that the notion that certain TIMPs might be capable of exerting a pleiotropic effect on tumor growth, metastasis, and angiogenesis has come to be appreciated. Since the first report that a TIMP could inhibit angiogenesis in vitro and tumor angiogenesis in vivo,45,46 a series of studies using a variety of endogenous MMP inhibitors have supported this suppression of neovascularization.15,47,48 At the time, the potential mechanisms of action focused on the ability of TIMPs to suppress mitogen-driven angiogenic events such as capillary EC proliferation, migration, and capillary tube and sprout formation. However, it was also reported that select TIMPs might also exert a stimulatory effect on EC functions required for successful angiogenesis. For example, TIMP-1 unlike TIMP-2, did not inhibit capillary EC proliferation15 but rather was reported to stimulate it.11

The inhibitory effects of TIMPs on EC migration have been shown both in vitro and in vivo.25,45,47,49 Given the critical role of EC migration during angiogenesis,50 this inhibition may account, at least in part, for the reduced tumor angiogenesis observed in TIMP-1-positive lymphoma tumor implants in vivo.

MMPs and TIMPs: Regulators of Angiogenic Signals

The process of tumor angiogenesis is governed by a complex signaling network.50 The establishment of the neovasculature is modulated by soluble growth factors, hormones, and cytokines,51 as well as by insoluble ECM that underlies the participating vessels.52,53 Metalloproteinases, together with TIMPs, have been shown to play pivotal roles during the angiogenic process, from processing latent growth factors and shedding receptors, to maintaining and remodeling EC basement membrane.18 These roles are discussed briefly here.

Bioavailability of Soluble Factors

Many growth factors involved in angiogenesis reside in the ECM, associated with either their endogenous inhibitors or extracellular proteoglycans.54 Therefore, to actively participate in angiogenesis, these sequestered growth factors must be released from their ECM compartments. A recent study has demonstrated that MMP-9 can liberate vascular endothelial growth factor from its ECM storage in a mouse pancreatic-islet carcinoma model.34 MMP-9 has also been shown to process latent transforming growth factor-ß or interleukin-8, which in turn, promote tumor invasion and angiogenesis, or activate neutrophils, respectively.55,56 In addition to governing the releasing and processing of active growth factors, MMPs and TIMPs are also involved in modulating cell surface receptors for these signaling molecules. For example, proteolytic cleavage mediated by MMP-2 has been shown to release a soluble active ectodomain of fibroblast growth factor receptor 1.57 In another case, the processing of cell-surface tumor necrosis factor-{alpha} and its receptors can be inhibited by broad-spectrum MMP inhibitors, as well as by TIMP-2 and TIMP-3.27,58-60 This inhibition, in turn, augments tumor necrosis factor-{alpha} signaling and induces tumor cell apoptosis in vitro and suppresses tumor growth in vivo.27,61

MMPs also process extracellular molecules into fragments with potent anti-angiogenic activities. For example, angiostatin, an internal fragment of plasminogen, is a potent inhibitor of angiogenesis, which specifically inhibits EC proliferation and tumor growth.31,62 The production of angiostatin has been linked to various MMPs,63 including tumor-expressed MMP-2,64 MMP-12 derived from tumor-associated macrophage,65 MMP-3,66 MMP-7, and MMP-9.67,68 Another angiogenesis inhibitor, endostatin, a 20-kd C-terminal fragment of collagen type XVIII, specifically inhibits endothelial cell proliferation and potently inhibits angiogenesis and tumor growth.32 Several lines of evidence have demonstrated that the release of endostatin from its precursor is mediated by a metal-dependent early step, followed elastase cleavage.69 The production of endostatin may also be mediated by cathepsin L secreted from endothelial-origin tumor cells.70 Recently, more matrix-derived peptide fragments have been shown to have anti-angiogenesis activity.71,72 Although the identity of proteases responsible for their release is still unclear, MMPs are expected to play an essential role in these anti-angiogenic-processing events as well.

Taken together then, MMPs not only proteolytically release matrix-bound pro-angiogenic growth factors, but can also directly process matrix molecules into anti-angiogenic fragments. The balance of these two opposing activities, pro-angiogenic and anti-angiogenic, respectively, is regulated by the activity of TIMPs, which in turn, can independently modulate the angiogenic process.

Modulation of Insoluble Factors Signaling

Tumor cell and EC behavior is also regulated by the underlying ECM and signals transduced by integrins after engagement of ligands.52,73 Both ECM integrity and subsequent signaling events are profoundly influenced by the local balance between MMPs and TIMPs. Changes in ECM structure and integrity can also feedback to modulate the proteolytic activity elicited by ECs.74,75 Excessive proteolytic cleavage of ECM by MMPs results in cell apoptosis, which can be rescued by overexpressing counteracting TIMPs.24,25 MMPs also influence cell behavior by exposing cryptic binding sites via proteolytic cleavage of ECM molecules.76 Similarly, the angiogenic potential of vascular EC is also regulated by the ECM, which in turn, is constantly remodeled by the synchronized actions of MMPs and TIMPs.74,77

TIMPs in Cancer Therapy and Diagnosis/Prognosis

For many of the reasons discussed above, MMP inhibitors, both synthetic and endogenous, have become attractive therapeutic candidates in recent years.78-80 The limited clinical success of broad-spectrum MMP inhibitors has been suggested to be due, at least in part, to their lack of specificity and associated side effects.81 Some of these side effects could be limited by designing more specific MMP inhibitors and a significant effort is being made to do so.82 However, targeting MMP specificity may represent only one of a number of potential approaches to resolving these problems. As shown in the study by Guedez and colleagues,96 TIMP-1 can initially promote tumor growth in the early stage by inhibiting apoptosis, whereas at a later stage, the secreted TIMP-1 acts on host ECs to block tumor angiogenesis and to ultimately suppress tumor growth. Given such divergent and even contradictory functions of MMPs and TIMPs during tumor progression and angiogenesis, it becomes very important that the schedule of administration of MMP inhibitors as cancer therapeutics be carefully determined based on the stage of tumor progression in order to achieve optimal therapeutic efficacy. Therefore, the clinical monitoring of tumor progression becomes a critical adjunct to inhibitor therapy.

The detection of MMPs and TIMPs in body fluids may provide a useful way to accomplish such monitoring. Elevated MMP levels in biological fluids, including serum, plasma, and urine from animals bearing experimental tumors or from cancer patients have been reported in several studies.83-88 In addition, elevated plasma levels of TIMP-1 and TIMP-2 have been detected in patients of late stage breast, colorectal, lung, and gastric cancer.89-95

Some of these options represent highly sensitive, specific, and noninvasive monitoring systems. For example, it has recently been reported that intact and biologically active MMPs can be detected in the urine of cancer patients and are independent predictors of disease status.88 These urine samples were obtained from patients with a variety of cancers, including prostate, renal, bladder, and breast carcinomas. Urinary MMP-2 and MMP-9 have been shown to be independent predictors of cancer. In addition to these two major gelatinase species, several MMP activities with molecular sizes greater than 100 kd were observed and were shown to be predictive of metastatic diseases. Combined with other conventional diagnostic tools, the detection of urinary MMP activity may provide the relevant information regarding tumor burden, tumor staging, and tumor angiogenic status that will be necessary to optimize both current and future cancer therapies.

Conclusion

The authors note in closing that their study highlights the need for a further understanding of the role of TIMPs in tumor progression. For example, it now becomes very important to identify the molecular players regulating the switch in TIMP-1’s activities in early and later stage tumor progression. At the very least, this information might lead to the discovery of new drug candidates for cancer therapy and to a new therapeutic and diagnostic paradigm for the monitoring and treatment of neoplastic disease.

Acknowledgements

We thank Dr. Jay Harper for helpful discussions.

Footnotes

Address reprint requests to Marsha A. Moses, Ph.D., Department of Surgery, Children’s Hospital, Harvard Medical School, 300 Longwood Ave., Boston, MA 02115. E-mail: moses_m{at}a1.tch.harvard.edu

Supported in part by grants from The National Cancer Institute, National Institutes of Health (RO1 CA83106), and The American Cancer Society (RPG-97-013-04-CSM).

Accepted for publication February 2, 2001.

References

  1. Woessner F, Nagase H, eds: Matrix Metalloproteinases and TIMPs. London, Oxford University Press, 2000
  2. Murphy G, Knauper V: Relating matrix metalloproteinase structure to function: why the "hemopexin" domain? Matrix Biol 1997, 15:511-518[Medline]
  3. Nagase H: Cell surface activation of progelatinase A (proMMP-2) and cell migration. Cell Res 1998, 8:179-186[Medline]
  4. Goldberg GI, Strongin A, Collier IE, Genrich LT, Marmer BL: Interaction of 92-kDa type IV collagenase with the tissue inhibitor of metalloproteinases prevents dimerization, complex formation with interstitial collagenase, and activation of the proenzyme with stromelysin. J Biol Chem 1992, 267:4583-4591[Abstract/Free Full Text]
  5. Kurschat P, Zigrino P, Nischt R, Breitkopf K, Steurer P, Klein CE, Krieg T, Mauch C: Tissue inhibitor of matrix metalloproteinase-2 regulates matrix metalloproteinase-2 activation by modulation of membrane-type 1 matrix metalloproteinase activity in high and low invasive melanoma cell lines. J Biol Chem 1999, 274:21056-21062[Abstract/Free Full Text]
  6. Gomez DE, Alonso DF, Yoshiji H, Thorgeirsson UP: Tissue inhibitors of metalloproteinases: structure, regulation and biological functions. Eur J Cell Biol 1997, 74:111-122[Medline]
  7. Gasson JC, Golde DW, Kaufman SE, Westbrook CA, Hewick RM, Kaufman RJ, Wong GG, Temple PA, Leary AC, Brown EL, Orr EC, Clark SC: Molecular characterization and expression of the gene encoding human erythroid-potentiating activity. Nature 1985, 315:768-771[Medline]
  8. Docherty AJ, Lyons A, Smith BJ, Wright EM, Stephens PE, Harris TJ, Murphy G, Reynolds JJ: Sequence of human tissue inhibitor of metalloproteinases and its identity to erythroid-potentiating activity. Nature 1985, 318:66-69[Medline]
  9. Fata JE, Leco KJ, Moorehead RA, Martin DC, Khokha R: Timp-1 is important for epithelial proliferation and branching morphogenesis during mouse mammary development. Dev Biol 1999, 211:238-254[Medline]
  10. Bertaux B, Hornebeck W, Eisen AZ, Dubertret L: Growth stimulation of human keratinocytes by tissue inhibitor of metalloproteinases. J Invest Dermatol 1991, 97:679-685[Medline]
  11. Hayakawa T, Yamashita K, Tanzawa K, Uchijima E, Iwata K: Growth-promoting activity of tissue inhibitor of metalloproteinases-1 (TIMP-1) for a wide range of cells. A possible new growth factor in serum. FEBS Lett 1992, 298:29-32[Medline]
  12. Yamashita K, Suzuki M, Iwata H, Koike T, Hamaguchi M, Shinagawa A, Noguchi T, Hayakawa T: Tyrosine phosphorylation is crucial for growth signaling by tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2). FEBS Lett 1996, 396:103-107[Medline]
  13. Saika S, Kawashima Y, Okada Y, Tanaka SI, Yamanaka O, Ohnishi Y, Ooshima A: Recombinant TIMP-1 and -2 enhance the proliferation of rabbit corneal epithelial cells in vitro and the spreading of rabbit corneal epithelium in situ. Curr Eye Res 1998, 17:47-52[Medline]
  14. Corcoran ML, Stetler-Stevenson WG: Tissue inhibitor of metalloproteinase-2 stimulates fibroblast proliferation via a cAMP-dependent mechanism. J Biol Chem 1995, 270:13453-13459[Abstract/Free Full Text]
  15. Murphy AN, Unsworth EJ, Stetler-Stevenson WG: Tissue inhibitor of metalloproteinases-2 inhibits bFGF-induced human microvascular endothelial cell proliferation. J Cell Physiol 1993, 157:351-358[Medline]
  16. Miyake H, Hara I, Gohji K, Yamanaka K, Hara S, Arakawa S, Nakajima M, Kamidono S: Relative expression of matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 in mouse renal cell carcinoma cells regulates their metastatic potential. Clin Cancer Res 1999, 5:2824-2829[Abstract/Free Full Text]
  17. Hoegy SE, Oh HR, Corcoran ML, Stetler-Stevenson WG: Tissue inhibitor of metalloproteinases-2 (TIMP-2) suppresses TKR-growth factor signaling independent of metalloproteinase inhibition. J Biol Chem 2000, 276:3222-3230[Abstract/Free Full Text]
  18. Moses MA: The regulation of neovascularization of matrix metalloproteinases and their inhibitors. Stem Cells 1997, 15:180-189[Abstract/Free Full Text]
  19. Chesler L, Golde DW, Bersch N, Johnson MD: Metalloproteinase inhibition and erythroid potentiation are independent activities of tissue inhibitor of metalloproteinases-1. Blood 1995, 86:4506-4515[Abstract/Free Full Text]
  20. Ritter LM, Garfield SH, Thorgeirsson UP: Tissue inhibitor of metalloproteinases-1 (TIMP-1) binds to the cell surface and translocates to the nucleus of human MCF-7 breast carcinoma cells. Biochem Biophys Res Commun 1999, 257:494-499[Medline]
  21. Zhao WQ, Li H, Yamashita K, Guo XK, Hoshino T, Yoshida S, Shinya T, Hayakawa T: Cell cycle-associated accumulation of tissue inhibitor of metalloproteinases-1 (TIMP-1) in the nuclei of human gingival fibroblasts. J Cell Sci 1998, 111:1147-1153[Abstract]
  22. Guedez L, Stetler-Stevenson WG, Wolff L, Wang J, Fukushima P, Mansoor A, Stetler-Stevenson M: In vitro suppression of programmed cell death of B cells by tissue inhibitor of metalloproteinases-1. J Clin Invest 1998, 102:2002-2010[Medline]
  23. Guedez L, Courtemanch L, Stetler-Stevenson M: Tissue inhibitor of metalloproteinase (TIMP)-1 induces differentiation and an antiapoptotic phenotype in germinal center B cells. Blood 1998, 92:1342-1349[Abstract/Free Full Text]
  24. Alexander CM, Howard EW, Bissell MJ, Werb Z: Rescue of mammary epithelial cell apoptosis and entactin degradation by a tissue inhibitor of metalloproteinases-1 transgene. J Cell Biol 1996, 135:1669-1677[Abstract/Free Full Text]
  25. Valente P, Fassina G, Melchiori A, Masiello L, Cilli M, Vacca A, Onisto M, Santi L, Stetler-Stevenson WG, Albini A: TIMP-2 over-expression reduces invasion and angiogenesis and protects B16F10 melanoma cells from apoptosis [published erratum appears in Int J Cancer 1999, 80: 485]. Int J Cancer 1998, 75:246-253[Medline]
  26. Ahonen M, Baker AH, Kahari VM: Adenovirus-mediated gene delivery of tissue inhibitor of metalloproteinases-3 inhibits invasion and induces apoptosis in melanoma cells. Cancer Res 1998, 58:2310-2315[Abstract/Free Full Text]
  27. Smith MR, Kung H, Durum SK, Colburn NH, Sun Y: TIMP-3 induces cell death by stabilizing TNF-{alpha} receptors on the surface of human colon carcinoma cells. Cytokine 1997, 9:770-780[Medline]
  28. Baker AH, Zaltsman AB, George SJ, Newby AC: Divergent effects of tissue inhibitor of metalloproteinase-1, -2, or -3 overexpression on rat vascular smooth muscle cell invasion, proliferation, and death in vitro. TIMP-3 promotes apoptosis. J Clin Invest 1998, 101:1478-1487[Medline]
  29. Bond M, Murphy G, Bennett MR, Amour A, Knauper V, Newby AC, Baker AH: Localization of the death domain of tissue inhibitor of metalloproteinase-3 to the N terminus. Metalloproteinase inhibition is associated with proapoptotic activity. J Biol Chem 2000, 275:41358-41363[Abstract/Free Full Text]
  30. Holmgren L, Jackson G, Arbiser J: p53 induces angiogenesis-restricted dormancy in a mouse fibrosarcoma. Oncogene 1998, 17:819-824[Medline]
  31. O’Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J: Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma [see comments]. Cell 1994, 79:315-328[Medline]
  32. O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J: Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 1997, 88:277-285[Medline]
  33. Fang J, Shing Y, Wiederschain D, Yan L, Butterfield C, Jackson G, Harper J, Tamvakopoulos G, Moses MA: Matrix metalloproteinase-2 is required for the switch to the angiogenic phenotype in a tumor model. Proc Natl Acad Sci USA 2000, 97:3884-3889[Abstract/Free Full Text]
  34. Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, Tanzawa K, Thorpe P, Itohara S, Werb Z, Hanahan D: Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2000, 2:737-744[Medline]
  35. Tanaka K, Iwamoto Y, Ito Y, Ishibashi T, Nakabeppu Y, Sekiguchi M, Sugioka Y: Cyclic AMP-regulated synthesis of the tissue inhibitors of metalloproteinases suppresses the invasive potential of the human fibrosarcoma cell line HT1080. Cancer Res 1995, 55:2927-2935[Abstract/Free Full Text]
  36. Yoneda T, Sasaki A, Dunstan C, Williams PJ, Bauss F, De Clerck YA, Mundy GR: Inhibition of osteolytic bone metastasis of breast cancer by combined treatment with the bisphosphonate ibandronate and tissue inhibitor of the matrix metalloproteinase-2. J Clin Invest 1997, 99:2509-2517[Medline]
  37. Kawamata H, Kawai K, Kameyama S, Johnson MD, Stetler-Stevenson WG, Oyasu R: Over-expression of tissue inhibitor of matrix metalloproteinases (TIMP1 and TIMP2) suppresses extravasation of pulmonary metastasis of a rat bladder carcinoma. Int J Cancer 1995, 63:680-687[Medline]
  38. Wang M, Liu YE, Greene J, Sheng S, Fuchs A, Rosen EM, Shi YE: Inhibition of tumor growth and metastasis of human breast cancer cells transfected with tissue inhibitor of metalloproteinase 4. Oncogene 1997, 14:2767-2774[Medline]
  39. Alexander CM, Werb Z: Targeted disruption of the tissue inhibitor of metalloproteinases gene increases the invasive behavior of primitive mesenchymal cells derived from embryonic stem cells in vitro. J Cell Biol 1992, 118:727-739[Abstract/Free Full Text]
  40. Baker AH, George SJ, Zaltsman AB, Murphy G, Newby AC: Inhibition of invasion and induction of apoptotic cell death of cancer cell lines by overexpression of TIMP-3. Br J Cancer 1999, 79:1347-1355[Medline]
  41. Folkman J: Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995, 1:27-31[Medline]
  42. Vu TH, Shipley JM, Bergers G, Berger JE, Helms JA, Hanahan D, Shapiro SD, Senior RM, Werb Z: MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell 1998, 93:411-422[Medline]
  43. Itoh T, Tanioka M, Yoshida H, Yoshioka T, Nishimoto H, Itohara S: Reduced angiogenesis and tumor progression in gelatinase A-deficient mice. Cancer Res 1998, 58:1048-1051[Abstract/Free Full Text]
  44. Martin DC, Sanchez-Sweatman OH, Ho AT, Inderdeo DS, Tsao MS, Khokha R: Transgenic TIMP-1 inhibits simian virus 40 T antigen-induced hepatocarcinogenesis by impairment of hepatocellular proliferation and tumor angiogenesis. Lab Invest 1999, 79:225-234[Medline]
  45. Moses MA, Sudhalter J, Langer R: Identification of an inhibitor of neovascularization from cartilage. Science 1990, 248:1408-1410[Abstract/Free Full Text]
  46. Moses MA, Langer R: Inhibitors of angiogenesis. Biotechnology 1991, 9:630-634[Medline]
  47. Johnson MD, Kim HR, Chesler L, Tsao-Wu G, Bouck N, Polverini PJ: Inhibition of angiogenesis by tissue inhibitor of metalloproteinase. J Cell Physiol 1994, 160:194-202[Medline]
  48. Anand-Apte B, Pepper MS, Voest E, Montesano R, Olsen B, Murphy G, Apte SS, Zetter B: Inhibition of angiogenesis by tissue inhibitor of metalloproteinase-3 [see comments]. Invest Ophthalmol Vis Sci 1997, 38:817-823[Abstract/Free Full Text]
  49. Fernandez HA, Kallenbach K, Seghezzi G, Grossi E, Colvin S, Schneider R, Mignatti P, Galloway A: Inhibition of endothelial cell migration by gene transfer of tissue inhibitor of metalloproteinases-1. J Surg Res 1999, 82:156-162[Medline]
  50. Klagsbrun M, Moses MA: Molecular angiogenesis. Chem Biol 1999, 6:R217-R224[Medline]
  51. Hanahan D, Folkman J: Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996, 86:353-364[Medline]
  52. Ingber DE, Folkman J: How does extracellular matrix control capillary morphogenesis? Cell 1989, 58:803-805[Medline]
  53. Ingber DE: Extracellular matrix as a solid-state regulator in angiogenesis: identification of new targets for anti-cancer therapy. Semin Cancer Biol 1992, 3:57-63[Medline]
  54. Taipale J, Keski-Oja J: Growth factors in the extracellular matrix. FASEB J 1997, 11:51-59[Abstract]
  55. Yu Q, Stamenkovic I: Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-ß and promotes tumor invasion and angiogenesis. Genes Dev 2000, 14:163-176[Abstract/Free Full Text]
  56. Van Den Steen PE, Proost P, Wuyts A, Van Damme J, Opdenakker G: Neutrophil gelatinase B potentiates interleukin-8 tenfold by amino terminal processing, whereas it degrades CTAP-III, PF-4, and GRO-{alpha} and leaves RANTES and MCP-2 intact. Blood 2000, 96:2673-2681[Abstract/Free Full Text]
  57. Levi E, Fridman R, Miao HQ, Ma YS, Yayon A, Vlodavsky I: Matrix metalloproteinase 2 releases active soluble ectodomain of fibroblast growth factor receptor 1. Proc Natl Acad Sci USA 1996, 93:7069-7074[Abstract/Free Full Text]
  58. Glaser KB, Pease L, Li J, Morgan DW: Enhancement of the surface expression of tumor necrosis factor {alpha} (TNF-{alpha}) but not the p55 TNF-{alpha} receptor in the THP-1 monocytic cell line by matrix metalloprotease inhibitors. Biochem Pharmacol 1999, 57:291-302[Medline]
  59. Lombard MA, Wallace TL, Kubicek MF, Petzold GL, Mitchell MA, Hendges SK, Wilks JW: Synthetic matrix metalloproteinase inhibitors and tissue inhibitor of metalloproteinase (TIMP)-2, but not TIMP-1, inhibit shedding of tumor necrosis factor-{alpha} receptors in a human colon adenocarcinoma (Colo 205) cell line. Cancer Res 1998, 58:4001-4007[Abstract/Free Full Text]
  60. Williams LM, Gibbons DL, Gearing A, Maini RN, Feldmann M, Brennan FM: Paradoxical effects of a synthetic metalloproteinase inhibitor that blocks both p55 and p75 TNF receptor shedding and TNF-{alpha} processing in RA synovial membrane cell cultures. J Clin Invest 1996, 97:2833-2841[Medline]
  61. Bian J, Wang Y, Smith MR, Kim H, Jacobs C, Jackman J, Kung HF, Colburn NH, Sun Y: Suppression of in vivo tumor growth and induction of suspension cell death by tissue inhibitor of metalloproteinases (TIMP)-3. Carcinogenesis 1996, 17:1805-1811[Abstract/Free Full Text]
  62. O’Reilly MS, Holmgren L, Chen C, Folkman J: Angiostatin induces and sustains dormancy of human primary tumors in mice. Nat Med 1996, 2:689-692[Medline]
  63. Lay AJ, Jiang XM, Kisker O, Flynn E, Underwood A, Condron R, Hogg PJ: Phosphoglycerate kinase acts in tumour angiogenesis as a disulphide reductase. Nature 2000, 408:869-873[Medline]
  64. O’Reilly MS, Wiederschain D, Stetler-Stevenson WG, Folkman J, Moses MA: Regulation of angiostatin production by matrix metalloproteinase-2 in a model of concomitant resistance. J Biol Chem 1999, 274:29568-29571[Abstract/Free Full Text]
  65. Cornelius LA, Nehring LC, Harding E, Bolanowski M, Welgus HG, Kobayashi DK, Pierce RA, Shapiro SD: Matrix metalloproteinases generate angiostatin: effects on neovascularization. J Immunol 1998, 161:6845-6852[Abstract/Free Full Text]
  66. Lijnen HR, Ugwu F, Bini A, Collen D: Generation of an angiostatin-like fragment from plasminogen by stromelysin-1 (MMP-3). Biochemistry 1998, 37:4699-4702[Medline]
  67. Patterson BC, Sang QA: Angiostatin-converting enzyme activities of human matrilysin (MMP-7) and gelatinase B/type IV collagenase (MMP-9). J Biol Chem 1997, 272:28823-28825[Abstract/Free Full Text]
  68. Pozzi A, Moberg PE, Miles LA, Wagner S, Soloway P, Gardner HA: Elevated matrix metalloprotease and angiostatin levels in integrin {alpha} knockout mice cause reduced tumor vascularization. Proc Natl Acad Sci USA 2000, 97:2202-2207[Abstract/Free Full Text]
  69. Wen W, Moses MA, Wiederschain D, Arbiser JL, Folkman J: The generation of endostatin is mediated by elastase. Cancer Res 1999, 59:6052-6056[Abstract/Free Full Text]
  70. Felbor U, Dreier L, Bryant RA, Ploegh HL, Olsen BR, Mothes W: Secreted cathepsin L generates endostatin from collagen XVIII. EMBO J 2000, 19:1187-1194[Medline]
  71. Grant MB, Caballero S, Bush DM, Spoerri PE: Fibronectin fragments modulate human retinal capillary cell proliferation and migration. Diabetes 1998, 47:1335-1340[Abstract]
  72. Petitclerc E, Boutaud A, Prestayko A, Xu J, Sado Y, Ninomiya Y, Sarras MP, Jr, Hudson BG, Brooks PC: New functions for non-collagenous domains of human collagen type IV. Novel integrin ligands inhibiting angiogenesis and tumor growth in vivo. J Biol Chem 2000, 275:8051-8061[Abstract/Free Full Text]
  73. Frisch SM, Ruoslahti E: Integrins and anoikis. Curr Opin Cell Biol 1997, 9:701-706[Medline]
  74. Haas TL, Davis SJ, Madri JA: Three-dimensional type I collagen lattices induce coordinate expression of matrix metalloproteinases MT1-MMP and MMP-2 in microvascular endothelial cells. J Biol Chem 1998, 273:3604-3610[Abstract/Free Full Text]
  75. Yan L, Moses MA, Huang S, Ingber DE: Adhesion-dependent control of matrix metalloproteinase-2 activation in human capillary endothelial cells. J Cell Sci 2000, 113:3979-3987[Abstract]
  76. Giannelli G, Falk-Marzillier J, Schiraldi O, Stetler-Stevenson WG, Quaranta V: Induction of cell migration by matrix metalloprotease-2 cleavage of laminin-5. Science 1997, 277:225-228[Abstract/Free Full Text]
  77. Colorado PC, Torre A, Kamphaus G, Maeshima Y, Hopfer H, Takahashi K, Volk R, Zamborsky ED, Herman S, Sarkar PK, Ericksen MB, Dhanabal M, Simons M, Post M, Kufe DW, Weichselbaum RR, Sukhatme VP, Kalluri R: Anti-angiogenic cues from vascular basement membrane collagen. Cancer Res 2000, 60:2520-2526[Abstract/Free Full Text]
  78. Yu AE, Hewitt RE, Connor EW, Stetler-Stevenson WG: Matrix metalloproteinases. Novel targets for directed cancer therapy. Drugs Aging 1997, 11:229-244[Medline]
  79. Jones L, Ghaneh P, Humphreys M, Neoptolemos JP: The matrix metalloproteinases and their inhibitors in the treatment of pancreatic cancer. Ann NY Acad Sci 1999, 880:288-307[Medline]
  80. Baker AH, Ahonen M, Kahari VM: Potential applications of tissue inhibitor of metalloproteinase (TIMP) overexpression for cancer gene therapy. Adv Exp Med Biol 2000, 465:469-483[Medline]
  81. Wojtowicz-Praga S, Torri J, Johnson M, Steen V, Marshall J, Ness E, Dickson R, Sale M, Rasmussen HS, Chiodo TA, Hawkins MJ: Phase I trial of Marimastat, a novel matrix metalloproteinase inhibitor, administered orally to patients with advanced lung cancer. J Clin Oncol 1998, 16:2150-2156[Abstract]
  82. Silletti S, Kessler T, Goldberg J, Boger DL, Cheresh DA: Disruption of matrix metalloproteinase 2 binding to integrin {alpha}vß3 by an organic molecule inhibits angiogenesis and tumor growth in vivo. Proc Natl Acad Sci USA 2001, 98:119-124[Abstract/Free Full Text]
  83. Margulies IM, Hoyhtya M, Evans C, Stracke ML, Liotta LA, Stetler-Stevenson WG: Urinary type IV collagenase: elevated levels are associated with bladder transitional cell carcinoma. Cancer Epidemiol Biomarkers Prev 1992, 1:467-474[Abstract]
  84. Nakajima M, Welch DR, Wynn DM, Tsuruo T, Nicolson GL: Serum and plasma M(r) 92,000 progelatinase levels correlate with spontaneous metastasis of rat 13762NF mammary adenocarcinoma. Cancer Res 1993, 53:5802-5807[Abstract/Free Full Text]
  85. Zucker S, Lysik RM, Zarrabi HM, Moll U, Tickle SP, Stetler-Stevenson W, Baker TS, Docherty AJ: Plasma assay of matrix metalloproteinases (MMPs) and MMP-inhibitor complexes in cancer. Potential use in predicting metastasis and monitoring treatment. Ann NY Acad Sci 1994, 732:248-262[Medline]
  86. Baker T, Tickle S, Wasan H, Docherty A, Isenberg D, Waxman J: Serum metalloproteinases and their inhibitors: markers for malignant potential. Br J Cancer 1994, 70:506-512[Medline]
  87. Garbisa S, Scagliotti G, Masiero L, Di Francesco C, Caenazzo C, Onisto M, Micela M, Stetler-Stevenson WG, Liotta LA: Correlation of serum metalloproteinase levels with lung cancer metastasis and response to therapy. Cancer Res 1992, 52:4548-4549[Abstract/Free Full Text]
  88. Moses MA, Wiederschain D, Loughlin KR, Zurakowski D, Lamb CC, Freeman MR: Increased incidence of matrix metalloproteinases in urine of cancer patients. Cancer Res 1998, 58:1395-1399[Abstract/Free Full Text]
  89. Holten-Andersen MN, Murphy G, Nielsen HJ, Pedersen AN, Christensen IJ, Hoyer-Hansen G, Brunner N, Stephens RW: Quantitation of TIMP-1 in plasma of healthy blood donors and patients with advanced cancer. Br J Cancer 1999, 80:495-503[Medline]
  90. Holten-Andersen MN, Stephens RW, Nielsen HJ, Murphy G, Christensen IJ, Stetler-Stevenson W, Brunner N: High preoperative plasma tissue inhibitor of metalloproteinase-1 levels are associated with short survival of patients with colorectal cancer. Clin Cancer Res 2000, 6:4292-4299[Abstract/Free Full Text]
  91. Remacle A, McCarthy K, Noel A, Maguire T, McDermott E, O’Higgins N, Foidart JM, Duffy MJ: High levels of TIMP-2 correlate with adverse prognosis in breast cancer. Int J Cancer 2000, 89:118-121[Medline]
  92. Ylisirnio S, Hoyhtya M, Turpeenniemi-Hujanen T: Serum matrix metalloproteinases -2, -9 and tissue inhibitors of metalloproteinases -1, -2 in lung cancer—TIMP-1 as a prognostic marker. Anticancer Res 2000, 20:1311-1316[Medline]
  93. Yoshikawa T, Suzuki K, Kobayashi O, Sairenji M, Motohashi H, Yanoma S, Noguchi Y, Tsuburaya A: Clinical significance of matrix metalloproteinase-9 and tissue inhibitor of matrix metalloproteinase-1 in peripheral blood of patients with gastric carcinoma. Gan To Kagaku Ryoho 1998, 25:1461-1464[Medline]
  94. Yoshikawa T, Saitoh M, Tsuburaya A, Kobayashi O, Sairenji M, Motohashi H, Yanoma S, Noguchi Y: Tissue inhibitor of matrix metalloproteinase-1 in the plasma of patients with gastric carcinoma. A possible marker for serosal invasion and metastasis. Cancer 1999, 86:1929-1935[Medline]
  95. Yoshikawa T, Tsuburaya A, Kobayashi O, Sairenji M, Motohashi H, Yanoma S, Noguchi Y: Prognostic value of tissue inhibitor of matrix metalloproteinase-1 in plasma of patients with gastric cancer. Cancer Lett 2000, 151:81-86[Medline]
  96. Guedez L, McMarlin AJ, Kingma DW, Bennett TA, Stetler-Stevenson M, Stetler-Stevenson WG: Tissue inhibitor of metalloproteinases (TIMP)-1 alters the tumorigenicity of Burkitt’s lymphoma via divergent effects on tumor growth and angiogenesis. Am J Pathol 2001, 158:1207-1215[Abstract/Free Full Text]




This Article
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
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 Google Scholar
Google Scholar
Right arrow Articles by Yan, L.
Right arrow Articles by Moses, M. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yan, L.
Right arrow Articles by Moses, M. A.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS