Stromal Matrix Metalloproteinase-9 Regulates the Vascular Architecture in Neuroblastoma by Promoting Pericyte Recruitment
01 Mar 2004-Cancer Research (American Association for Cancer Research)-Vol. 64, Iss: 5, pp 1675-1686
TL;DR: The data demonstrate that in neuroblastoma, stromally derived MMP-9 contributes to angiogenesis by promoting blood vessel morphogenesis and pericyte recruitment, and an inhibition in the architecture of the tumor vasculature in M MP-9-deficient mice, resulting in fewer and smaller blood vessels.
Abstract: Advanced stages of neuroblastoma show increased expression of matrix metalloproteinases MMP-2 and MMP-9 (Y. Sugiura et al ., Cancer Res., 58: 2209–2216, 1998) that have been implicated in many steps of tumor progression, suggesting that they play a contributory role. Using pharmacological and genetic approaches, we have examined the role of these MMPs in progression of SK-N-BE (2).10 human neuroblastoma tumors orthotopically xenotransplanted into immunodeficient mice. Mice treated with Prinomastat, a synthetic inhibitor of MMPs, showed an inhibition of tumor cell proliferation in implanted tumors and a prolonged survival (50 versus 39 days in control group, P < 0.035). Treatment with Prinomastat did not affect formation of liver metastases ( P = 0.52) but inhibited intravascular colonization by the tumor cells in the lung by 73.8% ( P = 0.03) and angiogenesis in both primary tumors and experimental liver metastases. The primary tumors from Prinomastat-treated mice showed a 39.3% reduction in endothelial area detected by PECAM/CD31 staining in tumor sections ( P < 0.001), primarily due to the presence of smaller vessels ( P = 0.004). MMP-2 is expressed by neuroblastoma tumor cells and stromal cells, whereas MMP-9 is exclusively expressed by stromal cells, particularly vascular cells. To examine the contribution of MMP-9 to tumor angiogenesis, we generated RAG1/MMP-9 double-deficient mice. We observed a significant inhibition of angiogenesis in the immunodeficient RAG1/MMP-9 double-deficient mice orthotopically implanted with tumor cells ( P = 0.043) or implanted s.c. with a mixture of tumor cells and Matrigel ( P < 0.001). Using an FITC-labeled lectin, we demonstrated an inhibition in the architecture of the tumor vasculature in MMP-9-deficient mice, resulting in fewer and smaller blood vessels. These changes were associated with a 48% decrease in pericytes present along microvessels. Taken together, the data demonstrate that in neuroblastoma, stromally derived MMP-9 contributes to angiogenesis by promoting blood vessel morphogenesis and pericyte recruitment.
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TL;DR: Recent studies in mice and flies point to essential roles of MMPs as mediators of change and physical adaptation in tissues, whether developmentally regulated, environmentally induced or disease associated.
Abstract: Matrix metalloproteinases (MMPs) were discovered because of their role in amphibian metamorphosis, yet they have attracted more attention because of their roles in disease. Despite intensive scrutiny in vitro, in cell culture and in animal models, the normal physiological roles of these extracellular proteases have been elusive. Recent studies in mice and flies point to essential roles of MMPs as mediators of change and physical adaptation in tissues, whether developmentally regulated, environmentally induced or disease associated.
2,634 citations
Cites background from "Stromal Matrix Metalloproteinase-9 ..."
...MMP9 and MMP14 have another effect on the vasculature: the perivascular (or smooth muscle) cells that ensheath the endothelial cells of the blood vessels are missing or their density is significantly decreased in normal vessels and during tumour neoangiogenesi...
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TL;DR: The major pieces of evidence that are most compelling and clearly determine the role and involvement of MMPs in the metastatic cascade are provided by molecular genetic studies employing knock-out or transgenic animals and tumor cell lines, modified to overexpress or downregulate a specific MMP.
Abstract: Functions of individual matrix metalloproteinases (MMPs) differentially expressed by tumor cells and stromal cells, are finely regulated by their spatial as well as temporal interactions with distinct cellular and extracellular components of the tumor microenvironment and also distant pre-metastatic sites. Certain aspects of MMP involvement in tumor metastasis such as tumor-induced angiogenesis, tumor invasion, and establishment of metastatic foci at the secondary site, have received extensive attention that resulted in an overwhelming amount of experimental and observational data in favor of critical roles of MMPs in these processes. In particular, dependency of tumor angiogenesis on the activity of MMPs, especially that of MMP-9, renders this step possibly the most effective target of synthetic MMP inhibitors. MMP functioning in other stages of metastasis, including the escape of individual tumor cells from the primary tumor, their intravasation, survival in circulation, and extravasation at the secondary site, have not yet received enough consideration, resulting in insufficient or controversial data. The major pieces of evidence that are most compelling and clearly determine the role and involvement of MMPs in the metastatic cascade are provided by molecular genetic studies employing knock-out or transgenic animals and tumor cell lines, modified to overexpress or downregulate a specific MMP. Findings from all of these studies implicate different functional mechanisms for both tumor and stromal MMPs during distinct steps of the metastatic cascade and indicate that MMPs can exhibit pro-metastatic as well as anti-metastatic roles depending on their nature and the experimental setting. This dual function of individual MMPs in metastasis has become a major focus of this review.
1,865 citations
Cites background from "Stromal Matrix Metalloproteinase-9 ..."
...Interestingly, this function of MMP9 appears confined to a specific setting within the tumor microenvironment, since in general the development of normal vasculature in MMP-9-deficient mice does not show any significant abnormalities [83]....
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...In this regard, treatment of MMP-9-deficient mice, carrying othotopically transplanted neuroblastoma tumors, with the MMP inhibitor, prinomastat, did not affect formation of liver metastasis in a spontaneous metastasis model, but inhibited intravascular lung colonization in an experimental metastasis model [83]....
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...MMP-9-mediated release of VEGF from the ECM [67, 76] and recruitment of pericytes to the angiogenic vasculature [80, 83], have been suggested as major mechanisms implicated in the now extensively reported contributions of host MMP-9 to tumor progression....
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TL;DR: Evidence is provided that Gr+CD11b+ cells of immune origin induced by tumors directly contribute to tumor growth and vascularization by producing MMP9 and differentiating into ECs.
1,084 citations
Cites result from "Stromal Matrix Metalloproteinase-9 ..."
...The data is in agreement with a recent publication that stromal MMP9 regulates the vascular architecture by promoting pericyte recruitment (Chantrain et al., 2004)....
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...Thispericytes (Chantrain et al., 2004)....
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TL;DR: Because of the multiple effects of MMPs on angiogenesis, careful testing of these MMP inhibitors is necessary to show that these compounds do not actually enhance angiogenic.
Abstract: Matrix metalloproteinases (MMPs) are a family of enzymes that proteolytically degrade various components of the extracellular matrix (ECM). Angiogenesis is the process of forming new blood vessels from existing ones and requires degradation of the vascular basement membrane and remodeling of the ECM in order to allow endothelial cells to migrate and invade into the surrounding tissue. MMPs participate in this remodeling of basement membranes and ECM. However, it has become clear that MMPs contribute more to angiogenesis than just degrading ECM components. Specific MMPs have been shown to enhance angiogenesis by helping to detach pericytes from vessels undergoing angiogenesis, by releasing ECM-bound angiogenic growth factors, by exposing cryptic proangiogenic integrin binding sites in the ECM, by generating promigratory ECM component fragments, and by cleaving endothelial cell-cell adhesions. MMPs can also contribute negatively to angiogenesis through the generation of endogenous angiogenesis inhibitors by proteolytic cleavage of certain collagen chains and plasminogen and by modulating cell receptor signaling by cleaving off their ligand-binding domains. A number of inhibitors of MMPs that show antiangiogenic activity are already in early stages of clinical trials, primarily to treat cancer and cancer-associated angiogenesis. However, because of the multiple effects of MMPs on angiogenesis, careful testing of these MMP inhibitors is necessary to show that these compounds do not actually enhance angiogenesis.
858 citations
TL;DR: It is demonstrated that SCF directly activates brain microvascular endothelial cells in vitro and induces a potent angiogenic response in vivo and the SCF/c-Kit pathway plays an important role in tumor- and normal host cell-induced angiogenesis within the brain.
773 citations
Cites background from "Stromal Matrix Metalloproteinase-9 ..."
...Since high-grade gliomas are characterized by a much greater amount of tumor-associated angiogenesis compared to low-grade gliomas, the positive correlation of SCF expression with increasing glioma grade is consistent with a potential role for SCF in glioma-associated angiogenesis....
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...…glioma-mediated degradation of the extracellular matrix through overexpression of metalloproteases, and release of neurotoxic excitatory molecules CANCER CELL APRIL 2006 such as glutamate (Forsyth et al., 1999; Takano et al., 2001; VanMeter et al., 2001; Davies, 2002; Chantrain et al., 2004)....
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References
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TL;DR: The cellular and molecular mechanisms underlying the formation of endothelium-lined channels and their maturation via recruitment of smooth muscle cells (arteriogenesis) during physiological and pathological conditions are summarized, alongside with possible therapeutic applications.
Abstract: Endothelial and smooth muscle cells interact with each other to form new blood vessels. In this review, the cellular and molecular mechanisms underlying the formation of endothelium-lined channels (angiogenesis) and their maturation via recruitment of smooth muscle cells (arteriogenesis) during physiological and pathological conditions are summarized, alongside with possible therapeutic applications.
4,154 citations
"Stromal Matrix Metalloproteinase-9 ..." refers background in this paper
...There are, however, significant differences between these physiological processes and tumor angiogenesis (48)....
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TL;DR: Molecular insights into the formation of new blood vessels are being generated at a rapidly increasing pace, offering new therapeutic opportunities that are currently being evaluated.
Abstract: Blood vessels constitute the first organ in the embryo and form the largest network in our body but, sadly, are also often deadly. When dysregulated, the formation of new blood vessels contributes to numerous malignant, ischemic, inflammatory, infectious and immune disorders. Molecular insights into these processes are being generated at a rapidly increasing pace, offering new therapeutic opportunities that are currently being evaluated.
4,137 citations
"Stromal Matrix Metalloproteinase-9 ..." refers background in this paper
...In tumor angiogenesis, the role of pericytes has recently been recognized as promoting the maturation of newly formed blood vessels and preventing their regression (51)....
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TL;DR: The studies that brought MPIs into clinical testing are reviewed and the design and outcome of the trials are discussed in light of new information about the cellular source, substrates, and mode of action of MMPs at different stages of tumor progression.
Abstract: For at least 30 years, matrix metalloproteinases (MMPs) have been heralded as promising targets for cancer therapy on the basis of their massive up-regulation in malignant tissues and their unique ability to degrade all components of the extracellular matrix. Preclinical studies testing the efficacy of MMP suppression in tumor models were so compelling that synthetic metalloproteinase inhibitors (MPIs) were rapidly developed and routed into human clinical trials. The results of these trials have been disappointing. Here we review the studies that brought MPIs into clinical testing and discuss the design and outcome of the trials in light of new information about the cellular source, substrates, and mode of action of MMPs at different stages of tumor progression. The important lessons learned from the MPI experience may be of great value for future studies of MPIs and for cancer drug development in general.
2,668 citations
"Stromal Matrix Metalloproteinase-9 ..." refers background in this paper
...Some of this evidence comes from observations showing a positive correlation between the presence and expression of these MMPs and the metastatic stage of a cancer (28, 29)....
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TL;DR: The results show that MMP-9 is a component of theAngiogenic switch, and MMP inhibitors reduce angiogenic switching, and tumour number and growth, as does genetic ablation of M MP-9.
Abstract: During carcinogenesis of pancreatic islets in transgenic mice, an angiogenic switch activates the quiescent vasculature Paradoxically, vascular endothelial growth factor (VEGF) and its receptors are expressed constitutively Nevertheless, a synthetic inhibitor (SU5416) of VEGF signalling impairs angiogenic switching and tumour growth Two metalloproteinases, MMP-2/gelatinase-A and MMP-9/gelatinase-B, are upregulated in angiogenic lesions MMP-9 can render normal islets angiogenic, releasing VEGF MMP inhibitors reduce angiogenic switching, and tumour number and growth, as does genetic ablation of MMP-9 Absence of MMP-2 does not impair induction of angiogenesis, but retards tumour growth, whereas lack of urokinase has no effect Our results show that MMP-9 is a component of the angiogenic switch
2,657 citations
"Stromal Matrix Metalloproteinase-9 ..." refers background in this paper
...In a murine model of pancreatic cancer, MMP-9 expression by inflammatory cells similarly coincides with the formation of angiogenic islands, and this process is delayed in the presence of an MMP inhibitor (11)....
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...It also increases the bioavailability of vascular endothelial cell growth factor (11)....
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...paired migratory or invasive behavior of neoplastic cells (11, 40)....
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TL;DR: Treatment with myeloablative therapy and autologous bone marrow transplantation improved event-free survival among children with high-risk neuroblastoma, and treatment with 13-cis-retinoic acid was beneficial for patients without progressive disease when it was administered after chemotherapy or transplantation.
Abstract: Background Children with high-risk neuroblastoma have a poor outcome. In this study, we assessed whether myeloablative therapy in conjunction with transplantation of autologous bone marrow improved event-free survival as compared with chemotherapy alone, and whether subsequent treatment with 13-cis-retinoic acid (isotretinoin) further improves event-free survival. Methods All patients were treated with the same initial regimen of chemotherapy, and those without disease progression were then randomly assigned to receive continued treatment with myeloablative chemotherapy, total-body irradiation, and transplantation of autologous bone marrow purged of neuroblastoma cells or to receive three cycles of intensive chemotherapy alone. All patients who completed cytotoxic therapy without disease progression were then randomly assigned to receive no further therapy or treatment with 13-cis-retinoic acid for six months. Results The mean (±SE) event-free survival rate three years after the first randomization was si...
1,762 citations