Extracellular Matrix-derived Peptide Binds to αvβ3 Integrin and Inhibits Angiogenesis

Maeshima, Yohei; Yerramalla, Udaya; Mohanraj, D.; Holthaus, Kathryn A.; Barbashov, Sergei F.; Kharbanda, Surender; Reimer, Corinne; Manfredi, Mark; Dickerson, W. Matthew; Kalluri, Raghu

doi:10.1074/jbc.m103024200

Cited by 198 publications

(171 citation statements)

References 34 publications

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“…Recent studies suggest that angiostatin can be generated by limited proteolysis of plasminogen by plasmin, uPA, tPA, or MMPs [79,80]. Other negative regulators are fragments of collagen type XV/restin [81] or collagen type IV, such as arresten, from the α1 chain [82], canstatin, from the α2 chain [83], and tumstatin, from the α3 chain [84][85][86]. Fragments from non-ECM molecules which may have an-gioinhibitory activity include at least MMP-2 (PEX), an-tithrombin [87], calreticulin (vasostatin) [88], and domain 5 of high-molecular-weight kininogen (kininostatin) [89].…”

Section: The Plasminogen System and Angiogenesismentioning

confidence: 99%

Role of plasminogen activator-plasmin system in tumor angiogenesis

Rakic¹,

Maillard²,

Jost³

et al. 2003

Cellular and Molecular Life Sciences (CMLS)

118

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New blood formation or angiogenesis has become a key target in therapeutic strategies aimed at inhibiting tumor growth and other diseases associated with neovascularization. Angiogenesis is associated with important extracellular remodeling involving different proteolytic systems among which the plasminogen system plays an essential role. It belongs to the large serine proteinase family and can act directly or indirectly by activating matrix metalloproteinases or by liberating growth factors and cytokines sequestered within the extracellular matrix. Migration of endothelial cells is associated with significant upregulation of proteolysis and conversely, immunoneutralization or chemical inhibition of the system reduces angiogenesis in vitro. On the other hand genetically altered mice developed normally without overt vascular anomalies indicating the possibility of compensation by other proteases in vivo. Nevertheless, they have in some experimental settings revealed unanticipated roles for previously characterized proteinases or their inhibitors. In this review, the complex mechanisms of action of the serine proteases in pathological angiogenesis are summarized alongside possible therapeutic applications.

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Section: The Plasminogen System and Angiogenesismentioning

confidence: 99%

Role of plasminogen activator-plasmin system in tumor angiogenesis

Rakic¹,

Maillard²,

Jost³

et al. 2003

Cellular and Molecular Life Sciences (CMLS)

118

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“…The progressive growth and metastasis of malignant neoplasms depend on new blood vessel formation from host vessels. Tumstatin inhibits the proliferation of endothelial cells, causes G1 arrest of VEGF-and bFGF-stimulated EC and induces apoptosis of proliferating EC through upregulation of caspase 3 (Maeshima et al 2000a;Maeshima et al 2000b;Maeshima et al 2001). To detect whether the secreted tum-5 protein has anti-angiogenic activity, the effect of the protein on HUVECs was investigated in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…Subsequently, the anti-angiogenic activity was localized to a 25 amino acid region encompassing amino acids 74-98, which contains the entire anti-angiogenic activity associated with tumstatin. Tum-5 domain binds and functions via avß3 in an RGD independent manner (Maeshima et al 2001). The full-length tumstatin and fragments containing regions 54-132 and 74-98 amino acids exhibit significant anti-angiogenesis activity in Matrigel plug assays.…”

Section: Introductionmentioning

confidence: 99%

“…The full-length tumstatin and fragments containing regions 54-132 and 74-98 amino acids exhibit significant anti-angiogenesis activity in Matrigel plug assays. They suppress tumor growth associated human renal carcinoma (786-O) and prostate carcinoma (PC-3) in mouse xenograft models and induced endothelial cell specific apoptosis (Maeshima et al 2000a;Maeshima et al 2000b;Maeshima et al 2001).…”

Section: Introductionmentioning

confidence: 99%

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Inhibition effect of pcDNA-tum-5 on the growth of S180 tumor

You

Xue

et al. 2007

Cytotechnology

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Tumor growth and metastasis depend on vessel formation, and inhibition of angiogenesis of tumor by production of anti-angiogenic drugs should be a promising approach for cancer therapy. Tumstatin is an angiogenesis inhibitor. The anti-angiogenic activity of tumstatin is localized to the 54-132 amino acids. The gene fragment encoding amino acids 45-132 of tumstatin (tum-5) was subcloned into pcDNA3.1 (pcDNA-tum5). Tum-5 protein could be expressed and secreted in CHO cells after transfection. The conditioned medium (containing tum-5 protein) from the transfectant has an anti-angiogenic effect on HUVEC cells in vitro. The anti-tumor effect of pcDNA-tum5 on mice bearing S180 tumors was evaluated. The results showed that pcDNA-tum-5 has a significant inhibition activity in the growth of the tumors. This study suggests that the gene delivery of tum-5 may be an effective strategy for cancer therapy.

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“…The noncollagenous domain of α3 chain of type IV collagen, namely tumstatin, has the antiangiogenic property by inhibiting endothelial cell proliferation and inducing their apoptosis via an interaction with αvß3 integrin (9)(10)(11)(12)(13)(14)(15). Antiangiogenic effect of tumstatin has been studied in xenograft models, where tumstatin repressed the growth of several cancer types including renal cell carcinoma, prostate cancer, melanoma and lung carcinoma (9)(10)(11)13).…”

Section: Introductionmentioning

confidence: 99%

Tum-1, a tumstatin fragment, gene delivery into hepatocellular carcinoma suppresses tumor growth through inhibiting angiogenesis

Goto

Ishikawa²,

Matsumoto³

et al. 2008

Int J Oncol

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Abstract. Since hepatocellular carcinoma (HCC) is a hypervascular cancer, anti-angiogenic therapy is a promising approach to treat HCC. In the present study, we investigated the antiangiogenic and antitumor effects of tum-1, a fragment of tumstatin, gene transduction into HCC in vitro and in vivo. Tum-1 gene was cloned into a pSecTag2B mammalian expression vehicle to construct pSecTag2B-tum-1. pSecTag2B-tum-1 or vehicle were transfected into human HCC cells, PLC/PRF/5 cells stably and Huh-7 cells transiently. pSecTag2B-tum-1 transfection slightly repressed the proliferation of both PLC/PRF/5 and Huh-7 cells in vitro. Addition of conditioned media (CM) from tum-1 expressing PLC/PRF/5 cells significantly inhibited the spontaneous and vascular endothelial growth factor (VEGF)-induced proliferation and migration of human umbilical vein endothelial cells (HUVEC) in vitro with diminishing the VEGF-induced phosphorylation of both Akt and extracellular signal-regulated kinase (ERK) that are known to mediate VEGF-induced proliferation and migration of endothelial cells. In in vivo experiments, intratumoral injection of pSecTag2B-tum-1 significantly repressed the growth of pre-established Huh-7 tumors in athymic mouse models accompanying the decreased density of CD34 positive vessels in tumors. In conclusion, our results suggest that antiangiogenic gene therapy using tum-1 gene may be an efficient strategy for the treatment of HCC.

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Extracellular Matrix-derived Peptide Binds to αvβ3 Integrin and Inhibits Angiogenesis

Cited by 198 publications

References 34 publications

Role of plasminogen activator-plasmin system in tumor angiogenesis

Role of plasminogen activator-plasmin system in tumor angiogenesis

Inhibition effect of pcDNA-tum-5 on the growth of S180 tumor

Tum-1, a tumstatin fragment, gene delivery into hepatocellular carcinoma suppresses tumor growth through inhibiting angiogenesis

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