In Vivo Gene Therapy with Interleukin-12 Inhibits Primary Vascular Tumor Growth and Induces Apoptosis in a Mouse Model1

Wang, Chong; Quevedo, Maria Eugenia; Lannutti, Brian J.; Gordon, Kenneth B.; Guo, Dan‐qing; Sun, Wenn H.; Paller, Amy S.

doi:10.1046/j.1523-1747.1999.00587.x

Cited by 36 publications

(27 citation statements)

References 16 publications

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“…All mice received a total injection volume of 150 l. Differences were statistically significant when comparing the incidence of HE in mice receiving EOMA cells alone vs. anti-MCP-1 treatment or IgG vs. anti-MCP-1 treatments for both 129P3 and C57Bl/6 strains. Among MCP-1 Ϫ/Ϫ mice treated, statistically significant differences were not observed with EOMA or EOMA ϩ aMCP-1, but there was a statistically significant difference between EOMA ϩ aMCP-1 and EOMA ϩ aMCP-1 ϩ M. *P Ͻ 0.05. batimastat, IL-12, and angiostatin (1,19,31,39,43), none of these agents focus on the contributions of macrophages. By removing MCP-1 from the local tumor environment at the time of EOMA cell inoculation, the significance of macrophages in allowing HE to develop was highlighted.…”

Section: Discussionmentioning

confidence: 99%

A key angiogenic role of monocyte chemoattractant protein-1 in hemangioendothelioma proliferation

Gordillo¹,

Onat²,

Stockinger³

et al. 2004

American Journal of Physiology-Cell Physiology

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A key angiogenic role of monocyte chemoattractant protein-1 in hemangioendothelioma proliferation. Am J Physiol Cell Physiol 287: C866 -C873, 2004. First published May 26, 2004 10.1152/ajpcell.00238. 2003.-Angiomatous lesions are common in infants and children. Hemangioendotheliomas (HE) represent one type of these lesions. Endothelial cell proliferation and the development of vascular/blood cell-filled spaces are inherent in the growth of HE. Therefore, understanding mechanisms that regulate the proliferation of these lesions should provide key insight into mechanisms regulating angiogenesis. A murine model was used to test the significance of monocyte chemoattractant protein (MCP)-1 in HE proliferation. EOMA cells, a cell line derived from a spontaneously arising murine HE, generate these lesions with 100% efficiency when injected subcutaneously into syngeneic mice. MCP-1 produced by EOMA cells recruit macrophages, which were shown to induce angiogenic behavior in EOMA cells by stimulating transwell migration and inducing sprout formation on type I collagen gels. When EOMA cells were injected into MCP-1 Ϫ/Ϫ mice, only 50% of the mice developed tumors, presumably because the low levels of MCP-1 expressed by the injected EOMA cells were enough to overcome any host deficits of this chemokine. When EOMA cells were coinjected with a neutralizing antibody to MCP-1, tumors failed to develop in any of the treated mice, including syngeneic 129P3, C57Bl/6 (wild type), and MCP-1 Ϫ/Ϫ . These results present the first evidence that MCP-1 is required for HE proliferation and may promote the growth of these lesions by stimulating angiogenic behavior of endothelial cells. This study has produced the first in vivo evidence of a complete response for any neoplasm, specifically a vascular proliferative lesion, to anti-MCP-1 therapy in animals with intact immune systems. endothelium; vascular; macrophage; redox; angiogenesis ANGIOMATOUS DISEASES AFFECT up to 3% of all children (31). Included in the scope of these pathological conditions are vascular neoplasms ranging in severity from benign infantile hemangiomas to malignant angiosarcomas. Hemangioendothelioma (HE) represents a vascular neoplasm of borderline or intermediate malignancy (8). It does not metastasize; however, in humans, the mortality rate for HE ranges from 12 to 24%. This lesion is associated with the development of KasabachMerritt syndrome (36, 47), a consumptive coagulopathy with a 20 -30% mortality rate (9). Vascular neoplasms are highly angiogenic because the growth of these lesions entails endothelial cell proliferation with the development of perfused vascular spaces. The fact that humans with proliferating hemangiomas can have urinary bFGF levels elevated 25-to 50-fold higher than those of healthy volunteers (37) attests to the degree of angiogenic activity associated with vascular neoplasms. Investigators at our laboratory (3) recently demonstrated that halting the growth of HE arrests angiogenesis that is inherent in this process and that these events ar...

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Section: Discussionmentioning

confidence: 99%

A key angiogenic role of monocyte chemoattractant protein-1 in hemangioendothelioma proliferation

Gordillo¹,

Onat²,

Stockinger³

et al. 2004

American Journal of Physiology-Cell Physiology

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“…JNK was selected as a potential target because one of the flavonoid components present in blueberry extract, epigallocatechin 3-gallate (ECGC), can activate transcription of the tumor suppressor gene p21 WAF1/CIP1 independent of p53, which forms a tight complex with JNK-1 to inactivate it (42,55). The outcome of JNK-1 activity is phosphorylation/activation of c-Jun and constituent activation of c-Jun in endothelial cells has been shown to result in MCP-1 expression (62). The in vitro effects of BBE and JNK inhibition observed in the EOMA model are consistent with other published reports.…”

Section: Discusssionmentioning

confidence: 99%

“…The endothelial cell phenotype of EOMA cells has been confirmed (38,50), and other investigators have used it to test antiangiogenic compounds for tumor therapy (1,28,37,60,62). When EOMA cells are injected subcutaneously into mice, they form hemangioendotheliomas (HE) with 100% efficiency.…”

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confidence: 94%

Oral Administration of Blueberry Inhibits Angiogenic Tumor Growth and Enhances Survival of Mice with Endothelial Cell Neoplasm

Fang

Khanna

Harper³

et al. 2009

Antioxidants & Redox Signaling

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Endothelial cell neoplasms are the most common soft tissue tumor in infants. Subcutaneous injection of spontaneously transformed murine endothelial (EOMA) cells results in development of hemangioendothelioma (HE). We have previously shown that blueberry extract (BBE) treatment of EOMA cells in vitro prior to injection in vivo can significantly inhibit the incidence and size of developing HE. In this study, we sought to determine whether oral BBE could be effective in managing HE and to investigate the mechanisms through which BBE exerts its effects on endothelial cells. A dose-dependent decrease in HE tumor size was observed in mice receiving daily oral gavage feeds of BBE. Kaplan-Meier survival curve showed significantly enhanced survival for mice with HE tumors given BBE, compared to control. BBE treatment of EOMA cells inhibited both c-Jun N-terminal kinase (JNK) and NF-B signaling pathways that culminate in monocyte chemoattractant protein-1 (MCP-1) expression required for HE development. Antiangiogenic effects of BBE on EOMA cells included decreased proliferation by BrdU assay, decreased sprouting on Matrigel, and decreased transwell migration. Thus, this work provides first evidence demonstrating that BBE can limit tumor formation through antiangiogenic effects and inhibition of JNK and NF-B signaling pathways. Oral administration of BBE represents a potential therapeutic antiangiogenic strategy for treating endothelial cell neoplasms in children. Antioxid Redox Signal 11, 47-58.

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“…15 -17 One of the most potent anticancer cytokines, IL -12, has been shown to suppress progression of experimental hemangiomas. 18,19 IP -10 (interferon -inducible protein with molecular weight of 10 kDa, recently classified as CXCL10 ) has been identified as a major IL -12-induced downstream effector of antitumor reactions, and found to inhibit the growth of several experimental tumors with varying efficacy, depending on the model and method of delivery. 20 -26 Although the mechanism of IP -10 -induced tumor suppression has not yet been fully elucidated, both antiangiogenic and immune system -mediated effects appear to be essential to the antitumor activity of this chemokine in vivo.…”

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confidence: 99%

Suppression of metastatic hemangiosarcoma by a parvovirus MVMp vector transducing the IP-10 chemokine into immunocompetent mice

et al. 2002

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We have previously shown that the growth of human tumor xenografts in immunodeficient mice can be efficiently suppressed upon infection with the autonomous parvovirus H -1 or with cytokine -transducing derivatives thereof. To further evaluate the benefits of implementing parvoviruses in cancer gene therapy, we have created a new recombinant vector, MVMp / IP -10, transducing the immunoactive, antiangiogenic chemokine IP -10, and used this virus to treat syngeneic tumors grown in immunocompetent mice. Intratumoral / intraperitoneal administration of only 3Â10 7 replication units of MVMp / IP -10 per animal strongly inhibited the progression of established H5V cell -induced vascular tumors, a highly malignant mouse model for human cavernous hemangioma and Kaposi's sarcoma. Retardation of recurrent tumor growth and suppression of life -threatening metastatic dissemination to internal organs were accompanied by a striking delay in hemangioma -associated mortality. Parental MVMp did not have a significant effect under these conditions up to the dose of 10 10 infectious units / animal, but had strong antihemangiosarcoma activity when used to infect H5V cells ex vivo prior to implantation. In all cases, virus therapy was very well tolerated. Virus -induced suppression of hemangiosarcoma was dependent on host T cells and associated with intratumoral persistence of IFN -expressing cytotoxic lymphocytes, and led to the reduced expression of hepatic plasminogen activator inhibitor -1 ( PAI -1 ), a metastasis -linked marker. This proof of principle study demonstrates that MVMp / IP -10 can aid the treatment of vascular tumors and that autonomous parvovirus -based vectors can be considered potent tools for cancer gene therapy purposes.

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In Vivo Gene Therapy with Interleukin-12 Inhibits Primary Vascular Tumor Growth and Induces Apoptosis in a Mouse Model1

Cited by 36 publications

References 16 publications

A key angiogenic role of monocyte chemoattractant protein-1 in hemangioendothelioma proliferation

A key angiogenic role of monocyte chemoattractant protein-1 in hemangioendothelioma proliferation

Oral Administration of Blueberry Inhibits Angiogenic Tumor Growth and Enhances Survival of Mice with Endothelial Cell Neoplasm

Suppression of metastatic hemangiosarcoma by a parvovirus MVMp vector transducing the IP-10 chemokine into immunocompetent mice

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