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Dive into the research topics where James Greenaway is active.

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Featured researches published by James Greenaway.


Journal of Cellular Physiology | 2007

Thrombospondin-1 Inhibits VEGF Levels in the Ovary Directly by Binding and Internalization Via the Low Density Lipoprotein Receptor-Related Protein-1 (LRP-1)

James Greenaway; Jack Lawler; Roger A. Moorehead; Paul Bornstein; Jonathan LaMarre; James J. Petrik

VEGF is a potent pro‐angiogenic factor whose effects are opposed by a host of anti‐angiogenic proteins, including thrombospondin‐1 (TSP‐1). We have previously shown that VEGF has important extravascular roles in the ovary and that VEGF and TSP‐1 are inversely expressed throughout the ovarian cycle. To date, however, a causal interaction between TSP‐1 and VEGF has not been identified. Here, we show that TSP‐1 has a direct inhibitory effect on VEGF by binding the growth factor and internalizing it via LRP‐1. Mice lacking TSP‐1 are subfertile and exhibited ovarian hypervascularization and altered ovarian morphology. Treatment of ovarian cells with TSP‐1 decreased VEGF levels and rendered the cells more susceptible to TNFα‐induced apoptosis. Knockdown of TSP‐1, through RNA interference, resulted in overexpression of VEGF and reduced cytokine‐induced apoptosis. In conclusion, we demonstrate a direct inhibitory effect of TSP‐1 on VEGF in the ovary. TSP‐1s regulation of VEGF appears to be an important mediator of ovarian angiogenesis and follicle development. J. Cell. Physiol. 210: 807–818, 2007.


Biology of Reproduction | 2005

Thrombospondin and vascular endothelial growth factor are cyclically expressed in an inverse pattern during bovine ovarian follicle development

James Greenaway; Patricia A. Gentry; Jean-Jacques Feige; Jonathan LaMarre; James J. Petrik

Abstract Angiogenesis does not normally occur in most adult tissues. However, in the ovary, there are cyclical vascular changes including angiogenesis that involve the interaction of numerous cytokines and growth factors. Angiogenic processes are regulated by a balance between pro- and antiangiogenic factors. The purpose of this study was to determine the expression of the antiangiogenic thrombospondin family and proangiogenic vascular endothelial growth factor (VEGF) in various sizes of healthy bovine follicles. Ovaries were collected from slaughterhouse animals and healthy follicles were sorted based on size (<0.5 cm, small; 0.5–1.0 cm, medium; >1.0 cm, large). Thrombospondin (TSP) protein levels were significantly higher in small follicles. Immunohistochemistry confirmed the granulosa layer as the primary area within the follicle involved in TSP generation and that small follicles had the highest proportion of immunopositive cells. TSP-1 and -2 mRNA levels were significantly higher in small follicles than either medium or large follicles. TSP colocalized with CD36 on granulosa cells (GC) in the follicle and in cultured cells. In contrast with TSP, VEGF expression increased during growth and development of the follicle. FSH stimulated GC expression of TSP, while LH had no effect. In summary, TSP-1 and -2 were coordinately expressed in the extravascular compartment of the ovary during early follicle development. VEGF was inversely expressed, with expression increasing as follicles developed. Regulated expression and localization of these proteins suggests that they may be involved in regulating growth and development of the follicle in a novel fashion.


Journal of Oncology | 2010

Extracellular Matrix Proteins and Tumor Angiogenesis

Nicole E Campbell; Lisa Kellenberger; James Greenaway; Roger A. Moorehead; N. M. Linnerth-Petrik; James J. Petrik

Tumor development is a complex process that relies on interaction and communication between a number of cellular compartments. Much of the mass of a solid tumor is comprised of the stroma which is richly invested with extracellular matrix. Within this matrix are a host of matricellular proteins that regulate the expression and function of a myriad of proteins that regulate tumorigenic processes. One of the processes that is vital to tumor growth and progression is angiogenesis, or the formation of new blood vessels from preexisting vasculature. Within the extracellular matrix are structural proteins, a host of proteases, and resident pro- and antiangiogenic factors that control tumor angiogenesis in a tightly regulated fashion. This paper discusses the role that the extracellular matrix and ECM proteins play in the regulation of tumor angiogenesis.


Molecular Cancer Therapeutics | 2009

ABT-510 induces tumor cell apoptosis and inhibits ovarian tumor growth in an orthotopic, syngeneic model of epithelial ovarian cancer

James Greenaway; Jack Henkin; Jack Lawler; Roger A. Moorehead; James J. Petrik

Epithelial ovarian cancer (EOC) is the fifth most common cancer in women and is characterized by a low 5-year survival rate. One strategy that can potentially improve the overall survival rate in ovarian cancer is the use of antitumor agents such as ABT-510. ABT-510 is a small mimetic peptide of the naturally occurring antiangiogenic compound thrombospondin-1 and has been shown to significantly reduce tumor growth and burden in preclinical mouse models and in naturally occurring tumors in dogs. This is the first evaluation of ABT-510 in a preclinical model of human EOC. Tumorigenic mouse surface epithelial cells were injected into the bursa of C57BL/6 mice that were treated with either 100 mg/kg ABT-510 or an equivalent amount of PBS. ABT-510 caused a significant reduction in tumor size, ascites fluid volume, and secondary lesion dissemination when compared with PBS controls. Analysis of the vasculature of ABT-510-treated mice revealed vascular remodeling with smaller diameter vessels and lower overall area, increased number of mature vessels, and decreased tissue hypoxia. Tumors of ABT-510-treated mice had a significantly higher proportion of apoptotic tumor cells compared with the PBS-treated controls. Immunoblot analysis of cell lysates revealed a reduction in vascular endothelial growth factor, vascular endothelial growth factor receptor-2, and proliferating cell nuclear antigen protein expression as well as expression of members of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase survival pathways. In vitro, ABT-510 induced tumor cell apoptosis in mouse and human ovarian cancer cells. This study shows ABT-510 as a promising candidate for inhibiting tumor growth and ascites formation in human EOC. [Mol Cancer Ther 2009;8(1):64–74]


Journal of Oncology | 2010

The role of dysregulated glucose metabolism in epithelial ovarian cancer.

Lisa Kellenberger; Jennifer E. Bruin; James Greenaway; Nicole E Campbell; Roger A. Moorehead; Alison C. Holloway; James J. Petrik

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer and also one of the most poorly understood. Other health issues that are affecting women with increasing frequency are obesity and diabetes, which are associated with dysglycemia and increased blood glucose. The Warburg Effect describes the ability of fast-growing cancer cells to preferentially metabolize glucose via anaerobic glycolysis rather than oxidative phosphorylation. Recent epidemiological studies have suggested a role for hyperglycemia in the pathogenesis of a number of cancers. If hyperglycemia contributes to tumour growth and progression, then it is intuitive that antihyperglycemic drugs may also have an important antitumour role. Preliminary reports suggest that these drugs not only reduce available plasma glucose, but also have direct effects on cancer cell viability through modification of molecular energy-sensing pathways. This review investigates the effect that hyperglycemia may have on EOC and the potential of antihyperglycemic drugs as therapeutic adjuncts.


Molecular Cancer Therapeutics | 2011

ABT-898 Induces Tumor Regression and Prolongs Survival in a Mouse Model of Epithelial Ovarian Cancer

Nicole E Campbell; James Greenaway; Jack Henkin; James J. Petrik

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy and is often not diagnosed until late stages due to its asymptomatic nature. Women diagnosed with EOC typically undergo surgical debulking followed by chemotherapy; however, disease recurrence often occurs. In this study, we evaluated the ability of the thrombospondin-1 mimetic peptide, ABT-898, to regress established, late-stage tumors in a mouse model of human EOC. Ovarian tumors were induced and ABT-898 treatment was initiated at time points that were representative of late stages of the disease to study tumor regression. ABT-898 induced tumor regression and reduced the morbidity of treated animals compared with controls. Analysis of tumors from ABT-898–treated animals showed reduced abnormal tumor vasculature, decreased expression of the proangiogenic compound VEGF, and reduced tumor tissue hypoxia. ABT-898 treatment initiated at late-stage disease also significantly prolonged disease-free survival compared with control animals. Results from this study show that ABT-898 is capable of regressing established ovarian tumors in an animal model of the disease. As most women are detected at advanced stage EOC, ABT-898 may improve our treatment of ovarian cancer. Mol Cancer Ther; 10(10); 1876–85. ©2011 AACR.


Oncotarget | 2016

Ovarian tumour growth is characterized by mevalonate pathway gene signature in an orthotopic, syngeneic model of epithelial ovarian cancer

James Greenaway; Carl Virtanen; Kata Osz; Tamas Revay; Daniel B. Hardy; Trevor G. Shepherd; Gabriel E. DiMattia; James J. Petrik

Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer and often is not detected until late stages when cancer cells transcoelomically metastasize to the abdomen and typically become resistant to therapy resulting in very low survival rates. We utilize an orthotopic, syngeneic mouse model to study late stage disease and have discovered that the tumor cells within the abdominal ascites are irreversibly re-programmed, with an increased tumorigenicity and resistance to apoptosis. The goal of this study was to characterize the reprogramming that occurred in the aggressive ascites-derived cells (28-2 cells) compared to the original cell line used for tumor induction (ID8 cells). Microarray experiments showed that the majority of genes upregulated in the 28-2 cells belonged to the mevalonate pathway, which is involved in cholesterol biosynthesis, protein prenylation, and activation of small GTPases. Upregulation of mevalonate appeared to be associated with the acquisition of a p53 mutation in the ascites-derived cells. Treatment with simvastatin to inhibit HMG CoA reductase, the rate limiting enzyme of this pathway, induced apoptosis in the 28-2 cell line. Rescue experiments revealed that mevalonate, but not cholesterol, could inhibit the simvastatin-mediated effects. In vivo, daily intraperitoneal simvastatin treatment significantly regressed advanced stage disease and induced death of metastatic tumor cells. These data suggest that ovarian cancer cells become reprogrammed, with genetic mutations, and upregulation of the mevalonate pathway, which facilitates the development of advanced stage disease. The use of statins to inhibit HMGCR may provide novel therapeutic opportunities for the treatment of advanced stage EOC.


Biochemistry and Cell Biology | 2012

The impact of the ovarian microenvironment on the anti-tumor effect of SPARC on ovarian cancer

James Greenaway; Anne Koehler; Christopher A. McCulloch; James J. Petrik; Theodore J. Brown; Maurice Ringuette

A lack of host-derived SPARC promotes disease progression in an intraperitoneal (IP) ID8 mouse model of epithelial ovarian cancer (EOC). Since orthotopic injection (OT) of ID8 cells better recapitulates high-grade serous cancer, we examined the impact of host-derived SPARC following OT injection. Sparc(-/-) and wild-type (WT) mice were injected with ID8 cells either OT or IP and tumors were analyzed at the moribund stage. Sparc(-/-) mice had reduced survival and fewer well-defined abdominal lesions compared with WT controls after IP injection, whereas no differences were observed in survival or abdominal lesions between Sparc(-/-) and WT mice after OT injection. No differences in mass or collagen content were observed in ovarian tumors between OT-injected Sparc(-/-) and WT mice. The abdominal wall of the IP-injected Sparc(-/-) mice exhibited immature and less abundant collagen fibrils compared with WT mice both in injected and non-injected controls. In contrast to human EOC, SPARC was expressed by the tumor cells but was absent in reactive stroma of WT mice. Exposure to the ovarian microenvironment through OT injections alters the metastatic behaviour of ID8 cells, which is not affected by the absence of host-derived SPARC.


Methods of Molecular Biology | 2013

Orthotopic, Syngeneic Mouse Model to Study the Effects of Epithelial–Stromal Interaction

James Greenaway; James J. Petrik

One of the difficulties in studying ovarian cancer historically has been the lack of a suitable animal model that replicates the human disease. Mouse models that utilize intraperitoneal implantation of tumorigenic cells lack interaction between the transformed ovarian epithelial cells and the ovarian stroma, which we have shown to be an integral component in replicating the etiology seen in human epithelial ovarian cancer (Greenaway, Gynecol Oncol 108:385-394, 2008). Xenograft models generally require the use of immunocompromised hosts, which then eliminates the influence of the immune system in disease progression, which also has been shown to be an important part of the progression of epithelial ovarian cancer (EOC). In this chapter, we describe the generation and optimization of an orthotopic, syngeneic mouse model and illustrate the importance of facilitating epithelial-stromal cell interaction to more closely replicate human EOC.


Cancer Research | 2011

Abstract 409: The influence of chronic low grade systemic inflammation on the progression of epithelial ovarian cancer

Amanda Kerr; Lisa Kellenberger; James Greenaway; James J. Petrik

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL It is established that inflammation can create a protumorigenic environment. Many sources of chronic inflammation, including viral and bacterial, have been associated with accelerated tumorigenesis. An epidemiological link has been discovered between chronic inflammatory diseases and ovarian cancer suggesting that inflammation can increase the risk of epithelial ovarian cancer (EOC) potentially by synergizing with the local ovarian inflammation associated with ovulation. The purpose of this study is to identify the impact of prolonged exposure to chronic low-grade inflammation on epithelial ovarian cancer cell viability in vitro and EOC tumor progression in vivo. We hypothesize that this level of systemic inflammation will enhance the growth and survival of epithelial ovarian tumors by increasing angiogenesis, cell survival and metastatic capability. We believe these effects will occur in part due to the interactions between the malignant ovarian surface epithelial cells and the various immune cells recruited to the stromal microenvironment of the tumor. The first objective to examine these relationships was to determine the effect of a proinflammatory environment in an in vitro model using normal ovarian surface epithelium (NOSE) and transformed human ovarian epithelial cell lines CAOV-3, ES-2, OVCAR-3 and SKOV-3. Cells were exposed to proinflammatory cytokines interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α and in response to this exposure, the ovarian cancer cells showed enhanced viability and proliferation. The next objective involves examining the influence of the epithelial-stromal interactions of tumor cells by utilizing a co-culture model to initiate communication between the human epithelial cell lines in objective one with a differentiated macrophage cell line. In additional trials with transformed murine epithelial and microvascular cell lines we have identified the expression of Toll-like receptor 4 (TLR4) using reverse transcription-PCR. TLR4 is the receptor through which the bacterial endotoxin lipopolysaccharide (LPS) acts as an inflammatory agent. Based on these preliminary results, we propose to evaluate the role of chronic inflammation in the progression of EOC in an established mouse model using LPS to induce a low-grade level of chronic inflammation. Analysis of tumor cell survival, angiogenesis, and local and systemic inflammation will be evaluated western blot, PCR, ELISA assay and immunofluorescence. Evaluation of the relationship between chronic, systemic inflammation and the progression of EOC may be useful in developing treatment approaches for EOC, specifically in terms of anti-inflammatory therapies, and could provide insight into the role of inflammation in the progression of other human cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 409. doi:10.1158/1538-7445.AM2011-409

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Jonathan LaMarre

Ontario Veterinary College

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Jack Henkin

Northwestern University

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Jack Lawler

Beth Israel Deaconess Medical Center

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Ann Hahnel

Ontario Veterinary College

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