Characterization of intraperitoneal, orthotopic, and metastatic xenograft models of human ovarian cancer

Shaw, Tanya J.; Senterman, Mary K.; Dawson, Kerri; Crane, Colleen; Vanderhyden, Barbara C.

doi:10.1016/j.ymthe.2004.08.013

Cited by 251 publications

(239 citation statements)

References 42 publications

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“…Endogenous MT1 expression and activity were positively correlated with invasiveness in the six ovarian cancer cell lines examined. Importantly, the levels of invasion indicated by our in vitro assays mirrored the reported abilities of the cell lines to form peritoneal tumours in vivo (Shaw et al, 2004). HEY, OVCA429, and ES-2 cell lines expressed the highest levels of MT1, and were consistently shown to be the most invasive in the in vitro assays used.…”

Section: Discussionsupporting

confidence: 70%

“…HEY, OVCA429, and ES-2 cell lines expressed the highest levels of MT1, and were consistently shown to be the most invasive in the in vitro assays used. These three cell lines also reproducibly formed invasive intraperitoneal tumours in mice (Shaw et al, 2004). Conversely, we found SKOV-3 and OVCAR-3 cells did not express MT1 and were incapable of invading polymerised collagen I matrices in vitro.…”

Section: Discussionmentioning

confidence: 64%

“…Membrane-type 1 expression by cells of orthotopically implanted human ovarian cancer biopsies has been linked to a more aggressive tumorigenicity (Drew et al, 2004), and inhibition of MT1 activity has been shown to block collagen invasion in one ovarian cancer cell line, DOV-13 (Ellerbroek et al, 1999;Ellerbroek et al, 2001). However, as different ovarian cancer cell lines display varying capacities for peritoneal tumour formation in vivo (Shaw et al, 2004), and may use different mechanisms for invasion, we sought to determine whether MT1 expression determines invasive behaviour within a diverse panel of human ovarian cancer cell lines. A polymerised collagen I matrix was used to assess invasion for several reasons: Collagen I plays a key involvement in ovarian cancer metastasis, being the most abundant matrix molecule in the submesothelial stroma, and is the preferred substrate for ovarian cancer cell attachment during peritoneal metastasis (Moser et al, 1996).…”

mentioning

confidence: 99%

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MT1-MMP is the critical determinant of matrix degradation and invasion by ovarian cancer cells

2007

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Membrane-type 1 matrix metalloproteinase (MT1-MMP), a transmembrane metalloprotease that plays an important role in the invasion of many solid tumour types, promotes pericellular matrix degradation and may also stimulate tumour cell motility. As both these processes are key contributors to intraperitoneal ovarian tumour metastasis, we examined six ovarian cancer cell lines to determine whether MT1 is a critical mediator of invasive behaviour for this tumour type. Our results indicated that only those cell lines that expressed MT1 were capable of penetrating a type I collagen barrier, with the capacity for both matrix degradation and invasion reflecting endogenous MT1 expression level. Ectopic MT1 expression endowed an invasive phenotype upon cell lines lacking MT1 that were previously non-invasive, indicating the crucial role of this protease. Conversely, invasion was abolished by tissue inhibitor of metalloproteinase-2 (TIMP-2), a potent inhibitor of MT1, yet was minimally affected when other (secreted) MMPs were inhibited using TIMP-1 and the gelatinase inhibitor SB-3CT. Whereas collagen I degradation was strikingly accelerated by ectopic MT1 expression, cell motility remained unchanged. We conclude that MT1 is necessary for collagen I invasion by ovarian cancer cells, and that its requisite activity is the promotion of matrix degradation, with no impact on cell motility.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 64%

mentioning

confidence: 99%

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MT1-MMP is the critical determinant of matrix degradation and invasion by ovarian cancer cells

2007

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“…Interestingly, SKOV3, which is perhaps the most widely used cell line used in cell biology studies of ovarian cancer, is not reported to be derived from a clear cell tumor, although it has been reported that the parental SKOV3 cell line can form tumors of a clear cell histology when xenografted orthotopically into nude mice. 45 Four EOC cell lines were xenografted, intra-peritoneally or subcutaneously, into immunocompromised mice to compare 3D spheroid cultures to the same cells grown in vivo. Two cell 3D microenvironment and EOCs JM Lee et al lines (UWB1.289 and UWB1.289 þ BRCA1) failed to form tumors.…”

Section: D Modeling Of Eoc Cell Lines Restores Features Of Histologimentioning

confidence: 99%

A three-dimensional microenvironment alters protein expression and chemosensitivity of epithelial ovarian cancer cells in vitro

Lee

Mhawech‐Fauceglia

Lee

et al. 2013

Laboratory Investigation

271

125

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For many cancers, there is a real need for more effective therapies. Although many drugs show promising results in vitro, most fail to translate into an in vivo model system, and only B5% show anti-tumor activity in clinical trials. It remains a significant challenge to accurately replicate in vitro the complex in vivo microenvironment in which cancers thrive, but this will be key to increasing the success of translating novel therapies into clinical practice. Three-dimensional (3D) cell culture models may better mimic primary tumors in vivo than traditional two-dimensional (2D) cultures. Therefore, we established and characterized 3D in vitro models of 31 epithelial ovarian cancer (EOC) cell lines, compared their biological and molecular features with 2D cultures and primary tumors, and tested their efficacy as models for evaluating chemoresponse. When cultured in 3D using polyhydroxoethylamethacrylate-coated plastics, EOC lines formed multicellular aggregates that could be classified as 'large dense', 'large loose', and 'small', based on size, light permeability, and proportion of cells incorporated into the complex structures. Features of histological differentiation characteristic of primary tumors that were not present in 2D cultures were restored in 3D. For many cell lines, the transition from a 2D to 3D microenvironment induced changes in the expression of several biomarkers relevant to disease. Generally, EOC cell lines proliferated more slowly and were more chemoresistant in 3D compared with 2D culture. In summary, 3D models of EOCs better reflect the histological, biological, and molecular features of primary tumors than the same cells cultured using traditional 2D techniques; 3D in vitro models also exhibit different sensitivities to chemotherapeutic agents compared with 2D models, which may have a significant impact on the success of drug testing pipelines for EOC. These findings could also impact in vitro modeling approaches and drug development strategies for other solid tumor types. The success rate of anti-cancer therapies translating from in vitro culture systems into the clinic is about 5%. 1 The vast majority of drugs that show promising results in vitro fail to replicate in an in vivo model system and even fewer make it into clinical trials. Nonetheless testing drugs in cell culture models is a vital part of any drug development process. It is likely that a major contributing factor to the low rates of in vivo translation of new therapeutic agents is the widespread use of two-dimensional (2D) monolayer culture systems used for in vitro drug discovery and development. 2D cultures fail to recapitulate the gradients of drugs, nutrients, gases, and waste products that characterize tumors in vivo; all are important factors influencing response to therapy. 2,3 Moreover, many of the signaling pathways involved in chemoresponsiveness are differentially activated in monolayer cultures, and as a result, 2D cultures are often more sensitive to drug therapies yielding many false-positive results in 2D dr...

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“…To test the effect of GnRH on tumor metastasis, a welldeveloped experimental metastasis mouse model was used to evaluate the effect of GnRH receptor short hairpin RNA (shRNA) against ovarian cancer cells growing in the peritoneal cavity of nude mice (Shaw et al, 2004). As shown in Figure 8, the tumor burden as Figure 3 IGF-1R is required for GnRH-induced activation of p120 ctn .…”

Section: Gnrh Receptor Inhibition Effectively Reduces Metastasis In Vivomentioning

confidence: 99%

P-cadherin cooperates with insulin-like growth factor-1 receptor to promote metastatic signaling of gonadotropin-releasing hormone in ovarian cancer via p120 catenin

et al. 2011

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Gonadotropin-releasing hormone (GnRH) is a potent prometastatic factor in ovarian cancer, but the intracellular signaling events are not well understood. The classical Ga q -phospholipase C signal transduction pathway known to operate in the pituitary is not involved in GnRH actions at non-pituitary targets. Here we showed that GnRH treatment of ovarian cancer cells led to a rapid and remarkable tyrosine phosphorylation of p120 catenin (p120 ctn ), which was mediated by P-cadherin. The use of P-cadherin small interfering RNA or neutralizing antibodies to inhibit P-cadherin expression and function resulted in diminished p120 ctn activation, confirming that the effect was P-cadherin specific. On exploring how P-cadherin, which lacks intrinsic kinase activity, might regulate the activation of p120 ctn , we found that P-cadherin could induce the ligandindependent activation of insulin-like growth factor-1 receptor (IGF-1R). Inhibition of IGF-1R expression or its activity significantly inhibited GnRH-induced p120 ctn activation, and the subsequent cell migration and invasion. In addition, we showed that IGF-1R regulation by P-cadherin was associated with complex formation between IGF-1R and P-cadherin, and this regulation was also observed to be in vivo correlated with metastasis. Furthermore, using a mouse model of ovarian cancer metastasis, GnRH receptor knockdown was shown to diminish peritoneal dissemination of tumors and ascites formation. These findings suggest for the first time that GnRH can initiate an outside-in p120 ctn signal transduction through the cross-talk between P-cadherin and IGF-1R, thus providing a novel molecular mechanism by which GnRH may control the high level of aggressiveness and invasion and metastasis potential that are characteristic of ovarian cancer.

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Characterization of intraperitoneal, orthotopic, and metastatic xenograft models of human ovarian cancer

Cited by 251 publications

References 42 publications

MT1-MMP is the critical determinant of matrix degradation and invasion by ovarian cancer cells

MT1-MMP is the critical determinant of matrix degradation and invasion by ovarian cancer cells

A three-dimensional microenvironment alters protein expression and chemosensitivity of epithelial ovarian cancer cells in vitro

P-cadherin cooperates with insulin-like growth factor-1 receptor to promote metastatic signaling of gonadotropin-releasing hormone in ovarian cancer via p120 catenin

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