Whole-Body Bioluminescent Imaging of Human Uveal Melanoma in a New Mouse Model of Local Tumor Growth and Metastasis

Notting, Irene C.; Buijs, Jeroen T.; Que, Ivo; Mintardjo, Ratna; Horst, Geertje van der; Karperien, Marcel; Missotten, Guy S.; Schalij‐Delfos, Nicoline E.; Keunen, J. E. E.; Pluijm, Gabri van der

doi:10.1167/iovs.04-0245

Cited by 21 publications

(23 citation statements)

References 17 publications

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“…Other studies have shown hepatic, bone, and visceral micrometastasis develop in a uveal melanoma xenograft model (34), as well as bone and visceral macrometastasis in an intracardiac metastatic mouse model (35). Another study has also demonstrated inhibition of micrometastasis using a VEGFR inhibitor after enucleation of the mouse eyes (36).…”

Section: Discussionmentioning

confidence: 96%

Crizotinib, a c-Met Inhibitor, Prevents Metastasis in a Metastatic Uveal Melanoma Model

Surriga

Rajasekhar

Ambrosini

et al. 2013

Molecular Cancer Therapeutics

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Uveal melanoma is the most common primary intraocular malignant tumor in adults and half of the primary tumors will develop fatal metastatic disease to the liver and the lung. Crizotinib, an inhibitor of c-Met, anaplastic lymphoma kinase (ALK), and ROS1, inhibited the phosphorylation of the c-Met receptor but not of ALK or ROS1 in uveal melanoma cells and tumor tissue. Consequently, migration of uveal melanoma cells was suppressed in vitro at a concentration associated with the specific inhibition of c-Met phosphorylation. This effect on cell migration could be recapitulated with siRNA specific to c-Met but not to ALK or ROS1. Therefore, we developed a uveal melanoma metastatic mouse model with EGFPluciferase-labeled uveal melanoma cells transplanted by retro-orbital injections to test the effect of crizotinib on metastasis. In this model, there was development of melanoma within the eye and also metastases to the liver and lung at 7 weeks after the initial transplantation. When mice were treated with crizotinib starting 1 week after the transplantation, we observed a significant reduction in the development of metastases as compared with untreated control sets. These results indicate that the inhibition of c-Met activity alone may be sufficient to strongly inhibit metastasis of uveal melanoma from forming, suggesting crizotinib as a potential adjuvant therapy for patients with primary uveal melanoma who are at high risk for the development of metastatic disease.

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Section: Discussionmentioning

confidence: 96%

Crizotinib, a c-Met Inhibitor, Prevents Metastasis in a Metastatic Uveal Melanoma Model

Surriga

Rajasekhar

Ambrosini

et al. 2013

Molecular Cancer Therapeutics

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“…Stable cell lines were generated by using the Flp-In system (Invitrogen, Breda, The Netherlands) according to manufacturer's protocol and as described previously (Notting et al, 2005). In short, an MDA-MB-231-Flp-in host cell line (MDA-MB-231-Frt3) was generated by a stable introduction of a single copy of an Flp-Recombinase target (FRT) site as an integral part of an antibiotic resistance gene (blasticidin) in the genome of these cells (5 mg/ml blasticidin was added to the culture medium).…”

Section: Generation Of Isogenic Cell Lines By Targeted Integrationmentioning

confidence: 99%

The BMP2/7 heterodimer inhibits the human breast cancer stem cell subpopulation and bone metastases formation

et al. 2011

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Accumulating evidence suggests that a subpopulation of breast cancer cells, referred to as cancer stem cells (CSCs), have the ability to propagate a tumor and potentially seed new metastases. Furthermore, stimulation of an epithelialto-mesenchymal transition by factors like transforming growth factor-b (TGFb) is accompanied with the generation of breast CSCs. Previous observations indicated that bone morphogenetic protein-7 (BMP7) antagonizes the protumorigenic and prometastatic actions of TGFb, but whether BMP7 action is mechanistically linked to breast CSCs has remained elusive. Here, we have studied the effects of BMP7, BMP2 and a BMP2/7 heterodimer on the formation of human breast CSCs (ALDH hi /CD44 hi / CD24 À/low ) and bone metastases formation in a preclinical model of intra-cardiac injection of MDA-MB-231 cells in athymic nude (Balb/c nu/nu) mice. The BMP2/7 heterodimer was the most efficient stimulator of BMP signaling and very effectively reduced TGFb-driven Smad signaling and cancer cell invasiveness. The tested BMPs-particularly the heterodimeric BMP2/7-strongly reduced the size of the ALDH hi /CD44 hi /CD24 À/low CSC subpopulation. In keeping with these in vitro observations, pretreatment of cancer cells with BMPs for 72 h prior to systemic inoculation of the cancer cells inhibited the formation of bone metastases. Collectively, our data support the notion that breast CSCs are involved in bone metastasis formation and describe heterodimeric BMP2/7 as a powerful TGFb antagonist with anti-metastatic potency.

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“…31) were selected to generate a stable cell line that overexpresses BMP7. Stable cell lines were generated using the Flp-In system (Invitrogen) according to the manufacturer's protocol (32). In short, a MDA-231-BO2-Flp-in host cell line (MDA-231-BO2-Frt11) was generated by stable introduction of a single copy of a Flp recombinase target (FRT) site as an integral part of an antibiotic resistancy gene in the genome of these cells.…”

Section: Introductionmentioning

confidence: 99%

“…Due to Flp-mediated recombination at the genomic FRT site, this targeting vector was incorporated in the genome. Simultaneously, a shift in antibiotic resistance was introduced allowing positive selection for integrants in the genomic FRT site only and negative selection for random integrants in one single step (32). This method allows the generation of isogenic stable cell lines, which only differ in sequence inserted in the genomic FRT site, thereby eliminating the need for clonal selection.…”

Section: Introductionmentioning

confidence: 99%

Bone Morphogenetic Protein 7 in the Development and Treatment of Bone Metastases from Breast Cancer

Buijs

Henriquez²,

Overveld³

et al. 2007

Cancer Research

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185

178

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Bone morphogenetic protein 7 (BMP7) counteracts the physiological epithelial-to-mesenchymal transition (EMT), a process that is indicative of epithelial plasticity. Because EMT is involved in cancer, we investigated whether BMP7 plays a role in breast cancer growth and metastasis. In this study, we show that decreased BMP7 expression in primary breast cancer is significantly associated with the formation of clinically overt bone metastases in patients with z10 years of follow-up. In line with these clinical observations, BMP7 expression is inversely related to tumorigenicity and invasive behavior of human breast cancer cell lines. Moreover, BMP7 decreased the expression of vimentin, a mesenchymal marker associated with invasiveness and poor prognosis, in human MDA-MB-231 (MDA-231)-B/Luc + breast cancer cells under basal and transforming growth factor-B (TGF-B)-stimulated conditions. In addition, exogenous addition of BMP7 to TGF-B-stimulated MDA-231 cells inhibited Smad-mediated TGF-B signaling. Furthermore, in a well-established bone metastasis model using whole-body bioluminescent reporter imaging, stable overexpression of BMP7 in MDA-231 cells inhibited de novo formation and progression of osteolytic bone metastases and, hence, their metastatic capability. In line with these observations, daily i.v. administration of BMP7 (100 Mg/kg/d) significantly inhibited orthotopic and intrabone growth of MDA-231-B/Luc + cells in nude mice. Our data suggest that decreased BMP7 expression during carcinogenesis in the human breast contributes to the acquisition of a bone metastatic phenotype. Because exogenous BMP7 can still counteract the breast cancer growth at the primary site and in bone, BMP7 may represent a novel therapeutic molecule for repression of local and bone metastatic growth of breast cancer. [Cancer Res 2007;67(18):8742-51]

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Whole-Body Bioluminescent Imaging of Human Uveal Melanoma in a New Mouse Model of Local Tumor Growth and Metastasis

Abstract: BLI enables continuous quantitative monitoring in the same animal of growth kinetics for each tumor and its metastases. This model will accelerate the understanding of the pathogenesis and treatment of uveal melanoma and metastasis.

Cited by 21 publications

References 17 publications

Crizotinib, a c-Met Inhibitor, Prevents Metastasis in a Metastatic Uveal Melanoma Model

Crizotinib, a c-Met Inhibitor, Prevents Metastasis in a Metastatic Uveal Melanoma Model

The BMP2/7 heterodimer inhibits the human breast cancer stem cell subpopulation and bone metastases formation

Bone Morphogenetic Protein 7 in the Development and Treatment of Bone Metastases from Breast Cancer

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