Optimization of the MB49 mouse bladder cancer model for adenoviral gene therapy

Loskog, Angelica; Ninalga, Christina; Hedlund, T.; Alimohammadi, Mohammed; Malmström, Per‐Uno; Tötterman, Thomas H.

doi:10.1258/002367705774286475

Cited by 45 publications

(45 citation statements)

References 23 publications

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“…the syngeneic MB49 murine bladder cancer cell line (42) subcutaneously into C57BL/6 mice and observed lung metastases in 3-4 weeks, consistent with prior findings (43). Interestingly, ET A R blockade by ZD4054 reduced subcutaneous MB49 tumor growth when this blockade was administered before inoculation, while it had less effect when initiated after inoculation.…”

Section: Figuresupporting

confidence: 84%

Tumor endothelin-1 enhances metastatic colonization of the lung in mouse xenograft models of bladder cancer

Said¹,

Smith²,

Sänchez‐Carbayo³

et al. 2011

J. Clin. Invest.

118

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Many patients with advanced bladder cancer develop lethal metastases to the lung. The vasoconstricting protein endothelin-1 (ET-1) has been implicated in this process, although the mechanism(s) by which it promotes metastasis remains unclear. Here, we have evaluated whether tumor ET-1 expression can serve as a biomarker for lung metastasis and whether it is required for metastatic disease. Evaluation of ET-1 mRNA and protein expression in four patient cohorts revealed that levels of ET-1 are higher in patients with muscle-invasive bladder cancers, which are associated with higher incidence of metastasis, and that high ET-1 levels are associated with decreased disease-specific survival. Consistent with its proinflammatory activity, we found that tumorderived ET-1 acts through endothelin-1 receptor A (ET A R) to enhance migration and invasion of both tumor cells and macrophages and induces expression of inflammatory cytokines and proteases. Using human and mouse cancer cells depleted of ET-1 and pharmacologic blockade of ET receptors in lung metastasis models, we found that tumor ET-1 expression and ET A R activity are necessary for metastatic lung colonization and that this process is preceded by and dependent on macrophage infiltration of the lung. In contrast, tumor ET-1 expression and ET A R activity appeared less important in established primary or metastatic tumor growth. These findings strongly suggest that ET A R inhibitors might be more effective as adjuvant therapeutic agents than as initial treatment for advanced primary or metastatic disease.

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Section: Figuresupporting

confidence: 84%

Tumor endothelin-1 enhances metastatic colonization of the lung in mouse xenograft models of bladder cancer

Said¹,

Smith²,

Sänchez‐Carbayo³

et al. 2011

J. Clin. Invest.

118

View full text Add to dashboard Cite

show abstract

“…Genomic DNA was extracted from 5 mouse lungs of each group and 12p real time PCR was performed for DNA PCR metastasis assay as described previously (25). Metastatic lesions were gross examined for metastasis in 10 mouse lungs of each group and the number of visible metastases was evaluated as explained previously (27). Animal experiments were performed with the approval of the Institutional Committee of Shanghai Jiaotong University School of Medicine for Animal Research.…”

Section: In Vivo Bladder Cancer Experimental Metastasis Assaymentioning

confidence: 99%

ATF3 Suppresses Metastasis of Bladder Cancer by Regulating Gelsolin-Mediated Remodeling of the Actin Cytoskeleton

et al. 2013

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Bladder cancer is associated with high recurrence and mortality rates due to metastasis. The elucidation of metastasis suppressors may offer therapeutic opportunities if their mechanisms of action can be elucidated and tractably exploited. In this study, we investigated the clinical and functional significance of the transcription factor activating transcription factor 3 (ATF3) in bladder cancer metastasis. Gene expression analysis revealed that decreased ATF3 was associated with bladder cancer progression and reduced survival of patients with bladder cancer. Correspondingly, ATF3 overexpression in highly metastatic bladder cancer cells decreased migration in vitro and experimental metastasis in vivo. Conversely, ATF3 silencing increased the migration of bladder cancer cells with limited metastatic capability in the absence of any effect on proliferation. In keeping with their increased motility, metastatic bladder cancer cells had increased numbers of actin filaments. Moreover, ATF3 expression correlated with expression of the actin filament severing protein gelsolin (GSN). Mechanistic studies revealed that ATF3 upregulated GSN, whereas ATF3 silencing reduced GSN levels, concomitant with alterations in the actin cytoskeleton. We identified six ATF3 regulatory elements in the first intron of the GSN gene confirmed by chromatin immunoprecipitation analysis. Critically, GSN expression reversed the metastatic capacity of bladder cancer cells with diminished levels of ATF3. Taken together, our results indicate that ATF3 suppresses metastasis of bladder cancer cells, at least in part through the upregulation of GSN-mediated actin remodeling. These findings suggest ATF3 coupled with GSN as prognostic markers for bladder cancer metastasis. Cancer Res; 73(12); 3625-37. Ó2013 AACR.

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“…Mice were implanted with tumor using the poly-L-lysine method as described (16). Treatments started at day 1 and were given once weekly.…”

Section: Resultsmentioning

confidence: 99%

“…The cells were cultured in DMEM supplemented with penicillinstreptomycin (1%), sodium pyruvate (0.1%), and fetal bovine serum (10%; Invitrogen, Paisley, Scotland). The orthotopic model using poly-L-lysine described elsewhere was used (16). Briefly, C57BL/6 mice were anesthetized and catheterized (INSYTE.w24Gx3/4, BD Biosciences, San Diego, CA).…”

Section: Methodsmentioning

confidence: 99%

AdCD40LGene Therapy Counteracts T Regulatory Cells and Cures Aggressive Tumors in an Orthotopic Bladder Cancer Model

Loskog

Fransson²,

Tötterman³

2005

Clinical Cancer Research

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Purpose: The aim of this study was to develop an immunostimulating gene therapy for the treatment of orthotopic bladder carcinoma by transferring the gene for CD40L into the tumor site. CD40L stimulation of dendritic cells induces interleukin-12 expression that drives Th1 type of immune responses with activation of cytotoxic T cells. Experimental Design: The gene for murine CD40L was transferred into bladders of tumorbearing mice using an adenoviral vector construct. To facilitate viral uptake, the bladders were pretreated with Clorpactin. Survival of mice as well as transgene expression and immunologic effect, such as resistance to tumor challenge and presence of T regulatory cells, were monitored. Results: On viral vector instillation, CD40L expression could be detected by reverse transcription-PCR. As a sign of transgene function, interleukin-12 (IL-12) expression was significantly increased. AdCD40L gene therapy cured 60% of mice with preestablished tumors. The cured mice were completely resistant to subcutaneous challenge with MB49 tumor cells, whereas the growth of a syngeneic irrelevant tumor was unaltered. Furthermore, the mRNA expression level of the T regulatory cell transcription factor Foxp3 was evaluated both in tumor biopsies and lymph nodes.There were no differences within the tumors of the different treatment groups. However, Foxp3 mRNA levels were down-regulated in the lymph nodes of AdCD40L-treated mice. Correspondingly,Tcells from AdCD40L-treated mice were not able to inhibit proliferation of naiveTcells as opposed toTcells from control-treated, tumor-bearing mice. Conclusions: AdCD40L gene therapy evokesTh1cytokine responses and counteractsT regulatory cell development and/or function.

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Optimization of the MB49 mouse bladder cancer model for adenoviral gene therapy

Cited by 45 publications

References 23 publications

Tumor endothelin-1 enhances metastatic colonization of the lung in mouse xenograft models of bladder cancer

Tumor endothelin-1 enhances metastatic colonization of the lung in mouse xenograft models of bladder cancer

ATF3 Suppresses Metastasis of Bladder Cancer by Regulating Gelsolin-Mediated Remodeling of the Actin Cytoskeleton

AdCD40LGene Therapy Counteracts T Regulatory Cells and Cures Aggressive Tumors in an Orthotopic Bladder Cancer Model

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