Abstract
BackgroundNovel theranostic options for high-risk non-muscle invasive bladder cancer are urgently needed. This requires a thorough evaluation of experimental approaches in animal models best possibly reflecting human disease before entering clinical studies. Although several bladder cancer xenograft models were used in the literature, the establishment of an orthotopic bladder cancer model in mice remains challenging.MethodsLuciferase-transduced UM-UC-3LUCK1 bladder cancer cells were instilled transurethrally via 24G permanent venous catheters into athymic NMRI and BALB/c nude mice as well as into SCID-beige mice. Besides the mouse strain, the pretreatment of the bladder wall (trypsin or poly-L-lysine), tumor cell count (0.5 × 106–5.0 × 106) and tumor cell dwell time in the murine bladder (30 min – 2 h) were varied. Tumors were morphologically and functionally visualized using bioluminescence imaging (BLI), magnetic resonance imaging (MRI), and positron emission tomography (PET).ResultsImmunodeficiency of the mouse strains was the most important factor influencing cancer cell engraftment, whereas modifying cell count and instillation time allowed fine-tuning of the BLI signal start and duration – both representing the possible treatment period for the evaluation of new therapeutics. Best orthotopic tumor growth was achieved by transurethral instillation of 1.0 × 106 UM-UC-3LUCK1 bladder cancer cells into SCID-beige mice for 2 h after bladder pretreatment with poly-L-lysine. A pilot PET experiment using 68Ga-cetuximab as transurethrally administered radiotracer revealed functional expression of epidermal growth factor receptor as representative molecular characteristic of engrafted cancer cells in the bladder.ConclusionsWith the optimized protocol in SCID-beige mice an applicable and reliable model of high-risk non-muscle invasive bladder cancer for the development of novel theranostic approaches was established.
Highlights
Novel theranostic options for high-risk non-muscle invasive bladder cancer are urgently needed
Around 75% of newly diagnosed patients present with non-muscle invasive bladder cancer (BCa) (NMIBC) that is confined to the mucosa or submucosa
To enable non-invasive visualization of tumor growth, UM-UC-3 cells were transduced with a retroviral pRevCMV-c-Luc vector containing the firefly luciferase gene (LUC+) [16] and a hygromycin B resistance cassette [17]
Summary
Novel theranostic options for high-risk non-muscle invasive bladder cancer are urgently needed This requires a thorough evaluation of experimental approaches in animal models best possibly reflecting human disease before entering clinical studies. Around 75% of newly diagnosed patients present with non-muscle invasive BCa (NMIBC) that is confined to the mucosa (stage Ta and carcinoma in situ) or submucosa (stage T1) Standard therapy for these patients is transurethral resection with adjuvant intravesical chemo- or immunotherapy [3]. Despite these therapies 21% of patients with high-risk NMIBC – for example patients with tumor stage T1 and/or high grade (= G3) tumors – progress to muscle invasive BCa and 14% die of BCa mainly within 4 years [4]. Alternative treatment options are needed which require thorough evaluation in preclinical models – first in cell culture and thereafter in animal models
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