A patient-derived orthotopic xenograft model enabling human high-grade urothelial cell carcinoma of the bladder tumor implantation, growth, angiogenesis, and metastasis
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Jessie Gills1,*, Ravan Moret2,*, Xin Zhang2, John Nelson1, Grace Maresh2, Linh Hellmers2, Daniel Canter1, M’Liss Hudson1,6, Shams Halat3, Marc Matrana4, Michael P. Marino5, Jakob Reiser5, Maureen Shuh2, Eric Laborde1, Maria Latsis1, Sunil Talwar1, Stephen Bardot1 and Li Li2
1Department of Urology, Ochsner Clinic Foundation, New Orleans, LA, USA
2Institution of Translational Research, Ochsner Clinic Foundation, New Orleans, LA, USA
3Department of Pathology, Ochsner Clinic Foundation, New Orleans, LA, USA
4Department of Hematology and Oncology, Ochsner Clinic Foundation, New Orleans, LA, USA
5Division of Cellular and Gene Therapies, The Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA
6Current address: Memorial Urology Associates, Houston, TX, USA
*These authors contributed equally to this work
Stephen Bardot, email: [email protected]
Li Li, email: [email protected]
Keywords: patient-derived orthotopic xenograft; high-grade/muscle invasive urothelial cell carcinoma; lymph node stromal cells
Received: June 26, 2018 Accepted: August 10, 2018 Published: August 24, 2018
High-grade urothelial cell carcinoma of the bladder has a poor prognosis when lymph nodes are involved. Despite curative therapy for clinically-localized disease, over half of the muscle-invasive urothelial cell carcinoma patients will develop metastases and die within 5 years. There are currently no described xenograft models that consistently mimic urothelial cell carcinoma metastasis. To develop a patient-derived orthotopic xenograft model to mimic clinical urothelial cell carcinoma progression to metastatic disease, the urothelial cell carcinoma cell line UM-UC-3 and two urothelial cell carcinoma patient specimens were doubly tagged with Luciferase/RFP and were intra-vesically (IB) instilled into NOD/SCID mice with or without lymph node stromal cells (HK cells). Mice were monitored weekly with bioluminescence imaging to assess tumor growth and metastasis. Primary tumors and organs were harvested for bioluminescence imaging, weight, and formalin-fixed for hematoxylin and eosin and immunohistochemistry staining. In this patient-derived orthotopic xenograft model, xenograft tumors showed better implantation rates than currently reported using other models. Xenograft tumors histologically resembled pre-implanted primary specimens from patients, presenting muscle-invasive growth patterns. In the presence of HK cells, tumor formation, tumor angiogenesis, and distant organ metastasis were significantly enhanced in both UM-UC-3 cells and patient-derived specimens. Thus, we established a unique, reproducible patient-derived orthotopic xenograft model using human high-grade urothelial cell carcinoma cells and lymph node stromal cells. It allows for investigating the mechanism involved in tumor formation and metastasis, and therefore it is useful for future testing the optimal sequence of conventional drugs or the efficacy of novel therapeutic drugs.
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