Abstract
In order to investigate the antitumor and antimetastatic efficacy of new chemotherapeutic agents, a novel, red-fluorescent, orthotopic model of pancreatic cancer was constructed in nude mice. MIA-PaCa-2 human pancreatic cancer cells were transduced with red fluorescent protein (RFP) and initially grown subcutaneously. Fluorescent tumor fragments were then transplanted onto the pancreas by surgical orthotopic implantation (SOI), facilitating high-resolution, real-time visualization of tumor and metastatic growth and dissemination in vivo. Tumor growth at the primary site was visible within the first postoperative week, while distant metastasis and the development of ascites became visible over the following week. This MIA-PaCa-2-RFP model produced extensive local disease and metastases to the retroperitoneum (100%), spleen (100%), intestinal and periportal lymph nodes (100%), liver (40%) and diaphragm (80%), and gave rise to malignant ascites and peritoneal carcinomatosis in 80% of cases. Growth and metastasis of tumor was more rapid and frequent than in previously described orthotopic pancreatic cancer models, leading to a median survival of only 21 days after tumor implantation. This unique, red fluorescent model rapidly and reliably simulates the highly aggressive course of human pancreatic cancer and can be easily non-invasively visualized in the live animal. The model can therefore be used for the discovery and evaluation of novel therapeutics for the treatment of this devastating disease.
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References
Jemal A, Thomas A, Murray T, Thun M. Cancer statistics, 2002. CA Cancer J Clin 2002; 52: 23–47.
Sener SF, Fremgen A, Menck HR, Winchester DP. Pancreatic cancer: A report of treatment and survival trends for 100,313 patients diagnosed from 1985-1995, using the National Cancer Database. J Am Coll Surg 1999; 189: 1–7.
Bouvet M, Gamagami RA, Gilpin EA et al. Factors influencing survival after resection for periampullary neoplasms. Am J Surg 2000; 180: 13–7.
Yeo CJ, Cameron JL, Sohn TA et al. Six hundred fifty consecutive pancreaticoduodenectomies in the 1990s: Pathology, complications, and outcomes. Ann Surg 1997; 226: 248–257; discussion 257-60.
Breslin TM, Hess KR, Harbison DB et al. Neoadjuvant chemoradiotherapy for adenocarcinoma of the pancreas: Treatment variables and survival duration. Ann Surg Oncol 2001; 8: 123–32.
Bouvet M, Ellis LM, Nishizaki M et al. Adenovirus-mediated wildtype p53 gene transfer down-regulates vascular endothelial growth factor expression and inhibits angiogenesis in human colon cancer. Cancer Res 1998; 58: 2288–92.
Kuo TH, Kubota T, Watanabe M et al. Site-specific chemosensitivity of human small-cell lung carcinoma growing orthotopically compared to subcutaneously in SCID mice: The importance of orthotopic models to obtain relevant drug evaluation data. Anticancer Res 1993; 13: 627–30.
Schwarz RE, McCarty TM, Peralta EA et al. An orthotopic in vivo model of human pancreatic cancer. Surgery 1999; 126: 562–7.
Fu X, Guadagni F, Hoffman RM. A metastatic nude-mouse model of human pancreatic cancer constructed orthotopically from histologically intact patient specimens. Proc Natl Acad Sci USA 1992; 89: 5645–9.
Morioka CY, Saito S, Ohzawa K, Watanabe A. Homologous orthotopic implantation models of pancreatic ductal cancer in Syrian golden hamsters: Which is better for metastasis research-cell implantation or tissue implantation? Pancreas 2000; 20: 152–7.
Reyes G, Villanueva A, Garcia C et al. Orthotopic xenografts of human pancreatic carcinomas acquire genetic aberrations during dissemination in nude mice. Cancer Res 1996; 56: 5713–9.
Yang M, Baranov E, Jiang P et al. Whole-body optical imaging of green fluorescent protein-expressing tumors and metastases. Proc Natl Acad Sci USA 2000; 97: 1206–11.
Bouvet M, Wang J, Nardin SR et al. Real-time optical imaging of primary tumor growth and multiple metastatic events in a pancreatic cancer orthotopic model. Cancer Res 2002; 62: 1534–40.
Matz MV, Fradkov AF, Labas YA et al. Fluorescent proteins from nonbioluminescent Anthozoa species. Nat Biotechnol 1999; 17: 969–73.
Bouvet M, Yang M, Nardin S et al. Chronologically-specific metastatic targeting of human pancreatic tumors in orthotopic models. Clin Exp Metastasis 2000; 18: 213–8.
Yang M, Baranov E, Wang JW et al. Direct external imaging of nascent cancer, tumor progression, angiogenesis, and metastasis on internal organs in the fluorescent orthotopic model. Proc Natl Acad Sci USA 2002; 99: 3824–9.
Alves F, Contag S, Missbach M et al. An orthotopic model of ductal adenocarcinoma of the pancreas in severe combined immunodeficient mice representing all steps of the metastatic cascade. Pancreas 2001; 23: 227–35.
Hoffman RM. Green fluorescent protein imaging of tumor growth, metastasis, and angiogenesis in mouse models. Lancet Oncol 2002; 3: 546–56.
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Katz, M.H., Takimoto, S., Spivack, D. et al. An imageable highly metastatic orthotopic red fluorescent protein model of pancreatic cancer. Clin Exp Metastasis 21, 7–12 (2004). https://doi.org/10.1023/B:CLIN.0000017160.93812.3b
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DOI: https://doi.org/10.1023/B:CLIN.0000017160.93812.3b