Dual-color imaging of nascent blood vessels vascularizing pancreatic cancer in an orthotopic model demonstrates antiangiogenesis efficacy of gemcitabine.

BACKGROUND The stem cell marker nestin recently has been shown to be expressed in nascent blood vessels in nestin-driven green fluorescent protein (ND-GFP) transgenic nude mice. MATERIALS AND METHODS In the present study, we visualized by dual-color fluorescence imaging tumor angiogenesis in the ND-GFP transgenic nude mice after orthotopic transplantation of the MIA PaCa-2 human pancreatic cancer line expressing red fluorescent protein. Mice were treated with gemcitabine at 150 mg/kg/dose on days 3, 6, 10, and 13 after tumor implantation. At day 14, mice were sacrificed and mean nascent blood vessel density and tumor volume were calculated and compared to control mice. RESULTS Nestin was highly expressed in proliferating endothelial cells and nascent blood vessels in the growing tumor. Results of immunohistochemical staining showed that CD31 co-localized in ND-GFP-expressing nascent blood vessels. The density of nascent blood vessels in the tumor was readily quantitated. Gemcitabine significantly decreased the mean nascent blood vessel density in the tumor as well as decreased tumor volume. CONCLUSION The dual-color model of the ND-GFP nude mouse orthotopically implanted with RFP-expressing pancreatic tumor cells enabled the simultaneous visualization and quantitation of tumor angiogenesis and tumor volume. These results demonstrated for the first time that gemcitabine is an inhibitor of angiogenesis as well as tumor growth in pancreatic cancer. The results have important implications for the clinical application of gemcitabine in this disease.

[1]  J. Folkman.  Role of angiogenesis in tumor growth and metastasis. , 2002, Seminars in oncology.

[2]  Robert M Hoffman,et al.  A novel red fluorescent protein orthotopic pancreatic cancer model for the preclinical evaluation of chemotherapeutics. , 2003, The Journal of surgical research.

[3]  Meng Yang,et al.  Nestin-linked green fluorescent protein transgenic nude mouse for imaging human tumor angiogenesis. , 2005, Cancer research.

[4]  R. Kerbel,et al.  Metronomic Low-Dose Chemotherapy Boosts CD95-Dependent Antiangiogenic Effect of the Thrombospondin Peptide ABT-510: A Complementation Antiangiogenic Strategy , 2005, Clinical Cancer Research.

[5]  M. Tempero,et al.  Treatment of metastatic pancreatic cancer. , 2005, Journal of the National Comprehensive Cancer Network : JNCCN.

[6]  A. Addeo,et al.  Circulating vascular endothelial growth factor and interferon-gamma-inducible protein-10 levels in pancreatic cancer during chemotherapy. , 2005, Anticancer research.

[7]  K. Katsuoka,et al.  Hair follicle-derived blood vessels vascularize tumors in skin and are inhibited by Doxorubicin. , 2005, Cancer research.

[8]  Xia Zhao,et al.  Combination of Low-Dose Gemcitabine and Recombinant Quail Vascular Endothelial Growth Factor Receptor-2 as a Vaccine Induces Synergistic Antitumor Activities , 2005, Oncology.

[9]  L. Ellis,et al.  Inhibition of growth and metastasis of human pancreatic cancer growing in nude mice by PTK 787/ZK222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases. , 2001, Cancer biotherapy & radiopharmaceuticals.

[10]  K. Katsuoka,et al.  Nascent blood vessels in the skin arise from nestin-expressing hair-follicle cells. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Lin Jia,et al.  Antiangiogenic therapy for human pancreatic carcinoma xenografts in nude mice. , 2005, World journal of gastroenterology.

[12]  Meng Yang,et al.  Antimetastatic efficacy of adjuvant gemcitabine in a pancreatic cancer orthotopic model , 2004, Clinical & Experimental Metastasis.

[13]  F. Guadagni,et al.  A metastatic nude-mouse model of human pancreatic cancer constructed orthotopically with histologically intact patient specimens. , 1992, Proceedings of the National Academy of Sciences of the United States of America.