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American Family Children's Hospital
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Scientific Accomplishments

William Dove, PhD – Cancer Genetics Program

Dr. Dove’s research team developed the Pirc rat as an alternative animal model of colon cancer. The Pirc rat harbors an ENU-induced mutation in Apc and develops macroadenomas and locally invasive adenocarcinomas of the colon at a high incidence (Figure 1; paraffin sections and H&E stained slides prepared by EPL). Importantly, the distribution of colon tumors in the intestinal tract of the Pirc rat closely resembles that of humans.

 

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Figure 1: Amos-Landgraf JM, Kwong LN, Kendziorski CM, Reichelderfer M, Torrealba J, Weichert J, Haag JD, Chen KS, Waller JL, Gould MN, Dove WF. A target-selected Apc-mutant rat kindred enhances the modeling of familial human colon cancer. Proc Natl Acad Sci USA. 2007;104(10):4036-41. PMCID: PMC1805486.

 

H&E stained slides (panels A-E) demonstrate invasion into the tumor stalk (A, B) and high grade dysplasia (C) in the Pirc rat tumors. Immunofluoresence staining for b-catenin reveals increased nuclear and cytoplasmic b-catenin in tumor cells in larger tumors (F, G) and in microadenomas (I, J). H&E stained tissues corresponding to the immunofluoresence images are shown in E and H.

 

 

Shannon Kenney, M.D. – Human Cancer Virology Program 

Dr. Kenney‘s team investigated the role of lytic viral infection in EBV pathogenesis and tumorigenesis in a new humanized NOD/LtSz- scid/IL2Rγnull (hNSG) mouse model that provides a more realistic immune background for EBV infection (Figure 2; paraffin sections prepared by EPL and H&E stained by EPL). Infection appeared well controlled in some animals, but others eventually developed CD20+ diffuse large B cell lymphomas (DLBCL; tumors occurred more commonly in control vs. replication defective virus infected animals. Dr. Sullivan served as the consulting pathologist and co-author for this study.

 

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Figure 2: Ma SD, Hegde S, Young KH, Sullivan R, Rajesh D, Zhou Y, Jankowska-Gan E, Burlingham WJ, Sun X, Gulley ML, Tang W, Gumperz JE, Kenney SC. A new model of Epstein-Barr virus infection reveals an important role for early lytic viral protein expression in the development of lymphomas. J Virol. 2011;85(1):165- 77. PMCID: PMC3014199. 

 

EBV-positive cells travel to specific regions of the reconstituted mouse spleen. H&E, EBV, CD20, CD3, and Ki67 staining was performed on spleen. EBV-positive cells were primarily located in the CD20-rich lymphoid zones (outlined with hatches) of the spleen.

 

 

Patricia Keely, PhD – Tumor Microenvironment Program

Advanced microscopy and analysis methods allow a wealth of molecular information to be obtained optically from tissues. Matthew Conklin, PhD of the Keely Laboratory has shown in paraffin sections prepared by the EPL that neoplastic tissue in the MMTV-PyVT mouse model of mammary cancer differs from nearby normal mammary epithelium in the intensity and lifetime of NADH and FAD (Figure 3). This finding is consistent with the underlying metabolic differences that generally exist in neoplastic vs normal tissue and may provide an optical marker of neoplastic transformation.

 

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Figure 3: Conklin MW, Provenzano PP, Eliceiri KW, Sullivan R, Keely PJ. Fluorescence lifetime imaging of endogenous fluorophores in histopathology sections reveals differences between normal and tumor epithelium in carcinoma in situ of the breast. Cell Biochem Biophys. 2009;53(3):145-57.

 

Fluorescence Lifetime Imaging Microscopy (FLIM) analysis of archived mouse samples: The fluorescent properties of normal and tumor epithelium differ. (A) H&E stained mouse mammary tumor showing normal and neoplastic tissues. (B) Fluorescence intensity image of the sequential unstained slide at 890nm excitation. (C) Color maps of the 1 (left) and 2 (right) components of the fluorescence lifetime, which illustrate the relatively longer lifetime values in tumor cells compared to normal epithelium. (D) Histogram analysis measuring the range of lifetime values of the two regions of interest drawn in (C) reveals the shift to longer lifetimes in tumor (red lines) cells compared to normal epithelium (color outline).