eRapport

Urinary bladder cancer: a translational research program

Prosjekt
Prosjektnummer
46022500
Ansvarlig person
Chun Mei Zhao
Institusjon
NTNU, IKM
Prosjektkategori
Forskerstipend 2008
Helsekategori
Cancer
Forskningsaktivitet
5. Treatment Developement
Rapporter
2010 - sluttrapport
In the AY-27 cell implant model, more than 4,000 genes were found to be differentially expressed and 24 KEGG pathways were differentially regulated in bladder cancer, of which 11 were concordant between rats and humans (both non-muscle-invasive and muscle-invasive tumors). Eleven of the 24 pathways were associated with host immune responses. The active pathways that are related with immunosurveillance included activation of antigen processing and presentation, T cell receptor signaling pathway, natural killer cell mediated cytotoxicity, Toll-like receptor signaling pathway, and B cell receptor signaling pathways. Moreover, cell adhesion molecules associated with the immune system were up-regulated and those associated with the neural system were down-regulated. The altered pathways and morphogenesis of the rat model corresponded more closely with those of human muscle-invasive rather than non-muscle-invasive tumors. Analysis by electron microscopy revealed a unique ultrastructure displaying microvillus-formed niches in small areas within the tumor of both rats and humans. These niches were interconnected with desmosomes between cancer cells, and in addition it was noted that niches were without infiltration of lymphocytes. siRNA in vivo showed that the labelled siRNA was highly accumulated in the cancer cells as early as 12 hours and remained so at least for 24 hours after a single dose. Potential targets for siRNA therapy in both animals and humans were proposed. The orthotopic rat bladder cancer model mimicked human bladder cancer with respect to gene expression profile and morphogenesis, especially with that of muscle-invasive human tumors. The host immune response, in the form of immunosurveillance, was fully active, but the tumor escaped by establishing the cancer stem cell niche which was formed by microvilli. The established siRNA delivery model could be used for evaluation of therapeutic strategies for urothelial carcinoma in the native organ, where hormonal, neural and immunological processes more closely resemble the clinical situation.
2009
The project has been carried out according to the plan and much advanced by utilizing the newly developed technology, such as iTRAQ and siRNA in 2009. The findings that have been published or are going to be published are original. This project will have great potentials for clinically understanding the bladder cancer and for development of evidence-based therapeutic strategies for the bladder cancer.1: Gene expression profiling and pathway analysis of superficial bladder cancer in rats We studied the bladder cancer by the state-of-the-art technology Affymetrix GeneChip with a newly developed bioinformatics program for the Kyoto Encyclopedia of Genes and Genomes (KEGG). The results have been presented in Bioinformatics Forum for Young Scientists at Trondheim, Kirurgisk Høstmøte I Oslo, European Urology Conference in Stockholm. The manuscript was published in Urology, one of the best international peer-reviewed journals in the field of urology (Article in Press doi:10.1016/j.urology.2009.03.008) by Arum CJ, Anderssen E, Tømmerås K, Lundgren S, Chen D, Zhao CM. 2: Cancer immunoediting from immunosurveillance to tumour escape in microvillus-formed niche. A study of syngeneic orthotopic rat bladder cancer model in comparison with human bladder cancer We have tested the “cancer immunoediting” hypothesis by means of bioinformatics and morphology. A manuscript reporting these results has been submitted to Neoplasia, one of the best journals in the field of cancer research. The reviewers have marked this study with very high degrees of originality and significance. The editor of this journal invites us to submit the revised version before Feb. 21, 2010 for consideration of publication. The authors are Carl-Jørgen Arum, Endre Anderssen, Trond Viset, Yosuke Kodama, Steinar Lundgren, Duan Chen and Chun-Mei Zhao. 3. Characterization of genotype-phenotype correlation in rat model of bladder cancer We have completed a comprehensive animal experiment in which more than 200 rats were included. The newly developed state-of-the-art technology, Illumina (genomics), iTRAQ (proteomics) and the best standard histology (pathology and immunohistochemistry) are being used. According to the plan, the data analysis will be completed in the spring and the manuscript will be ready during the summer period. It is our ambitious to make this study to be published in the top journals in 2010. 4. Gene expression profiling and pathway analysis of transgenic mouse model of bladder cancer In collaboration with New York University, we have established the transgenic mouse model of bladder cancer in our laboratory; verified by genotyping (Real time-PCR) and phenotyping (pathology). The bladder samples have been collected from both wild-type and transgenic mice for Illumina analysis. A manuscript will be prepared afterwards for publication. 5. A rat model of intravesical delivery of small interfering RNA for studying urinary bladder cancer We have established i) rat models of in vivo delivery of siRNA into bladder cancer, and ii) potential targets for siRNA in this study. A manuscript reporting these results has been submitted for publication in World Journal of Urology, one of the best journals in the field of urology research. The paper is currently under review process. The are Carl-Jørgen Arum, Yosuke Kodama, Natale Rolim, Marius Widerøe, Endre Andessen, Trond Viset, Marit Otterlei, Steinar Lundgren, Duan Chen, and Chun-Mei Zhao. 6. Intracellular mechanism behind the novel photodynamic therapy (PDT). An in vitro study. Last year, we published the article entitled “Monitoring of hexyl 5-aminolevulinate-induced photodynamic therapy in rat bladder cancer by optical spectroscopy by Eivind L.P. Larsen, Lise L. Randeberg, Odrun A. Gederaas, Carl-Jørgen Arum, Chun-Mei Zhao, Duan Chen, Astrid Hjelde, Hans E. Krokan, Dag R. Hjelme, Lars O. Svaasand.” in Journal of Biomedical Optics. In a follow-up study, we have to perform a detailed analysis of ultrastructural changes in response to the PDT with focusing on the formation of lipofucin bodies. A manuscript will be prepared in the near future for publication. 7. Teaching activities I have been co-supervisor for PhD students Carl-Jørgen Arum and Yosuke Kodama and supervisor in PBL for medical students through 2009. I am also involved in Linda Helander’s PhD work on bladder cancer.
2008
This 3-year project has been carried out for one year (started on January, 2008). The following is a summary of up-dated results with respect to experiments and publications according to the original project description.1) Gene expression profiling and pathway analysis of superficial bladder cancer in rats In this study, we have developed a rat model of bladder cancer and found >4,000 genes to be differentially expressed and 20 KEGG pathways actively involved in the bladder. Based on our results, we conclude that the bladder cancer developed aggressively; in spite of active host immune responses. Conceivably, the cancer immunoediting process is associated with the progression of bladder cancer in this model. These novel findings have been presented orally at the national conference of surgery in Oslo (20-24, Oct., 2008) and are pending for publication in Urology, one of the best journals in the field. Revised version has been submitted by Carl-Jørgen Arum, Endre Anderssen, Karin Tømmerås, Steiner Lundgren, Duan Chen, Chun-Mei Zhao. 2) Gene expression profiles of bladder cancer: comparison between orthotopic rat bladder cancer model and human bladder cancer patients In this study, we have made a further comparison between our model and human patients using bioinformatics approach, revealing that our model mimics very well the human bladder cancer. The preliminary results will be presented in European Urology conference in Stockholm 2009. The manuscript is in the preparation for submission for publication. 3) Monitoring of hexyl 5-aminolevulinate-induced photodynamic therapy in rat bladder cancer by optical spectroscopy In this study, we have used our rat model for testing a newly developed treatment of hexyl-ALA PDT by Dept. of Telecommunication, NTNU. The results have been published by Journal of Biomedical Optics, one of the best journals in biophysics. 4) Gene expression profiling and pathway analysis of genetically manipulated mouse model of bladder cancer In collaboration with the New York University, we have established a transgenic mouse model of bladder cancer at Trondheim. Genotyping and phenotyping of these mice are being performed in collaboration with NTNU FUGE microarray platform. 5) Genomic and proteomic analysis of chemically-induced bladder cancer in rats In collaboration with Nanjing Medical University, we are conducting the same animal experiment in Trondheim and Nanjing in order to have a reproducible animal model and enough samples for both genomic and proteomic analyses. The animal experiments include more than 200 rats for a period of 10 months and are going to be finished by August 2009.
Vitenskapelige artikler
Arum Carl-Jørgen, Anderssen Endre, Viset Trond, Kodama Yosuke, Lundgren Steinar, Chen Duan, Zhao Chun-Mei

Cancer immunoediting from immunosurveillance to tumor escape in microvillus-formed niche: a study of syngeneic orthotopic rat bladder cancer model in comparison with human bladder cancer.

Neoplasia 2010 Jun;12(6):434-42.

PMID: 20563246

Arum Carl-Jørgen, Kodama Yosuke, Rolim Natale, Widerøe Marius, Anderssen Endre, Viset Trond, Otterlei Marit, Lundgren Steinar, Chen Duan, Zhao Chun-Mei

A rat model of intravesical delivery of small interfering RNA for studying urinary carcinoma.

World J Urol 2010 Aug;28(4):479-85. Epub 2010 apr 8

PMID: 20376453

Arum Carl-Jørgen, Anderssen Endre, Tømmerås Karin, Lundgren Steiner, Chen Duan, Zhao Chun-Mei

Gene expression profiling and pathway analysis of superficial bladder cancer in rats.

Urology 2010 Mar;75(3):742-9. Epub 2009 aug 3

PMID: 19647301

Larsen Eivind L P, Randeberg Lise L, Gederaas Odrun A, Arum Carl-Jørgen, Hjelde Astrid, Zhao Chun-Mei, Chen Duan, Krokan Hans E, Svaasand Lars O

Monitoring of hexyl 5-aminolevulinate-induced photodynamic therapy in rat bladder cancer by optical spectroscopy.

J Biomed Opt 2008 Jul-Aug;13(4):044031.

PMID: 19021358

Arum C, Gederas O, Larsen Ø, Anderssen E, Zhao CM

Forsøk med Hexyl-5-Aminoleuvinnate inducert fotodynamisk behandling på blærecancer i rottemodeller

Norsk Kirurgisk Forening Høstmøte 2009, møte supplement

Arum C, Anderssen E, Tømmerås K, Zhao CM, Chen D

Gene expression profiles of bladder cancer: comparison between orthotopic rat bladder cancer model and human bladder cancer

European Association of Urology, annual meeting Stockholm 2009, meeting supplement

Arum, Carl-Jørgen; Anderssen, Endre; Zhao, Chun-Mei; Chen, Duan.

Gene expression profiles of bladder cancer: Comparison between rat bladder cancer model and human bladder cancer patients.

Bioinformatics Forum for Young Scientists; 2009-04-24 - 2009-04-26

Arum, Carl-Jørgen; Anderssen, Endre; Tømmerås, Karin; Zhao, Chun-Mei; Chen, Duan.

VERTSIMMUNRESPONS TIL UROTELIALKREFTCELLEINVASJON: DNA MIKROARRAY OG PATHWAY ANALYSE AV ORTOTOPISK ROTTEBLÆREKREFTMODELL.

Kirurgisk Høstmøte 2008; 2008-10-20 - 2008-10-24

eRapport er utarbeidet av Sølvi Lerfald og Reidar Thorstensen, Regionalt kompetansesenter for klinisk forskning, Helse Vest RHF, og videreutvikles av de fire RHF-ene i fellesskap, med støtte fra Helse Vest IKT

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