Urinary bladder cancer: a translational research program

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.

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.

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.