Annual Report 2018
Division of Carcinogenesis and Cancer Prevention(Environmental Carcinogenesis and Cancer Prevention Group)
Yukari Totsuka, Yutaka Shoji, Haruna Sato, Yuya Maesako, Syouma Kamio, Shungo Saito, Michihiro Mutoh, Gen Fujii, Takahiro Hamoya, Yurie Kurokawa, Maiko Takahashi, Yui Matsuzawa, Kohei Miki, Takahiro Teruya, Ken-ichi Yoshioka, Yusuke Matsuno, Haruka Fujimori, Mai Hyodo
Introduction
Cancer is a disease associated with aging and environmental risk factors. It is well known that chemical substances form DNA adducts, which are considered to be a 'trigger' of mutagenesis. As cancer risk elevates in association with aging, genomic destabilization frequently arises in the cells of the elderly, which is associated with the impairment of DNA repair functions. The aims of our research projects are exploration of novel cancer etiology via identification of DNA adducts that are important for human cancer development, and clarification of the mechanisms for genomic instability associated with aging. On the other hand, cancer chemoprevention is one of the preemptive approaches that is strongly expected to reduce cancer morbidity and mortality. We are working to develop novel candidates for cancer chemopreventive agents and aim for their practical application using the concept of drug repositioning.
The Team and What We Do
1. Establishment of novel genotoxicity evaluation systems suitable for nanomaterials / Exploration of cancer etiology using whole genome/exome analysis and comprehensive DNA adduct analysis. (Totsuka group)
2. Studying mechanistic aspects of genome destabilization and the associated effects on mutation induction and the resulting clonal evolution. This group also studies mechanisms to maintain genome stability. (Yoshioka group)
3. Prevention of colorectal cancer. (Mutoh group)
Research activities
1. Establishment of novel genotoxicity evaluation systems suitable for nanomaterials based on nanotoxicologic mechanisms (Totsuka group)
Inflammatory responses via macrophage phagocytosis can be considered as one of the mechanisms for the genotoxic action of nanomaterials. To establish an evaluation system based on the nanotoxicology mechanisms, we examined genotoxicity induced by nanomaterials using a co-culture system of GDL1 cells and a murine macrophage, RAW264.7. GDL1 cells were cultured with RAW264.7 and exposed to multiwalled carbon nanotube (MWCNT) then the gpt mutations were analyzed. Mutation frequency induced by MWCNT was significantly increased by coexistence of RAW264.7 compared with singly cultured GDL1. Moreover, mutation spectra observed in the co-culture system were distinguished from the single-culture system, but similar to those observed in mice lungs exposed to nanomaterials. Based on these findings, it is indicated that novel in vitro assay featuring a co-culture system of tissue resident cells with immune cells is suitable to evaluate the genotoxicity of nanomaterials.
2. Genomic destabilization risk increased by radiation (Yoshioka group)
Radiation exposure that primarily causes multiple types of DNA damage is associated with cancer risk. However, it is still elusive which types of damage increase due to radiation that are associated with cancer risk. Here we found that replication stress-associated DSBs that increased due to radiation was associated with genomic destabilization risk with the associated mutation induction. This further leads to clonal evolution of cells abrogating their defense systems.
3. Prevention of colorectal cancer (Mutoh group)
Familial adenomatous polyposis (FAP) patients are a well-known high-risk group with colorectal cancer (CRC). We are evaluating the usefulness and safety of thorough endoscopic polypectomy and of cancer chemopreventive agents in FAP patients. Based on these findings, we are trying to clarify the underlying mechanism of colorectal carcinogenesis in a laboratory study. Moreover, we are searching for novel chemopreventive agents against CRC using a high-throughput screening approach and animal models of FAP.
Education
Ten undergraduate and graduate students in local universities worked as trainees in our lab and had cancer research training.
Future prospects
- Establishment of novel genotoxicity evaluation systems suitable for nanomaterials / Explore the novel cancer etiology using whole genome analysis and comprehensive DNA adduct analysis
- Uncover the elevation genomic destabilization risk by radiation exposure and establish a strategy to block the cancer risk.
- Develop novel candidates for cancer chemopreventive agents and aim for their practical application
List of papers published in 2018
Journal
1. Fukai E, Sato H, Watanabe M, Nakae D, Totsuka Y. Establishment of an in vivo simulating co-culture assay platform for genotoxicity of multi-walled carbon nanotubes. Cancer Sci, 109:1024- 1031, 2018
2. Toyoda T, Totsuka Y, Matsushita K, Morikawa T, Miyoshi N, Wakabayashi K, Ogawa K. gamma-H2AX formation in the urinary bladder of rats treated with two norharman derivatives obtained from o-toluidine and aniline. J Appl Toxicol, 38:537-543, 2018
3. Shimizu A, Fujimori H, Minakawa Y, Matsuno Y, Hyodo M, Murakami Y, Yoshioka KI. Onset of deaminase APOBEC3B induction in response to DNA double-strand breaks. Biochem Biophys Rep, 16:115-121, 2018
4. Matsuno Y, Hyodo M, Fujimori H, Shimizu A, Yoshioka KI. Sensitization of Cancer Cells to Radiation and Topoisomerase I Inhibitor Camptothecin Using Inhibitors of PARP and Other Signaling Molecules. Cancers (Basel), 10:2018
5. Hori M, Mutoh M, Ishigamori R, Imai T, Takahashi M. Activated Ductal Proliferation Induced by N-Nitrosobis (2-oxopropyl)amine in Fat-infiltrated Pancreas of KK-A(y) Mice. In Vivo, 32:499-505, 2018
6. Takahashi M, Hori M, Ishigamori R, Mutoh M, Imai T, Nakagama H. Fatty pancreas: A possible risk factor for pancreatic cancer in animals and humans. Cancer Sci, 109:3013-3023, 2018
7. Terasaki M, Ogawa Y, Endo T, Maeda H, Hamada J, Osada K, Miyashita K, Mutoh M. Glycine Is a Predictor for a Suppressive Effect of Fucoxanthinol on Colonosphere Formation Under Hypoxia. Anticancer Res, 38:2169-2179, 2018
8. Kawano A, Ishikawa H, Mutoh M, Kubota H, Matsuda K, Tsuji H, Matsumoto K, Nomoto K, Tanaka R, Nakamura T, Wakabayashi K, Sakai T. Higher enterococcus counts indicate a lower risk of colorectal adenomas: a prospective cohort study. Oncotarget, 9:21459-21467, 2018
9. Terasaki M, Mima M, Kudoh S, Endo T, Maeda H, Hamada J, Osada K, Miyashita K, Mutoh M. Glycine and succinic acid are effective indicators of the suppression of epithelial-mesenchymal transition by fucoxanthinol in colorectal cancer stem-like cells. Oncol Rep, 40:414-424, 2018