Annual Report 2018
Division of Cancer Pathophysiology
Yasuhito Uezono, Kanako Miyano, Sadamoto Zenda, Sei Manabe, Miki Nonaka, Miaki Uzu, Junko Ezuka, Kiyoshi Terawaki, Katsuya Ohbuchi, Chika Miyagi, Tohru Yokoyama, Satoshi Murakami, Hideya Kokubun, Shigeto Hirayama, Yoshiyuki Nagumo, Seiji Shiraishi, Yuriko Fujii, Daisuke Nakayama, Yoshiyuki Meguro, Yui Kuroda, Akane Komatsu, Katsuyuki Oki, Yuji Shimogawa, Yasuhiro Nose, Seiichi Yoshihara, Kurumi Kishimoto
Introduction
Since its establishment in January 2009, the Division of Cancer Pathophysiology has focused on two major research issues regarding 1) the improvement of the quality of life (QOL) of patients with cancer suffering from severe or intolerable pain, and 2) the prevention and development of novel treatments for cancer cachexia symptoms. On the basis of the Second Basic Plan to Promote Cancer Control Programs since 2016, basic to clinical, and clinical to basic translational collaborative research with the clinical laboratory groups comprises our main research protocols and has been ongoing. Since 2015, the chief of this division holds both the posts in the Division of Supportive Care Research in the Exploratory Oncology Research and Clinical Trial Center (EPOC) (for phase I clinical study) and the Innovation Center for Supportive, Palliative and Psychosocial Care at the NCCH (for phase II and III clinical studies), to accelerate the development of innovative medicines for cancer patients.
The Team and What We Do
A weekly conference/research seminar is held with all members including laboratory staff, graduate and undergraduate students at the Division of Cancer Pathophysiology.
Research activities
1. Translational research to innovate new strategies to improve pain analgesia in cancer patients
The aim of our studies is to develop new therapies for chemotherapy-induced peripheral neuropathy and refractory cancer pain, both of which make the QOL of cancer patients even worse. One of the targets is oral stomatitis induced by chemotherapy and/or radiotherapy.
Cancer patients who undergo chemotherapy, radiotherapy and terminal palliative care often have a wide range of stomatitis, which induces severe pain and limits the fundamental basics of life such as eating, drinking, and talking. Since 2015, we have been developing a new painkiller drug for stomatitis, namely "compound X". Based on our research results, the new painkiller compound X was found to remove oral pain without changing the texture and taste of food. The project was supported intellectually and financially by the Project Promoting Support for Drug Discovery from the Japan Agency for Medical Research and Development (AMED). The compound X has been successfully licensed out to a pharmaceutical company, Maruho Co. Ltd.
The second target is chronic and intolerable pain. In collaboration with the Department of Lipid Signaling and the National Center for Global Health and Medicine (NCGM), we discovered that knocking out of inducible platelet-activating factor (PAF) synthase type 2 suppressed neuropathic pain. We are working together to find novel PAF receptor and PAF synthase antagonists with the support of the Project for Cancer Research and Therapeutic Evolution (P-CREATE) from AMED. Accordingly, we found several specific antagonists for PAF synthase type 2 and are collaborating with a pharmaceutical company.
2. Prevention and decrease of the cachexic symptoms by orexigenic hormone acylghrelin and des-acyl ghrelin
We established novel cancer cachexia animal models, and then undertook molecular and cellular analyses to identify the mechanisms of action of the expected compounds to improve the QOL of patients suffering from cancer cachexia. We found that both acylghrelin and des-acylghrelin, which is removed acyl residue from ghrelin, improved cachexia-induced cardiac dysfunction in a mouse model. Also, we identified a novel receptor specific for desacylghrelin, supposed to be a novel target for drug innovation.
Education
Two postdoctoral fellows, three graduates, three master's degree and 22 undergraduate students have been trained in the field of cancer, supportive and palliative care at the Division of Cancer Pathophysiology.
Future prospects
The goal of the Division of Cancer Pathophysiology is to improve the QOL of cancer patients, hopefully by overcoming unmet medical needs.
List of papers published in 2018
Journal
1. Okubo R, Noguchi H, Hamazaki K, Sekiguchi M, Kinoshita T, Katsumata N, Narisawa T, Uezono Y, Xiao J, Matsuoka YJ. Fear of cancer recurrence among breast cancer survivors could be controlled by prudent dietary modification with polyunsaturated fatty acids. J Affect Disord, 245:1114-1118, 2019
2. Sato H, Uzu M, Kashiba T, Fujiwara T, Hatakeyama H, Ueno K, Hisaka A. Trichostatin A modulates cellular metabolism in renal cell carcinoma to enhance sunitinib sensitivity. Eur J Pharmacol, 847:143-157, 2019
3. Kokubun H, Takigawa C, Miyano K, Uezono Y. A Novel Method for Determination of Methadone in the Serum by High-Performance Liquid Chromatography with Electrochemical Detection. Biol Pharm Bull, 41:649-651, 2018
4. Arase K, Hashimoto H, Sonoda S, Ueno H, Saito R, Motojima Y, Yoshimura M, Maruyama T, Hirata K, Uezono Y, Ueta Y. Possible involvement of central oxytocin in cisplatin-induced anorexia in rats. J Physiol Sci, 68:471-482, 2018
5. Uzu M, Sin WC, Shimizu A, Sato H. Conflicting Roles of Connexin43 in Tumor Invasion and Growth in the Central Nervous System. Int J Mol Sci, 19:2018
6. Horishita T, Yanagihara N, Ueno S, Okura D, Horishita R, Minami T, Ogata Y, Sudo Y, Uezono Y, Kawasaki T. The neurosteroid allopregnanolone sulfate inhibits Nav13 alpha subunit-containing voltage-gated sodium channels, expressed in Xenopus oocytes. J Pharmacol Sci, 137:93-97, 2018
7. Meguro Y, Miyano K, Hirayama S, Yoshida Y, Ishibashi N, Ogino T, Fujii Y, Manabe S, Eto M, Nonaka M, Fujii H, Ueta Y, Narita M, Sata N, Yada T, Uezono Y. Neuropeptide oxytocin enhances mu opioid receptor signaling as a positive allosteric modulator. J Pharmacol Sci, 137:67-75, 2018
8. Miyano K, Nonaka M, Uzu M, Ohshima K, Uezono Y. Multifunctional Actions of Ninjinyoeito, a Japanese Kampo Medicine: Accumulated Scientific Evidence Based on Experiments With Cells and Animal Models, and Clinical Studies. Front Nutr, 5:93, 2018
9. Komatsu T, Katsuyama S, Uezono Y, Sakurada C, Tsuzuki M, Hamamura K, Bagetta G, Sakurada S, Sakurada T. Possible involvement of the peripheral Mu-opioid system in antinociception induced by bergamot essential oil to allodynia after peripheral nerve injury. Neurosci Lett, 686:127-132, 2018
10. Okubo R, Noguchi H, Hamazaki K, Sekiguchi M, Kinoshita T, Katsumata N, Narisawa T, Uezono Y, Xiao J, Matsuoka YJ. Association between blood polyunsaturated fatty acid levels and depressive symptoms in breast cancer survivors. Prostaglandins Leukot Essent Fatty Acids, 139:9-13, 2018
11. Sudo Y, Otsuka H, Miyakawa R, Goto A, Kashiwase Y, Terawaki K, Miyano K, Hirao Y, Taki K, Tagawa R, Kobayashi M, Okita N, Uezono Y, Higami Y. Differential Metabolic Responses to Adipose Atrophy Associated with Cancer Cachexia and Caloric Restriction in Rats and the Effect of Rikkunshito in Cancer Cachexia. Int J Mol Sci, 19:2018
12. Kokubun Hideya, Honma Masashi, Miyano Kanako, Uezono Yasuhito. A Novel Method for Determination of Tapentadol in the Serum of Cancer Patients by High-performance Liquid Chromatography with Electrochemical Detection. Jpn.J.Pham.Palliat. Care Sci. 11:131-133, 2018
13. Terawaki K, Kashiwase Y, Uzu M, Nonaka M, Sawada Y, Miyano K, Higami Y, Yanagihara K, Yamamoto M, Uezono Y. Leukemia inhibitory factor via the Toll-like receptor 5 signaling pathway involves aggravation of cachexia induced by human gastric cancer-derived 85As2 cells in rats. Oncotarget, 9:34748-34764, 2018
14. Yokoyama T, Terawaki K, Minami K, Miyano K, Nonaka M, Uzu M, Kashiwase Y, Yanagihara K, Ueta Y, Uezono Y. Modulation of synaptic inputs in magnocellular neurones in a rat model of cancer cachexia. J Neuroendocrinol, 30:e12630, 2018
Book
1. Uezono Y, Miyano K. Visceral hypersensitivity in functional dyspepsia (FD) - Therapeutic approaches to FD based on suppression of visceral hypersensitivity. In: Tominaga T, Kusunoki H (ed), Functional Dyspepsia: Evidences in Pathophysiology and Treatment, Singapore, Springer Singapore, pp 167-178, 2018