Annual Report 2021

Division of Cancer Pathophysiology

Minoru Narita, Kanako Miyano, Yukari Totsuka, Michiko Narita, Naoko Kuzumaki, Yusuke Hamada, Yukari Suda, Ichiro Inaba

Introduction

 A new cancer treatment is greatly needed not only for the eradication of cancer cells, but also for the establishment of next-generation cancer supportive and palliative care in the presence of cancer, due to the increasing number of cancer survivors. Particularly, cancer progression is markedly affected by individual differences in the patient cancer genome, and also by a history of non-cancer disease. Thus, an understanding of cancer pathology in the presence of non-cancer disease is important for the establishment of effective cancer treatment with high-quality cancer supportive care. Furthermore, cancer pathology must be studied by elucidating the brain-periphery linkage, because the peripheral nervous system is actively involved in cancer pathology in the tumor microenvironment. Therefore, in FY2021, we mainly analyzed the changes in cancer pathology associated with non-cancer diseases such as pain or basic health conditions. We also analyzed the changes in the properties of cancer cells and neuronal cells in tumor cell-neuron interaction.

Research activities

1) Analysis of cancer pathology and the peripheral immune system associated with pain and metabolic disorders:

 We found changes in tumor transplant and splenic immune cells, etc., in various types of pain models and high-fat diet diabetes models, and have been studying them in detail.

2) Analysis of human iPS cell-derived sensory neuron-human cancer cell interaction:

 We found that cultured cancer cells may be altered by the activation of iPS cell-derived sensory neurons, and that iPS cell-derived sensory neurons may be altered by substances derived from cancer cells.

3) Cohort study of cancer patients with severe pain:

 To understand the pathology of cancer patients at the molecular level using a cohort study and patient-derived biopsy samples, we have been planning to perfome research and applying to the ethics committee in collaboration with the Department of Palliative Medicine, National Cancer Center Hospital (NCCH).

4) Development of a novel in vitro genotoxicity study using mouse organoids:

 Exposure of food-borne carcinogens (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and acrylamide) to lung- and large intestine-derived organoids in transgenic mice was generally consistent with the results of an vivo study, indicating that the present experimental method is useful as a novel in vitro test system that mimics biological tissues.

Education

 We accepted 40 individuals from NCCH and collaborating universities (Juntendo University, Hoshi University, Tokyo University of Science, etc.) as partnering graduate students, external research staff and trainees, and provided them with research and education opportunities through paper publication and research presentation. Furthermore, two doctoral program students obtained a Ph.D. degree (doctor of pharmacy and doctor of medical science).

Future Prospects

 We mainly aim to reveal the molecular basis of cancer progression and prognosis through the global analysis of afferent-efferent networks based on neuron-immune cell-tumor cell interaction. Thus, we will follow through on a comprehensive phenomics analysis of neural network-mediated cancer pathology associated with the activation of sensory neurons. Furthermore, we will clarify the bidirectional modulatory action of cancer cells and neurons and its related changes in three-dimensional culture systems constructed from human iPS cell-derived sensory neurons and human cancer organoids. For these approaches, our goal is to establish a novel treatment method/supportive care/palliative care for cancer patients and cancer survivors.

List of papers published in 2021

Journal

1. Mizobuchi Y, Miyano K, Manabe S, Uezono E, Komatsu A, Kuroda Y, Nonaka M, Matsuoka Y, Sato T, Uezono Y, Morimatsu H. Ketamine Improves Desensitization of µ-Opioid Receptors Induced by Repeated Treatment with Fentanyl but Not with Morphine. Biomolecules, 12:426, 2022

2. Ueno T, Yatsuoka W, Ishiki H, Miyano K, Uezono Y. Effects of an oral mucosa protective formulation on chemotherapy- and/or radiotherapy-induced oral mucositis: a prospective study. BMC Cancer, 22:90, 2022

3. Mori T, Yamashita K, Takahashi K, Mano S, Sato D, Narita M. Characterization of the discriminative stimulus effect of quinpirole: Further evidence for functional interaction between central dopamine D1/D2-receptors. Pharmacology Biochemistry and Behavior, 213:173314, 2022

4. Sato D, Narita M, Hamada Y, Mori T, Tanaka K, Tamura H, Yamanaka A, Matsui R, Watanabe D, Suda Y, Senba E, Watanabe M, Navratilova E, Porreca F, Kuzumaki N, Narita M. Relief of neuropathic pain by cell-specific manipulation of nucleus accumbens dopamine D1- and D2-receptor-expressing neurons. Molecular Brain, 15:10, 2022

5. Sato D, Hamada Y, Narita M, Mori T, Tezuka H, Suda Y, Tanaka K, Yoshida S, Tamura H, Yamanaka A, Senba E, Kuzumaki N, Narita M. Tumor suppression and improvement in immune systems by specific activation of dopamine D1-receptor-expressing neurons in the nucleus accumbens. Molecular Brain, 15:17, 2022

6. Miyano K, Ikehata M, Ohshima K, Yoshida Y, Nose Y, Yoshihara SI, Oki K, Shiraishi S, Uzu M, Nonaka M, Higami Y, Uezono Y. Intravenous administration of human mesenchymal stem cells derived from adipose tissue and umbilical cord improves neuropathic pain via suppression of neuronal damage and anti-inflammatory actions in rats. PLOS ONE, 17:e0262892, 2022

7. Katsuda Y, Tanaka K, Mori T, Narita M, Takeshima H, Kondo T, Yamabe Y, Matsufuji M, Sato D, Hamada Y, Yamaguchi K, Ushijima T, Inada E, Kuzumaki N, Iseki M, Narita M. Histone modification of pain-related gene expression in spinal cord neurons under a persistent postsurgical pain-like state by electrocautery. Molecular Brain, 14:146, 2021

8. Takemura Y, Iwase Y, Hamada Y, Narita M, Yamashita K, Nakahama M, Suda Y, Miyano K, Yamazaki M, Kuzumaki N, Mori T, Narita M. Pharmacological Analysis of Hydromorphone Acting as a β-Arrestin-Nonpreferred Strong µ-Opioid Receptor Ligand. Japanese Journal of Pharmaceutical Palliative Care and Sciences, 14:83-89, 2021

9. Miyano K, Yoshida Y, Hirayama S, Takahashi H, Ono H, Meguro Y, Manabe S, Komatsu A, Nonaka M, Mizuguchi T, Fujii H, Higami Y, Narita M, Uezono Y. Oxytocin Is a Positive Allosteric Modulator of κ-Opioid Receptors but Not δ-Opioid Receptors in the G Protein Signaling Pathway. Cells, 10:2651, 2021

10. Miyano K, Hasegawa S, Asai N, Uzu M, Yatsuoka W, Ueno T, Nonaka M, Fujii H, Uezono Y. The Japanese Herbal Medicine Hangeshashinto Induces Oral Keratinocyte Migration by Mediating the Expression of CXCL12 Through the Activation of Extracellular Signal-Regulated Kinase. Frontiers in Pharmacology, 12:695039, 2021

11. Kuroda Y, Nonaka M, Kamikubo Y, Ogawa H, Murayama T, Kurebayashi N, Sakairi H, Miyano K, Komatsu A, Dodo T, Nakano-Ito K, Yamaguchi K, Sakurai T, Iseki M, Hayashida M, Uezono Y. Inhibition of endothelin A receptor by a novel, selective receptor antagonist enhances morphine-induced analgesia: Possible functional interaction of dimerized endothelin A and µ-opioid receptors. Biomedicine & Pharmacotherapy, 141:111800, 2021

12. Karaki F, Oki T, Sakao Y, Sato N, Hirayama S, Miyano K, Uezono Y, Fujii H. Identification of a Putative β-Arrestin Superagonist of the Growth Hormone Secretagogue Receptor (GHSR). ChemMedChem, 16:3463-3476, 2021

13. Karasawa Y, Miyano K, Fujii H, Mizuguchi T, Kuroda Y, Nonaka M, Komatsu A, Ohshima K, Yamaguchi M, Yamaguchi K, Iseki M, Uezono Y, Hayashida M. In Vitro Analyses of Spinach-Derived Opioid Peptides, Rubiscolins: Receptor Selectivity and Intracellular Activities through G Protein- and β-Arrestin-Mediated Pathways. Molecules, 26:6079, 2021

14. Kobayashi T, Toyoda T, Tajima Y, Kishimoto S, Tsunematsu Y, Sato M, Matsushita K, Yamada T, Shimamura Y, Masuda S, Ochiai M, Ogawa K, Watanabe K, Takamura-Enya T, Totsuka Y, Wakabayashi K, Miyoshi N. o-Anisidine Dimer, 2-Methoxy-N4-(2-methoxyphenyl) Benzene-1,4-diamine, in Rat Urine Associated with Urinary bladder Carcinogenesis. Chemical Research in Toxicology, 34:912-919, 2021

15. Komiya M, Ishigamori R, Naruse M, Ochiai M, Miyoshi N, Imai T, Totsuka Y. Establishment of Novel Genotoxicity Assay System Using Murine Normal Epithelial Tissue-Derived Organoids. Frontiers in Genetics, 12:768781, 2021

16. Totsuka Y, Watanabe M, Lin Y. New horizons of DNA adductome for exploring environmental causes of cancer. Cancer Science, 112:7-15, 2021