Annual Report 2020
Division of Cancer Pathophysiology
Minoru Narita, Kanako Miyano, Michiko Narita, Yusuke Hamada, Yukari Suda, Katsuya Ohbuchi, Ichiro Inaba.
Introduction
Since the number of cancer survivors has been increasing yearly because of recent improvements in cancer treatment, there is a strong need for the establishment of next-generation-related cancer supportive and palliative care that improves quality of life in individual cancer patients. Individual differences in cancer progression or susceptibility to anti-cancer drugs may be significantly affected by changes in the biological response to a history of non-cancer diseases, as well as by differences based on the genome background of the patient's cancer. Understanding the impact of an underlying non-cancer disease on cancer pathology is therefore an important key to advancing effective cancer treatment and high-quality cancer supportive care. The peripheral nerves have been reported to be actively involved in heterologous cell-cell interactions in the cancer microenvironment, and research into "cancer pathology-related sensing systems" that encompass brain-peripheral nerve linkages is now required. To analyze the occurrence and exacerbation of cancer in complex non-cancer diseases (pain diseases, diabetes mellitus, emotional disorders, etc.) with a neurological abnormal response, various animal models of non-cancer neurological disease were created and analyzed for cancer pathology after cancer cell transplantation by manipulating the activities of specific networks using neuroscience and genetic engineering technology. Furthermore, we are constructing an analysis of the interaction between human iPS cell-derived sensory nerve cells and human cancer tissue organoids using genetic engineering neuroactivity control technology.
Research activities
1) Analysis of cancer pathology due to pain
In a basic study on the effect of non-cancer pain stimuli on cancer pathology in animal models of pain disease, alterations in cancer conditions were observed with sustained pain. These results suggest that sustained stimulation of the sensory nerves associated with pain may affect the tumor microenvironment.
2) Analysis of cancer pathology in the development of metabolic disorders
We investigated the effects on cancer pathology using animal models of metabolic disease (e.g., leptin deficiency (ob/ob) model and leptin receptor deficiency (db/db) model). The results showed alterations in cancer pathology with hyperglycemia.
3) Analysis of cancer pathology in emotional disorders
We investigated the effect of artificially controlling the activity of the mesolimbic dopamine neural network for emotional control on tumor progression. Modulation of dopamine neurons in the ventral tegmental area resulted in alterations in cancer pathology.
4) Construction of an interaction analysis of human iPS cell-derived sensory neurons and human cancer tissue organoids
A method for inducing sensory neurons from human iPS cells has been established, and a co-culture system with human cancer tissue organoids is currently being developed.
Education
The NPA accepted four doctoral programs at the collaborating graduate school (Hoshi University), three doctoral programs at Hoshi University, and one master's course, and provided education on research and presentation materials.
Future Prospects
We will analyze heterologous cell linkages, including neuronal-immune-tumor cells, and conduct an integrated analysis of the "Cancer Pathology-related Sensing System" that encompasses the biosensory system and the afferent and efferent nerve networks. We will also perform an analysis of the interaction between human iPS cell-derived sensory neurons and human cancer tissue organoids. Various cutting-edge technologies will be used to develop an integrated phenomics analysis of cancer pathology mediated by neural networks using control systems of sensory neuron activity, and the sensory neuron-tumor cell interaction using human cancer tissue organoids and human iPS cell-derived differentiated sensory neurons will be analyzed. These approaches will not only elucidate the dynamic role of sensory neurons in the tumor microenvironment, but will also allow the addition of entirely new anti-cancer drug therapies that target "sensory neuron-derived factors" in anti-cancer drug treatment algorithms that target "cancer cell killers" and "cancer immunomodulators," which have been the mainstay therapies for cancer conditions. These efforts may also provide new scientific evidence that perceptual neural networks as traditional warning and physiological sensing systems play a role as nutritional pathways in cancer tissues and systemic migration of cancer cells during cancer pathology, and new physiological and pathophysiological mechanisms may be elucidated entirely in the process of analyzing these cancer pathology-related sensing systems.
List of papers published in 2020
Journal
1. Mori T, Takemura Y, Arima T, Iwase Y, Narita M, Miyano K, Hamada Y, Suda Y, Matsuzawa A, Sugita K, Matsumura S, Sasaki S, Yamauchi T, Higashiyama K, Uezono Y, Yamazaki M, Kuzumaki N, Narita M. Further investigation of the rapid-onset and short-duration action of the G protein-biased μ-ligand oliceridine. Biochem Biophys Res Commun, 534:988-994, 2021
2. Setsu T, Hamada Y, Oikawa D, Mori T, Ishiuji Y, Sato D, Narita M, Miyazaki S, Furuta E, Suda Y, Sakai H, Ochiya T, Tezuka H, Iseki M, Inada E, Yamanaka A, Kuzumaki N, Narita M. Direct evidence that the brain reward system is involved in the control of scratching behaviors induced by acute and chronic itch. Biochem Biophys Res Commun, 534:624-631, 2021
3. Suda Y, Nakashima T, Matsumoto H, Sato D, Nagano S, Mikata H, Yoshida S, Tanaka K, Hamada Y, Kuzumaki N, Narita M. Normal aging induces PD-1-enriched exhausted microglia and A1-like reactive astrocytes in the hypothalamus. Biochem Biophys Res Commun, 541:22-29, 2021
4. Miyano K, Ohbuchi K, Sudo Y, Minami K, Yokoyama T, Yamamoto M, Uzu M, Nonaka M, Shiraishi S, Murata H, Higami Y, Uezono Y. A novel method for evaluating activity of transient receptor potential channels using a cellular dielectric spectroscopy. J Pharmacol Sci, 143:320-324, 2020
5. Miyano K, Manabe S, Komatsu A, Fujii Y, Mizobuchi Y, Uezono E, Ohshima K, Nonaka M, Kuroda Y, Narita M, Uezono Y. The G Protein Signal-Biased Compound TRV130; Structures, Its Site of Action and Clinical Studies. Curr Top Med Chem, 20:2822-2829, 2020