Annual Report 2022
Division of Cancer Pathophysiology
Minoru Narita, Yasuyuki Nagumo, Michiko Narita, Yukari Totsuka, Mitsuaki Yamazaki, Hiroshi Nagse, Naoko Kuzumaki, Yusuke Hamada, Yukari Suda, Kanako Miyano, Fukiko Matsuyama, Ichiro Inaba
Introduction
In an era of increasing numbers of new cancer patients and cancer survivors, it is necessary to establish next-generation cancer supportive care and palliative care as well as cancer-eradication treatment. The progression of cancer pathology is significantly influenced not only by individual differences in patient cancer genomes, but also by the history and coexistence of non-cancer diseases. Therefore, a basic scientific understanding of cancer pathology with coexisting non-cancer conditions is key to establishing effective and high-quality cancer treatment and supportive/palliative care. In FY2022, as part of an analysis of the central-cancer immune crosstalk mechanism, we examined changes in cell properties involved in the cancer cell-neural cell linkage in the tumor microenvironment, focusing on cancer pathological changes associated with factors of non-cancer diseases such as pain and stress.
Research Activities
1) Interaction analysis between human iPS cell-derived sensory neurons and human cancer cells
We have established a three-dimensional culture system for human iPS cell-derived sensory neurons and patient-derived cancer organoids, and revealed changes in the gene expression levels of catecholamine synthesis-related factors and cancer cell property-related factors in sensory neurons and cancer cells, respectively, in two-dimensional cultures. We also artificially activated iPS cell-derived sensory neurons expressing channel rhodopsin 2 with blue light and analyzed metabolites derived from them that may cause alterations in cancer cell properties.
2) Establishment of a patient-derived xenograft (PDX) mouse model with chronic pain
We have established a mouse model of cancer pathology in which PDX mice experience postoperative pain using the J-PDX library. We will analyze the changes in intracellular characteristics of tumor tissue grafts due to postoperative pain in the future.
3) Prediction of cancer pathology using human disease databases and pathological analysis using pathological specimens from cancer patients
In collaboration with the Department of Palliative Medicine of the National Cancer Center Hospital (NCCH), we have performed a cohort study on the relationship between persistent pain and the survivability of cancer patients, and have also analyzed pathological specimens from cancer patients in collaboration with the Department of Pathology of the NCCH.
4) Study on changes in the tumor microenvironment induced by specific stimulation of C-fiber sensory nerves
Genetic engineering-based specific stimulation of C-fiber sensory neurons induced an increase in tumor volume and M2 polarization of tumor-associated macrophages in tumor tissue.
5) Analysis of the central nerve-cancer immune linkage by activation of stress-responsive neurons
Artificial activation of hypothalamic stress-responsive innervation by a pharmacogenetic technique induced a marked increase in tumor volume, a decrease in CD8 tumor-infiltrating lymphocytes, functional changes in suppressor immune cells and changes in cancer cell properties.
6) Comprehensive analysis of DNA adducts formed from candidate chemicals for occupational bladder cancer
DNA was extracted from the bladder epithelium of rats treated with an aromatic amine, such as o-toluidine, and a comprehensive analysis of DNA adducts was performed. A principal component analysis revealed that a characteristic product of o-toluidine was oxidative damage. This suggests that oxidative stress may be involved in the toxicity of rat bladder mucosa exposed to aromatic amines.
Education
We accepted 48 individuals from NCCH and collaborating universities (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 PhD degree (Doctor of Pharmacy).
Future Prospects
The goal is to further reveal the molecular mechanisms that influence the quantitative and functional changes in cancer cells and immune cells in the tumor microenvironment and the survivability of patients. To this end, we will attempt an integrated analysis of the mechanisms for modification of the cancer pathology based on the crosstalk of the nervous system and the immune system, covering the "brain-based" afferent and efferent nervous systems. Therefore, we will continue an integrative phenomics analysis of the mechanisms for modification of the cancer pathophysiology with or without non-cancer disease through a neural network. On the other hand, we will comprehensively analyze the bidirectional linkage by cancer and nerves using three-dimensional cultures of human sensory neuron organoids–PDX organoids. Additionally, we will analyze the clinically relevant cancer pathology by developing basic research using biobank samples and a cohort analysis using patient-genome information and clinical practice information. Through these approaches, we will establish a novel treatment method/supportive care/palliative care for cancer patients and cancer survivors based on fundamental scientific research.
List of papers published in 2022
Journal
1. Mizuguchi T, Miyano K, Yamauchi R, Yoshida Y, Takahashi H, Yamazaki A, Ono H, Inagaki M, Nonaka M, Uezono Y, Fujii H. The first structure-activity relationship study of oxytocin as a positive allosteric modulator for the µ opioid receptor. Peptides, 159:170901, 2023
2. Tanaka K, Kondo T, Narita M, Muta T, Yoshida S, Sato D, Suda Y, Hamada Y, Tezuka H, Kuzumaki N, Narita M. Repeated activation of Trpv1-positive sensory neurons facilitates tumor growth associated with changes in tumor-infiltrating immune cells. Biochemical and Biophysical Research Communications, 648:36-43, 2023
3. Yoshida S, Hamada Y, Narita M, Sato D, Tanaka K, Mori T, Tezuka H, Suda Y, Tamura H, Aoki K, Kuzumaki N, Narita M. Elucidation of the mechanisms underlying tumor aggravation by the activation of stress-related neurons in the paraventricular nucleus of the hypothalamus. Molecular Brain, 16:18, 2023
4. Tanaka K, Kondo T, Narita M, Muta T, Yoshida S, Sato D, Suda Y, Hamada Y, Shimizu T, Kuzumaki N, Narita M. Cancer aggravation due to persistent pain signals with the increased expression of pain-related mediators in sensory neurons of tumor-bearing mice. Molecular Brain, 16:19, 2023
5. Yoshida S, Tanaka K, Narita M, Yamabe Y, Mori T, Hamada Y, Suda Y, Kuzumaki N, Narita M. Repeated activation of corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus prolongs postsurgical pain. Japanese Journal of Pharmaceutical Palliative Care and Sciences, 16:31-37, 2023
6. Suzuki H, Mitsunaga S, Ikeda M, Aoyama T, Yoshizawa K, Yamaguchi M, Suzuki M, Narita M, Kawasaki T, Ochiai A. Interleukin 6/gp130 axis promotes neural invasion in pancreatic cancer. Cancer Medicine, 11:5001-5012, 2022
7. Narita T, Tsunematsu Y, Miyoshi N, Komiya M, Hamoya T, Fujii G, Yoshikawa Y, Sato M, Kawanishi M, Sugimura H, Iwashita Y, Totsuka Y, Terasaki M, Watanabe K, Wakabayashi K, Mutoh M. Induction of DNA damage in mouse colorectum by administration of colibactin-producing escherichia coli, isolated from a patient with colorectal cancer. In Vivo, 36:628-634, 2022
8. Komatsu A, Miyano K, Nakayama D, Mizobuchi Y, Uezono E, Ohshima K, Karasawa Y, Kuroda Y, Nonaka M, Yamaguchi K, Iseki M, Uezono Y, Hayashida M. Novel opioid analgesics for the development of transdermal opioid patches that possess morphine-like pharmacological profiles rather than fentanyl: Possible opioid switching alternatives among patch formula. Anesthesia & Analgesia, 134:1082-1093, 2022
9. Gondoh E, Hamada Y, Mori T, Iwazawa Y, Shinohara A, Narita M, Sato D, Tezuka H, Yamauchi T, Tsujimura M, Yoshida S, Tanaka K, Yamashita K, Akatori H, Higashiyama K, Arakawa K, Suda Y, Miyano K, Iseki M, Inada E, Kuzumaki N, Narita M. Possible mechanism for improving the endogenous immune system through the blockade of peripheral µ-opioid receptors by treatment with naldemedine. British Journal of Cancer, 127:1565-1574, 2022
10. Kobayashi T, Kishimoto S, Watanabe S, Yoshioka Y, Toyoda T, Ogawa K, Watanabe K, Totsuka Y, Wakabayashi K, Miyoshi N. Cytotoxic homo- and hetero-dimers of o-toluidine, o-anisidine, and aniline formed by in vitro metabolism. Chemical Research in Toxicology, 35:1625-1630, 2022
11. Yamaguchi M, Miyano K, Hirayama S, Karasawa Y, Ohshima K, Uezono E, Komatsu A, Nonaka M, Fujii H, Yamaguchi K, Iseki M, Hayashida M, Uezono Y. Evaluation of the intracellular signaling activities of κ-opioid receptor agonists, nalfurafine analogs; Focusing on the selectivity of G-protein- and β-arrestin-mediated pathways. Molecules, 27:7065, 2022