Annual Report 2023
Division of Cancer Pathophysiology
Minoru Narita, Yasuyuki Nagumo, Michiko Narita, Yukari Totsuka, Mitsuaki Yamazaki, Hiroshi Nagase,
Naoko Kuzumaki, Yusuke Hamada, Yukari Suda, Kanako Miyano, Hironori Sato, Fukiko Matsuyama
Introduction
The Fourth Basic Plan to Promote Cancer Control Programs aims to improve the quality of life of cancer patients and survivors by promoting the expansion of cancer supportive care and palliative care in both the fields of cancer treatment and coexistence with cancer. 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 fundamental scientific understanding of cancer pathology in coexisting non-cancer conditions is the key to establishing effective and high-quality cancer treatments, supportive care, and palliative care. This year, we continued our efforts to elucidate the changes in cancer pathology associated with comorbidities, focusing on the bidirectional interplay between the nervous, immune, and cancer systems.
Research Activities
1) Analysis of the Interactions Between Sensory Neurons, Cancer Cells, and Immune Cells
To analyze in vitro interactions between human cells, sensory neurons were differentiated from human iPS cells. A co-culture system was established with iPS cell-derived sensory neurons, human cancer cells (e.g., lung and breast cancer), and human immune cells. In this co-culture system, sensory neurons were selectively activated, and the resulting changes in the characteristics of these cells, including cancer cells, were analyzed.
2) Cancer Pathology Prediction Using a Human Disease Database
In collaboration with the Department of Palliative Medicine of the National Cancer Hospital (NCCH), we conducted a cohort study on persistent pain in patients with cancer. This study revealed that persistent pain may affect survival prognosis, duration of pharmacological treatment, and immune evasion by cancer cells. Based on these cohort analyses, we selected patient blood samples and conducted serum analyses.
3) Analysis of Pain Stress in Patient-Derived Xenograft (PDX) Models
We obtained PDX strains from the J-PDX library and established PDX models by transplanting patient tumor tissues. Using these models, we analyzed cancer pathology under persistent postoperative pain. Additionally, we attempted to establish PDX mice with a reconstituted human immune system.
4) Analysis of Cancer Cachexia Progression Modulation Through the Gut-Brain Axis
A cancer cachexia mouse model showed that the disruption of gut microflora, particularly an increase in anaerobic bacteria such as Firmicutes, led to the activation of inflammatory microglia in the hypothalamus via endotoxins. This activation resulted in decreased expression of inhibitory immune checkpoint receptors and overproduction of lipocalin 2 in the microglia. Consequently, hyperactivation of the hypothalamic paraventricular nucleus of the hypothalamic-pituitary-adrenal axis was observed, contributing to peripheral immune suppression and exacerbation of cachexia symptoms.
5) Comprehensive Analysis of DNA Adducts Formed from Candidate Chemicals for Ccupational Bladder Cancer
DNA adductome analysis using rat bladder epithelia suggested that oxidative stress may be involved in the development of bladder cancer induced by o-toluidine (OTD), a causative chemical for occupational bladder cancer. To verify this, we administered the antioxidant apocynin to this rat model and found that the OTD-induced hyperplasia of the bladder epithelia was suppressed. These findings indicate that oxidative stress may contribute to the development of OTD-induced urinary cancer .
Education
We accepted 27 individuals from the NCCH and collaborating universities (Hoshi University, Tokyo University of Science, etc.) as partnering graduate students and trainees, and provided them with research and education opportunities through paper publication and research presentation. Furthermore, one doctoral program student obtained a PhD degree (Doctor of Pharmacy).
Future Prospects
It is crucial to elucidate the interactions between the brain, the immune system, and cancer to gain a detailed understanding of cancer pathology. Based on this, we will continue to investigate the mechanisms underlying cancer progression and pathological changes using experimental models that focus on intercellular communication between neurons, immune cells, and cancer cells. Since non-cancer comorbidities, such as persistent pain, are likely to influence drug sensitivity and metastatic characteristics of cancer cells, we will advance fundamental analyses through cohort studies and biobank samples. Furthermore, we aim to elucidate not only the changes in cancer cells but also the functional changes in neuronal and immune cells through comprehensive analyses using omics, phenomics, and computational approaches to uncover the complex intercellular interactions and functional changes. Thus, we aim to establish novel cancer therapies and supportive and palliative care based on fundamental research.
List of papers published in 2023
Journal
1. Kajitani N, Okada-Tsuchioka M, Inoue A, Miyano K, Masuda T, Boku S, Iwamoto K, Ohtsuki S, Uezono Y, Aoki J, Takebayashi M. G protein-biased LPAR1 agonism of prototypic antidepressants: Implication in the identification of novel therapeutic target for depression. Neuropsychopharmacology, 49:561-572, 2024
2. Sugawara H, Date A, Fuke S, Nakachi Y, Kato T, Narita M, Bundo M, Iwamoto K. Quantification of cytosine modifications in the aged mouse brain. Neuropsychopharmacology Reports, 44:250-255, 2024
3. Uezono E, Mizobuchi Y, Miyano K, Ohbuchi K, Murata H, Komatsu A, Manabe S, Nonaka M, Hirokawa T, Yamaguchi K, Iseki M, Uezono Y, Hayashida M, Kawagoe I. Distinct profiles of desensitization of µ-opioid receptors caused by remifentanil or fentanyl: In vitro assay with cells and three-dimensional structural analyses. International Journal of Molecular Sciences, 24:8369, 2023
4. Tanaka K, Kuzumaki N, Hamada Y, Suda Y, Mori T, Nagumo Y, Narita M. Elucidation of the mechanisms of exercise-induced hypoalgesia and pain prolongation due to physical stress and the restriction of movement. Neurobiology of Pain, 14:100133, 2023
5. Karasawa Y, Miyano K, Yamaguchi M, Nonaka M, Yamaguchi K, Iseki M, Kawagoe I, Uezono Y. Therapeutic potential of orally administered rubiscolin-6. International Journal of Molecular Sciences, 24:9959, 2023
6. Kawamura Y, Oka K, Semba T, Takamori M, Sugiura Y, Yamasaki R, Suzuki Y, Chujo T, Nagase M, Oiwa Y, Fujioka S, Homma S, Yamamura Y, Miyawaki S, Narita M, Fukuda T, Sakai Y, Ishimoto T, Tomizawa K, Suematsu M, Yamamoto T, Bono H, Okano H, Miura K. Cellular senescence induction leads to progressive cell death via the INK4a-RB pathway in naked mole-rats. The EMBO Journal, 42:e111133, 2023
7. Suzuki S, Gi M, Komiya M, Obikane A, Vachiraarunwong A, Fujioka M, Kakehashi A, Totsuka Y, Wanibuchi H. Evaluation of the mechanisms involved in the development of bladder toxicity following exposure to occupational Bladder cancer causative chemicals using DNA adductome analysis. Biomolecules, 14:36, 2023