Annual Report 2023
Division of Innovative Pathology and Laboratory Medicine (Kashiwa Campus)
Genichiro Ishii, Miyuu Ibe, Jun Suzuki, Toshihiro Nakamura
Introduction
Some members are from the Department of Pathology and Clinical Laboratories and Department of Clinical Laboratories in the National Cancer Center Hospital East (NCCHE).
The Team and What We Do
Our goal is to provide a basis for the development of new cancer therapies that focus on the microenvironment, particularly cancer associated fibroblasts (CAFs) and tumor associated macrophages (TAMs), which are the primary stromal cells in cancer tissue.
Research Activities
The following are the major research results of this year.
1. Patients with high tumor-peripheral alveolar macrophage counts (p-exAMs) had significantly shorter recurrence-free survival (RFS) and overall survival (OS) compared to patients with low p-exAMs. Multivariate analysis showed that high p-exAMs was an independent predictor of RFS. Alveolar macrophages (AMs) were collected from the tumor periphery and remote areas of 13 resected lungs by bronchoalveolar lavage (BAL) technique, and mRNA expression was compared. AMs from the tumor periphery expressed significantly higher levels of IL-10 and CCL2 than AMs from the remote areas. Furthermore, IL-10 and CCL2 significantly induced PC9 cell proliferation and migration in vitro. This study suggests that p-exAMs should be considered as tumor-promoting factors in the tumor microenvironment.
2. Compared to adenocarcinoma of the papillary predominant subtype (PPA) with WT, PPA with EGFR mutations had smaller invasive size and less frequent vascular invasion. However, PPA with EGFR mutations had significantly poorer 5-ys recurrence-free survival (RFS) compared to PPA with WT. In contrast, no significant differences were observed in the other predominant subtypes. In the TCGA cohort, PPA with EGFR mutations tended to have higher galectin-3 expression, which is associated with tumor metastasis and resistance to anoikis, compared to those with WT. Immunohistochemical evaluation revealed that galectin-3 expression was significantly higher in PPAs with EGFR mutations than in WT PPAs.
3. EGFR-mt-positive lung adenocarcinomas had more lymph node and lung metastases than EGFR-wild type lung adenocarcinomas (EGFR-wt), despite the smaller size of the invasive component; disease-free survival (DFS) for EGFR-mt patients tended to be shorter than that for EGFR-wt patients. In an analysis based on primary subtype, EGFR-mt with the papillary-dominant subtype had a significantly shorter 5-year DFS than EGFR-wt with the papillary-dominant subtype. Immunohistochemical analysis of EGFR-mt revealed that the non-acinar or lepidic subtype (including the papillary predominant subtype) had a higher frequency of podoplanin-positive CAFs compared to the acinar or lepidic predominant subtype, and CD204-positive TAM counts, and a higher median number of positive TAMs. In pathologic stage II-III EGFR-mt lung adenocarcinomas, the non-acinar and lepidic predominant subtypes were predictors of recurrence and had a more aggressive tumor microenvironment.
4. The number of AMs present around the tumor (peritumoral alveolar macrophages [pAMs]) and those present away from the tumor (distant macrophages; dAMs) were measured. In 73 patients with neuroendocrine carcinoma (NEC: small cell lung cancer and large cell neuroendocrine carcinoma), the group with high pAMs had shorter recurrence-free survival (RFS) than the group with low pAMs. Bivariate analysis showed that the number of pAMs was an independent predictor of poor RFS. In contrast, in the carcinoid tumor cohort, there was no statistically significant correlation between higher and lower number of pAMs in RFS. Furthermore, we examined the correlation between genomic alterations and the number of pAMs in the NEC and found no significant correlation.
Education
We provide special lectures to the clinical residents who belong to the doctoral programs of Juntendo University Graduate School, which are affiliated with the National Cancer Center. Some of the staff also serve as adjunct faculty at the Graduate School of Frontier Sciences, University of Tokyo, where they provide research guidance and education. We also provide research guidance and education to the clinical residents of the National Cancer Center Hospital East.
Future Prospects
1) We are currently establishing a microenvironment model that includes cancer cells, CAFs, and TAMs. We would like to clarify how CAFs and TAMs are involved in cancer cell invasion and drug resistance, and if so, the molecular mechanism of their involvement.
2) Analysis of the microenvironment after drug administration is crucial for the development of effective drug therapies. We focused on the microenvironment after drug administration and succeeded in generating drug-resistant cancer cells and drug-resistant CAFs. In the future, we will attempt to identify subpopulations of drug-resistant CAFs that are involved in the development of drug-resistant cancer cells.
List of papers published in 2023
Journal
1. Nomura K, Aokage K, Kaminuma Y, Nakai T, Wakabayashi M, Ikeno T, Koike Y, Taki T, Miyoshi T, Tane K, Samejima J, Ishii G, Tsuboi M. EGFR mutation impacts recurrence in high-risk early-stage lung adenocarcinoma in the IASLC grading system. International journal of clinical oncology, 29:248-257, 2024
2. Tabata S, Umemura S, Narita M, Udagawa H, Ishikawa T, Tsuboi M, Goto K, Ishii G, Tsuchihara K, Ochiai A, Kobayashi SS, Soga T, Makinoshima H. Metabolic Hallmarks for Purine Nucleotide Biosynthesis in Small Cell Lung Carcinoma. Molecular cancer research, 22:82-93, 2024
3. Kitagawa S, Zenke Y, Taki T, Aokage K, Sakai T, Shibata Y, Izumi H, Nosaki K, Umemura S, Matsumoto S, Yoh K, Sakamoto N, Sakashita S, Kojima M, Tsuboi M, Goto K, Ishii G. Prognostic value of predominant subtype in pathological stage II-III lung adenocarcinoma with epidermal growth factor receptor mutation. Lung cancer (Amsterdam, Netherlands), 188:107453, 2024
4. Sasaki T, Kuno H, Hiyama T, Oda S, Masuoka S, Miyasaka Y, Taki T, Nagasaki Y, Ohtani-Kim SJ, Ishii G, Kaku S, Shroff GS, Kobayashi T. 2021 WHO Classification of Lung Cancer: Molecular Biology Research and Radiologic-Pathologic Correlation. Radiographics, 44:e230136, 2024
5. Adachi M, Taki T, Sakamoto N, Kojima M, Hirao A, Matsuura K, Hayashi R, Tabuchi K, Ishikawa S, Ishii G, Sakashita S. Extracting interpretable features for pathologists using weakly supervised learning to predict p16 expression in oropharyngeal cancer. Scientific reports, 14:4506, 2024
6. Nagasaki Y, Taki T, Nomura K, Tane K, Miyoshi T, Samejima J, Aokage K, Ohtani-Kim SJ, Kojima M, Sakashita S, Sakamoto N, Ishikawa S, Suzuki K, Tsuboi M, Ishii G. Spatial intratumor heterogeneity of programmed death-ligand 1 expression predicts poor prognosis in resected non-small cell lung cancer. Journal of the National Cancer Institute, djae053, 2024
7. Minakata N, Sakashita S, Wakabayashi M, Nakamura Y, Sunakawa H, Yoda Y, Ishii G, Yano T. Immunohistochemistry and oxygen saturation endoscopic imaging reveal hypoxia in submucosal invasive esophageal squamous cell carcinoma. Cancer medicine, 12:15809-15819, 2023
8. Kojima M, Yokota M, Yanagisawa N, Kitamura S, Amemiya K, Kawano S, Tsukada Y, Sakuyama N, Nagayasu K, Hashimoto T, Nakashima K, Jiang K, Kanemitsu Y, Fujita F, Akiba J, Notohara K, Itakura J, Sekine S, Sakashita S, Sakamoto N, Ishikawa S, Nakanishi Y, Yao T, Liang WY, Lauwers GY, Ito M, Sakamoto K, Ishii G, Ochiai A. Assessment of Elastic Laminal Invasion Contributes to an Objective pT3 Subclassification in Colon Cancer. The American journal of surgical pathology, 47:1122-1133, 2023
9. Yoshida T, Yatabe Y, Kato K, Ishii G, Hamada A, Mano H, Sunami K, Yamamoto N, Kohno T. The evolution of cancer genomic medicine in Japan and the role of the National Cancer Center Japan. Cancer biology & medicine, 21:29-44, 2023
10. Tanabe K, Nakanishi Y, Okubo N, Matsumoto S, Umino Y, Kataoka M, Yajima S, Yoshida T, Miyazaki S, Kuwata T, Ishii G, Watanabe R, Masuda H. Prevalence and characteristics of patients with upper urinary tract urothelial carcinoma having potential Lynch syndrome identified by immunohistochemical universal screening and Amsterdam criteria II. BMC cancer, 23:940, 2023
11. Takeshita N, Enokida T, Okano S, Fujisawa T, Wada A, Sato M, Tanaka H, Tanaka N, Onaga R, Hoshi Y, Sakashita S, Ishii G, Tahara M. Weekly paclitaxel, carboplatin and cetuximab (PCE) combination followed by nivolumab for recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). Oral oncology, 147:106615, 2023
12. Konishi Y, Taki T, Nakai T, Kuroe T, Morisue R, Miyoshi T, Tane K, Samejima J, Aokage K, Miyazaki S, Sakamoto N, Sakashita S, Watanabe R, Kojima M, Suzuki K, Tsuboi M, Ishii G. Clinicopathological features and prognostic impact of dirty necrosis in metastatic lung cancers from the colon and rectum. Cancer science, 114:2169-2177, 2023
13. Ohtani-Kim SJ, Taki T, Tane K, Miyoshi T, Samejima J, Aokage K, Nagasaki Y, Kojima M, Sakashita S, Watanabe R, Sakamoto N, Goto K, Tsuboi M, Ishii G. Efficacy of Preoperative Biopsy in Predicting the Newly Proposed Histologic Grade of Resected Lung Adenocarcinoma. Modern pathology, 36:100209, 2023
14. Tanaka T, Umemura S, Miyoshi T, Nakai T, Noritake O, Suzuki J, Tane K, Samejima J, Aokage K, Mimaki S, Tsuchihara K, Taki T, Miyazaki S, Watanabe R, Sakashita S, Sakamoto N, Kojima M, Goto K, Ikeda N, Tsuboi M, Ishii G. The prognostic impact of a high number of peritumoral alveolar macrophages in neuroendocrine carcinoma in the lung. Pathology international, 73:497-508, 2023
15. Tanaka Y, Nakai T, Suzuki A, Kagawa Y, Noritake O, Taki T, Hashimoto H, Sakai T, Shibata Y, Izumi H, Nosaki K, Udagawa H, Zenke Y, Matsumoto S, Yoh K, Miyazaki S, Sakamoto N, Sakashita S, Kojima M, Watanbe R, Tsuboi M, Goto K, Ishii G. Clinicopathological significance of peritumoral alveolar macrophages in patients with resected early-stage lung squamous cell carcinoma. Cancer immunology, immunotherapy, 72:2205-2215, 2023
16. Kagawa Y, Nakai T, Taki T, Hashimoto H, Tanaka Y, Sakai T, Shibata Y, Izumi H, Nosaki K, Udagawa H, Zenke Y, Matsumoto S, Yoh K, Miyazaki S, Watanabe R, Kojima M, Sakashita S, Sakamoto N, Tsuboi M, Goto K, Ishii G. Prognostic impact and gene expression analysis of peri-tumoral alveolar macrophage in resected lung adenocarcinoma. Cancer science, 114:3423-3432, 2023
17. Adachi M, Aoyama N, Kojima M, Sakamoto N, Miyazaki S, Taki T, Watanabe R, Matsuura K, Kotani D, Kojima T, Fujita T, Tabuchi K, Ishii G, Sakashita S. The area of residual tumor predicts esophageal squamous cell carcinoma prognosis following neoadjuvant chemotherapy. Journal of cancer research and clinical oncology, 149:4663-4673, 2023
18. Akimoto E, Kuwata T, Shitara K, Kawazoe A, Sakamoto N, Ishii G, Ochiai A, Kinoshita T. Impact of Programmed Death-Ligand 1 Expression on Mismatch Repair Deficiency and Epstein-Barr Virus Status on Survival Outcomes in Patients with Stage II/III Gastric Cancer After Surgery. Annals of surgical oncology, 30:5227-5236, 2023
19. Igata Y, Kojima M, Suzuki T, Ishii G, Morisue R, Suzuki T, Kudo M, Sugimoto M, Kobayashi S, Martin JD, Stylianopoulos T, Cabral H, Kano MR, Konishi M, Gotohda N. Relationships between physical and immunological tumor microenvironment in pancreatic ductal adenocarcinoma. Cancer science, 114:3783-3792, 2023
20. Morisue R, Kojima M, Suzuki T, Watanabe R, Sakamoto N, Sakashita S, Harada K, Nakai T, Ishii G, Nakatsura T, Gotohda N, Ishikawa S. Common clinicopathological and immunological features of sarcomatoid carcinoma across organs: A histomorphology-based cross-organ study. International journal of cancer, 153:1997-2010, 2023
21. Kondo R, Sakamoto N, Harada K, Hashimoto H, Morisue R, Yanagihara K, Kinoshita T, Kojima M, Ishii G. Cancer-associated fibroblast-dependent and -independent invasion of gastric cancer cells. Journal of cancer research and clinical oncology, 149:5309-5319, 2023
22. Sakashita S, Sakamoto N, Kojima M, Taki T, Miyazaki S, Minakata N, Sasabe M, Kinoshita T, Ishii G, Ochiai A. Requirement of image standardization for AI-based macroscopic diagnosis for surgical specimens of gastric cancer. Journal of cancer research and clinical oncology, 149:6467-6477, 2023