Annual Report 2022
Division of Innovative Pathology and Laboratory Medicine (Kashiwa Campus)
Genichiro Ishii, Hiroshi Yamakawa, Hiroko Hashimoto
Introduction
The Division of Innovative Pathology and Laboratory Medicine was established at the Exploratory Oncology Research and Clinical Trial Center (EPOC) in 2016. Most of the 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 develop therapies that target the cancer microenvironment, specifically cancer associated fibroblasts (CAFs). To this end, we are developing in vitro models that mimic the human cancer microenvironment and validating them clinicopathologically.
Research Activities
The following are the major research results of this year.
1. In lung adenocarcinoma, patients with a high peri-tumoral alveolar macrophages (AM) content had significantly shorter disease-free survival than patients with a low peri-tumoral AM content. Gene expression analysis of TCGA stage I lung adenocarcinoma revealed enrichment of biological processes, such as chemotaxis and epithelial proliferation, in patients with a high peri-tumoral AM content.
2. Extratumoral lymphatic permeation (ly-ext) has been reported as an independent poor prognostic factor for lung adenocarcinoma, but whether or not the number of ly-ext foci is associated with prognosis and its relationship to the immune microenvironment is unclear. We found that a high number of ly-ext foci was an independent poor prognostic factor. Moreover, tumors with high numbers of ly-ext foci had a more immunosuppressive microenvironment.
3. The area of residual tumor (ART) is a prognostic factor in patients treated with neoadjuvant chemotherapy (NAC) for lung, pancreatic, and rectal cancers. We aimed to evaluate the usefulness of ART as a method for predicting the prognosis of triple-negative breast cancer (TNBC) patients after NAC. We concluded that ART is a candidate histopathological evaluation method for predicting the prognosis of TNBC patients treated with NAC. Furthermore, postoperative chemotherapy could be omitted in patients with ART-0 and ypN(-) (pathological complete response) and those with ART-low and ypN(-).
4. Positron emission tomography is a useful technique for diagnosing lymph node (LN) metastasis. We aimed to elucidate the association between fluorodeoxyglucose accumulation and the microenvironment in metastatic LNs in lung adenocarcinoma. Our results indicated a strong association between LN SUVmax and poor prognosis in patients with N2 lung adenocarcinoma. Moreover, LN SUVmax was suggested to be associated with the presence of tumor-promoting stromal cells in metastatic LNs.
5. Cancer cells are known to exhibit a cancer-associated fibroblast (CAF)-dependent invasive mode in the presence of CAFs. We investigated whether intrinsic factors of gastric cancer cells influence the CAF-dependent invasive mode of cancer cells. We observed dynamic movement of CAFs, and cancer cells, by time-lapse imaging of 2-D and 3-D collagen invasion models, and evaluated invasion modes of gastric cancer cell lines (MKN-7, MKN-45, and HSC44PE). We further examined whether modification of invasive capacity of CAFs can alter invasive mode of MKN-7, and HSC44PE cells. The results indicate that in presence of CAFs, gastric cancer cells exhibit both CAF-dependent and -independent modes of invasion, the determinants of which may depend on the intrinsic properties of the gastric cancer cells.
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 generate novel in vitro models that mimic human cancer microenvironment in vivo. Currently, we are using two types of cells, cancer cells and CAFs. In the future, we would like to start creating a microenvironment model that includes multicellularity by adding lymphocytes and macrophages.
2) We will accelerate research on the development of therapies targeting CAFs themselves, basic studies on how CAFs affect the immune microenvironment, identification of tumor-promoting subpopulations of CAFs, and development of therapies targeting them.
3) After drug administration, cancer cell re-development occurs at a high frequency. Therefore, analysis of the microenvironment after drug administration is critical for the development of effective drug therapies. Focusing on the microenvironment after drug administration, we will analyze stromal cells, especially CAFs subpopulations, which are involved in the progression of drug-resistant cancer cells.
List of papers published in 2022
Journal
1. Kuroe T, Watanabe R, Morisue R, Miyazaki S, Kojima M, Murata SC, Nakai T, Taki T, Sakashita S, Sakamoto N, Matsubara N, Masuda H, Ushiku T, Ishii G. Dirty necrosis in renal cell carcinoma is associated with NETosis and systemic inflammation. Cancer medicine, 12:4557-4567, 2023
2. Sakai T, Aokage K, Miyoshi T, Tane K, Ishii G, Goto K, Tsuboi M. Tumor size exceeding 5 cm as a valid prognostic factor in all stages of thymic epithelial tumors. Surgery today, 53:42-50, 2023
3. 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
4. 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
5. 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, 2023
6. 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, 2023
7. Hattori H, Sakashita S, Tsuboi M, Ishii G, Tanaka T. Tumor-identification method for predicting recurrence of early-stage lung adenocarcinoma using digital pathology images by machine learning. Journal of pathology informatics, 14:100175, 2023
8. Itahashi K, Irie T, Yuda J, Kumagai S, Tanegashima T, Lin YT, Watanabe S, Goto Y, Suzuki J, Aokage K, Tsuboi M, Minami Y, Ishii G, Ohe Y, Ise W, Kurosaki T, Suzuki Y, Koyama S, Nishikawa H. BATF epigenetically and transcriptionally controls the activation program of regulatory T cells in human tumors. Science immunology, 7:eabk0957, 2022
9. 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, 2022
10. Eguchi Y, Nakai T, Kojima M, Wakabayashi M, Sakamoto N, Sakashita S, Miyazaki S, Taki T, Watanabe R, Watanuki R, Yamauchi C, Iwatani T, Mukohara T, Onishi T, Ishii G. Pathologic method for extracting good prognosis group in triple-negative breast cancer after neoadjuvant chemotherapy. Cancer science, 113:1507-1518, 2022
11. Nomura K, Nakai T, Nishina Y, Sakamoto N, Miyoshi T, Tane K, Samejima J, Aokage K, Kojima M, Sakashita S, Taki T, Miyazaki S, Watanabe R, Suzuki K, Tsuboi M, Ishii G. 18F-fluorodeoxyglucose uptake in PET is associated with the tumor microenvironment in metastatic lymph nodes and prognosis in N2 lung adenocarcinoma. Cancer science, 113:1488-1496, 2022
12. Niimi T, Nakai T, Aokage K, Tane K, Miyoshi T, Samejima J, Miyazaki S, Taki T, Sakamoto N, Sakashita S, Watanabe R, Kojima M, Suzuki K, Tsuboi M, Ishii G. Prognostic impact of count of extratumoral lymphatic permeation in lung adenocarcinoma and its relation to the immune microenvironment. Cancer science, 113:1497-1506, 2022
13. Noritake O, Aokage K, Suzuki A, Tane K, Miyoshi T, Samejima J, Yoshikawa T, Murata SC, Nakai T, Tsuboi M, Ishii G. Prognostic impact of the number of peri-tumoral alveolar macrophages in patients with stage I lung adenocarcinoma. Journal of cancer research and clinical oncology, 148:3437-3447, 2022
14. Kamigaichi A, Aokage K, Katsumata S, Ishii G, Wakabayashi M, Miyoshi T, Tane K, Samejima J, Tsuboi M. Prognostic impact of examined mediastinal lymph node count in clinical N0 non-small cell lung cancer. European journal of cardio-thoracic surgery, 62:ezac359, 2022
15. Tamiya Y, Nakai T, Suzuki A, Mimaki S, Tsuchihara K, Sato K, Yoh K, Matsumoto S, Zenke Y, Nosaki K, Izumi H, Shibata Y, Sakai T, Taki T, Miyazaki S, Watanabe R, Sakamoto N, Sakashita S, Kojima M, Hashimoto N, Tsuboi M, Goto K, Ishii G. The impact of tertiary lymphoid structures on clinicopathological, genetic and gene expression characteristics in lung adenocarcinoma. Lung cancer (Amsterdam, Netherlands), 174:125-132, 2022
16. Yagi N, Suzuki T, Mizuno S, Kojima M, Kudo M, Sugimoto M, Kobayashi S, Gotohda N, Ishii G, Nakatsura T. Component with abundant immune-related cells in combined hepatocellular cholangiocarcinoma identified by cluster analysis. Cancer science, 113:1564-1574, 2022
17. Kudo M, Ishii G, Gotohda N, Konishi M, Takahashi S, Kobayashi S, Sugimoto M, Martin JD, Cabral H, Kojima M. Histological tumor necrosis in pancreatic cancer after neoadjuvant therapy. Oncology reports, 48:121, 2022
18. 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, 2022
19. Panagi M, Mpekris F, Chen P, Voutouri C, Nakagawa Y, Martin JD, Hiroi T, Hashimoto H, Demetriou P, Pierides C, Samuel R, Stylianou A, Michael C, Fukushima S, Georgiou P, Papageorgis P, Papaphilippou PC, Koumas L, Costeas P, Ishii G, Kojima M, Kataoka K, Cabral H, Stylianopoulos T. Polymeric micelles effectively reprogram the tumor microenvironment to potentiate nano-immunotherapy in mouse breast cancer models. Nature communications, 13:7165, 2022