Annual Report 2021
Division of Innovative Pathology and Laboratory Medicine (Kashiwa Campus)
Genichiro Ishii, Nobuo Kuninaka, 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 provide a foundation for the elucidation of the pathogenesis of cancer and its susceptibility to treatment by linking a wealth of morphological, clinical, biological, and genetic information to histopathological specimen information.
Our members need to perform the following missions. 1) Promotion of translational research using quality-controlled specimens, 2) Training for translational research.
Research activities
The following are the major research results of this year.
1) Clinicopathological analysis revealed that lung adenocarcinoma with necrosis has a poor prognosis. Using the TCGA data base, we found that the expression of genes involved in the cell cycle and hypoxic response is enriched in adenocarcinoma with necrosis. Furthermore, using the results of previously performed exome analysis, we found that adenocarcinomas with necrosis have higher SNV values. These results indicate that lung adenocarcinoma with necrosis is a distinctive subtype in terms of clinicopathology, gene expression, and gene mutation.
2) In resected non-small cell lung cancer after preoperative treatment (CT and CRT groups), we examined the correlation between percent viable tumor cells (%VTC) and the tumor microenvironment. %VTC was significantly lower in the CRT group than in the CT group. In addition, the number of CD204 (+) TAMs was associated with %VTC and poor prognosis in the CRT group, suggesting that these cells may have tumor-promoting effects on residual lung cancer in the microenvironment after CRT.
3) We investigated whether the percentage of necrosis in lung neuroendocrine carcinoma correlates with prognosis. CIR and LC-CID were significantly higher in patients with ≥10% necrosis than in those with <10%. Using the results of previously performed genetic mutation analysis, the frequency of genetic mutations in the PI3K/AKT/mTOR pathway, MYC family, and MAPK/ERK pathway did not differ between the ≥10% necrosis and <10% necrosis groups. In surgically resected neuroendocrine carcinomas, a high rate of tumor necrosis (>10%) was a poor prognostic factor, but no characteristic gene mutations were found.
4) Cancer progression after chemotherapy is a major obstacle to effective cancer treatment. We aimed to evaluate the role of drug-exposed cancer-associated fibroblasts in the progression of drug-exposed gastric cancer cells and to explore their molecular mechanisms. Drug-exposed cancer-associated fibroblasts promote the invasion of drug-exposed gastric cancer cells and some of their interactions are mediated by the gp130 ligand. These results present the importance of the interaction between gastric cancer cells and fibroblasts in the tumor microenvironment after chemotherapy and suggest that the ligand for gp130 may be a novel therapeutic target to inhibit gastric cancer cell metastasis.
5) Tumor necrosis (TN) is one of the poor prognostic factors in renal cell carcinoma (RCC). Two patterns of tumor necrosis, dirty necrosis and ghost necrosis, were identified and their morphological characteristics and poor prognostic impact were investigated. 39% of TN was dirty necrosis and 61% was ghost necrosis. Tumors with dirty necrosis (excluding stage IV) had significantly shorter disease-free survival than those with ghost necrosis and those without TN. Dirty necrosis was a potential indicator of poor prognosis in surgically resected RCC.
6) We investigated whether PDPN+ CAFs, a subpopulation of tumor-promoting cancer-associated fibroblasts (CAFs), contribute to an immunosuppressive microenvironment in lung squamous cell carcinoma (SqCC). TCGA database analysis of lung SqCC revealed significantly higher expression of IL-1A, IL-1B, IL-6, IL-10, CCL, FGF2, LGALS1, PDGFA, PDGFB, and TGFB1 in the PDPN high-expressing group compared to the PDPN low group. Among these, TGFB1 expression was also high in PDPN+ CAFs derived from resected lung cancer tissue. Immunohistochemical analysis showed that CD204+ TAMs infiltrated more tumor tissue in cases with PDPN+ CAFs than in cases with PDPN- CAFs. Furthermore, even within the same tumor, CD204+ TAMs were more prevalent in areas enriched in PDPN+ CAFs. These findings suggest that PDPN+ CAFs exhibit high expression of TGFB1 and are associated with CD204+ TAM infiltration in lung SqCC and an immunosuppressive tumor microenvironment.
Education
We provide research guidance and education to the residents of the East Hospital. We also provide special lectures to the 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.
Future Prospects
1) Using a wealth of pathology paraffin blocks (including tissue arrays), patient-derived viable cells such as cancer-associated fibroblasts (CAFs), and detailed clinical information, we will work with clinicians and companies to develop new diagnostics/treatments and explore biomarkers. In particular, 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.
2) We will investigate interactions between drug-resistant CAFs and cancer cells to create a basis for the development of effective drug therapies.
3) WWe will accelerate the generation of in vitro models that reproduce the cancer microenvironment in humans in vivo, and can be analyzed in three dimensions and spatiotemporally.
List of papers published in 2021
Journal
1. Kumagai S, Koyama S, Itahashi K, Tanegashima T, Lin YT, Togashi Y, Kamada T, Irie T, Okumura G, Kono H, Ito D, Fujii R, Watanabe S, Sai A, Fukuoka S, Sugiyama E, Watanabe G, Owari T, Nishinakamura H, Sugiyama D, Maeda Y, Kawazoe A, Yukami H, Chida K, Ohara Y, Yoshida T, Shinno Y, Takeyasu Y, Shirasawa M, Nakama K, Aokage K, Suzuki J, Ishii G, Kuwata T, Sakamoto N, Kawazu M, Ueno T, Mori T, Yamazaki N, Tsuboi M, Yatabe Y, Kinoshita T, Doi T, Shitara K, Mano H, Nishikawa H. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer cell, 40:201-218.e9, 2022
2. Nakajima H, Harano K, Nakai T, Kusuhara S, Nakao T, Funasaka C, Kondoh C, Matsubara N, Naito Y, Hosono A, Mitsunaga S, Ishii G, Mukohara T. Impacts of clinicopathological factors on efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer. Breast (Edinburgh, Scotland), 61:136-144, 2022
3. Tane K, Miyoshi T, Samejima J, Aokage K, Ishii G, Tsuboi M. Lymph node metastasis and predictive factors in clinical stage IA squamous cell carcinoma of the lung based on radiological findings. General thoracic and cardiovascular surgery, 70:52-58, 2022
4. Suzuki J, Tsuboi M, Ishii G. Cancer-associated fibroblasts and the tumor microenvironment in non-small cell lung cancer. Expert review of anticancer therapy, 22:169-182, 2022
5. 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
6. Hoshino H, Aokage K, Miyoshi T, Tane K, Kojima M, Sugano M, Kuwata T, Ochiai A, Suzuki K, Tsuboi M, Ishii G. Correlation between the number of viable tumor cells and immune cells in the tumor microenvironment in non-small cell lung cancer after induction therapy. Pathology international, 71:512-520, 2021
7. Nakasone S, Suzuki A, Okazaki H, Onodera K, Zenkoh J, Ishii G, Suzuki Y, Tsuboi M, Tsuchihara K. Predictive markers based on transcriptome modules for vinorelbine-based adjuvant chemotherapy for lung adenocarcinoma patients. Lung cancer (Amsterdam, Netherlands), 158:115-125, 2021
8. Oiwa H, Aokage K, Suzuki A, Sato K, Kuroe T, Mimaki S, Tane K, Miyoshi T, Samejima J, Tsuchihara K, Goto K, Funai K, Tsuboi M, Nakai T, Ishii G. Clinicopathological, gene expression and genetic features of stage I lung adenocarcinoma with necrosis. Lung cancer (Amsterdam, Netherlands), 159:74-83, 2021
9. Nomura K, Aokage K, Nakai T, Sakashita S, Miyoshi T, Tane K, Samejima J, Suzuki K, Tsuboi M, Ishii G. Prognostic impact of extranodal extension in patients with pN1-N2 lung adenocarcinoma. Journal of cancer research and clinical oncology, 147:3699-3707, 2021
10. Katsumata S, Tane K, Suzuki J, Miyoshi T, Samejima J, Aokage K, Ishii G, Tsuboi M. Mediastinal lymph node dissection for the elderly with clinical stage I non-small cell lung cancer. General thoracic and cardiovascular surgery, 69:1560-1566, 2021
11. Izumi H, Matsumoto S, Liu J, Tanaka K, Mori S, Hayashi K, Kumagai S, Shibata Y, Hayashida T, Watanabe K, Fukuhara T, Ikeda T, Yoh K, Kato T, Nishino K, Nakamura A, Nakachi I, Kuyama S, Furuya N, Sakakibara-Konishi J, Okamoto I, Taima K, Ebi N, Daga H, Yamasaki A, Kodani M, Udagawa H, Kirita K, Zenke Y, Nosaki K, Sugiyama E, Sakai T, Nakai T, Ishii G, Niho S, Ohtsu A, Kobayashi SS, Goto K. The CLIP1-LTK fusion is an oncogenic driver in non-small-cell lung cancer. Nature, 600:319-323, 2021
12. Sakai T, Udagawa H, Kirita K, Nomura S, Itotani R, Tamiya Y, Sugimoto A, Ota T, Naito T, Izumi H, Nosaki K, Ikeda T, Zenke Y, Matsumoto S, Yoh K, Niho S, Nakai T, Ishii G, Goto K. Comparison of the efficiency of endobronchial ultrasound-guided transbronchial needle aspiration using a 22G needle versus 25G needle for the diagnosis of lymph node metastasis in patients with lung cancer: a prospective randomized, crossover study. Translational lung cancer research, 10:3745-3758, 2021
13. Yoh K, Matsumoto S, Furuya N, Nishino K, Miyamoto S, Oizumi S, Okamoto N, Itani H, Kuyama S, Nakamura A, Nishi K, Fukuda I, Tsuta K, Hayashi Y, Motoi N, Ishii G, Goto K. Comprehensive assessment of PD-L1 expression, tumor mutational burden and oncogenic driver alterations in non-small cell lung cancer patients treated with immune checkpoint inhibitors. Lung cancer (Amsterdam, Netherlands), 159:128-134, 2021
14. Sugimoto A, Umemura S, Miyoshi T, Nakai T, Kuroe T, Nosaki K, Ikeda T, Udagawa H, Kirita K, Zenke Y, Matsumoto S, Yoh K, Niho S, Tsuboi M, Goto K, Ishii G. High proportion of tumor necrosis predicts poor survival in surgically resected high-grade neuroendocrine carcinoma of the lung. Lung cancer (Amsterdam, Netherlands), 157:1-8, 2021
15. Ishii T, Suzuki A, Kuwata T, Hisamitsu S, Hashimoto H, Ohara Y, Yanagihara K, Mitsunaga S, Yoshino T, Kinoshita T, Ochiai A, Shitara K, Ishii G. Drug-exposed cancer-associated fibroblasts facilitate gastric cancer cell progression following chemotherapy. Gastric cancer: official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association, 24:810-822, 2021
16. Komine R, Kojima M, Ishi G, Kudo M, Sugimoto M, Kobayashi S, Takahashi S, Konishi M, Kobayashi T, Akimoto T, Murakami A, Sasaki M, Tanaka M, Matsuzaki A, Ohike N, Uchida K, Sugiyama T, Hirabayashi K, Tajiri T, Ishida K, Kai K, Omori Y, Notohara K, Yamaguchi H, Matsuda Y, Naito Y, Fukumura Y, Hamada Y, Mihara Y, Masugi Y, Gotohda N, Harada K, Fukushima N, Furukawa T. Recognition and pathological features of periampullary region adenocarcinoma with an indeterminable origin. Cancer medicine, 10:3499-3510, 2021
17. Takeuchi Y, Tanegashima T, Sato E, Irie T, Sai A, Itahashi K, Kumagai S, Tada Y, Togashi Y, Koyama S, Akbay EA, Karasaki T, Kataoka K, Funaki S, Shintani Y, Nagatomo I, Kida H, Ishii G, Miyoshi T, Aokage K, Kakimi K, Ogawa S, Okumura M, Eto M, Kumanogoh A, Tsuboi M, Nishikawa H. Highly immunogenic cancer cells require activation of the WNT pathway for immunological escape. Science immunology, 6:eabc6424, 2021
18. Okubo S, Suzuki T, Hioki M, Shimizu Y, Toyama H, Morinaga S, Gotohda N, Uesaka K, Ishii G, Takahashi S, Kojima M. The immunological impact of preoperative chemoradiotherapy on the tumor microenvironment of pancreatic cancer. Cancer science, 112:2895-2904, 2021
19. Kudo M, Kobayashi S, Kojima M, Kobayashi T, Sugimoto M, Takahashi S, Konishi M, Ishii G, Gotohda N. Impact of previous history of choledochojejunostomy on the incidence of organ/space surgical site infection after hepatectomy. Asian journal of surgery, 44:1520-1528, 2021
20. Terao T, Yuda J, Yamauchi N, Guo YM, Shimada K, Sugano M, Ishii G, Minami Y. Brentuximab vedotin maintenance after autologous stem cell transplantation for refractory gray zone lymphoma with long-term remission. Molecular and clinical oncology, 14:125, 2021
21. Katsumata S, Aokage K, Ishii G, Hoshino H, Suzuki J, Miyoshi T, Tane K, Samejima J, Tsuboi M. Pathological features and prognostic implications of ground-glass opacity components on computed tomography for clinical stage I lung adenocarcinoma. Surgery today, 51:1188-1202, 2021
22. Kuroe T, Watanabe R, Kojima M, Morisue R, Sugano M, Kuwata T, Masuda H, Kusuhara S, Matsubara N, Oda S, Ushiku T, Ishii G. Evaluation of the morphological features and unfavorable prognostic impact of dirty necrosis in renal cell carcinoma. Journal of cancer research and clinical oncology, 147:1089-1100, 2021