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Annual Report 2019

Division of Biomarker Discovery (Kashiwa Campus)

Atsushi Ochiai, Syuichi Mitsunaga, Tomofumi Miura, Kazuyoshi Yanagihara, Yuki Iino, Yuka Nakamura, Aya Endo, Misato Ohasi, Mariko Yajima, Michiko Hamamoto, Teruo Komatsu, Takahiro Iimura, Sachiko Fukuda, Motoko Suzaki, Akiko Nagatsuma, Aoi Sukeda

Introduction

In the translational research field for the exploration of biomarkers, we have been exploring biomarkers which enable the prediction of the prognoses of cancer patients and biological figures of cancer, and constructing companion diagnoses that relate to the clinical studies with the aim to achieve personalized (optimized) medicine.

The Team and What We Do

Research activities

The research achievements of this year are summarized into the following four points:

1) The accomplishment of a novel cancer therapy based on liquid biopsy is an important agenda. The research and development of the +diagnosis markers for pancreatic cancer, which is one of the representative intractable cancers, and biliary tract cancer, which affects many individuals in Japan, may have an internationally high clinical significance for the possible contribution to the comprehensive improvement of the treatment results by providing opportunities for early treatment. With the aim of establishing a pancreatic and biliary tract cancer serum microRNA diagnosis which has superior performance to the existing tumor markers, we conducted a study on 1,203 subjects enrolled from 11 facilities in Japan, and have accomplished establishing a serum microRNA diagnosis of which both the sensitivity and the specificity surpass the conventional markers’ performances of 80%. Now, this diagnosis is the subject item of the “Sakigake (Pioneer) Designation Scheme” of the Japanese Health, Labour and Welfare Ministry, as the in vitro diagnosis kit of pancreatic and biliary tract cancer. Now, we are working hard to provide the system with the robustness to exhibit a higher reproducibility.

2) The cachexia of pancreatic cancer will develop in over 70% of the patient population who are receiving the primary chemotherapy for the cancer, and is associated with a strong gastrointestinal toxicity. The characteristic metabolism includes the reductive tricarboxylic acid cycle and the hypercatabolism of lipids which helped develop the validation study of serum amino acid markers to predict the cachexia. We supported conducting the Phase I clinical trial to administrate Gemcitabine hydrochloride and re-administrate nab-paclitaxel (GN) to refractory patients with pancreatic cancer and conducted a TR study on it. The disease control ratio was extremely high, at about 70%. In the study using the paired biopsy, the percentage of the suppression of the tumor stroma was up to 63%, and the IL-6 signal suppression effect was observed in 83% of the population.

3) Patient-derived xenografts (PDXs) from patients with gastric carcinoma were prepared in the Discovery and Establishment of new biomarkers For gastric cancer (DEF) Study. The PDXs and established cultures (PDXs: 35, cell lines: 32) were prepared as a distributable resource and were controlled and maintained. Additionally, we wrote the method for preparing cell lines of human origin and the method for preparing the PDX model for gastric carcinoma as the standard operation procedures for this study. Furthermore, we prepared standard operation procedures for the three subjects as follows: 1) orthotopic grafts of gastric carcinoma and esophageal cancer; 2) orthotopic grafts of pancreatic cancer and duodenal cancer; 3) preparation of a cancerous cachexia model and the analysis of its biological characteristics. We also published a book titled “Practical Guide for the Cancer Research using Patient-Derived Experimental Model”. Additionally, we developed PDXs of pancreatic cancer, and established a cultured cell line derived from the PDXs and a cell line-derived xenograft (CDX) from these cells. We also established 13-linage patient-derived preclinical models in which the “trio” matches up.

4) We guided a pathological study and instructed researchers of EPOC and NCCHE on how to prepare slices from pathological specimens, immunostaining procedures and how to evaluate the results of immunostaining. For the purpose of supporting the study using pathological specimens in the EPOC, we supported the preparation of specimens as shown in the table below.

Table 1. Slicing and dyeing (cumulative totals April 2019 to March 2020)
Table 1. Slicing and dyeing (cumulative totals April 2019 to March 2020)

Future prospects

In addition to the genomic medicine which started last year, the utilization of liquid biopsy using genomic information from the blood will become increasingly important. We are working on the development of a novel diagnostic method in this field. We are aiming to put the method into practical clinical application as soon as possible.

List of papers published in 2019

Journal

1. Shinmura K, Ikematsu H, Kojima M, Nakamura H, Osera S, Yoda Y, Hori K, Oono Y, Ochiai A, Yano T. Safety of endoscopic procedures with monopolar versus bipolar instruments in an ex vivo porcine model. BMC Gastroenterol, 20:27, 2020

2. Hatogai K, Fujii S, Kitano S, Kojima T, Daiko H, Yoshino T, Ohtsu A, Takiguchi Y, Doi T, Ochiai A. Relationship between the immune microenvironment of different locations in a primary tumour and clinical outcomes of oesophageal squamous cell carcinoma. Br J Cancer, 122:413-420, 2020

3. Maeda M, Takeshima H, Iida N, Hattori N, Yamashita S, Moro H, Yasukawa Y, Nishiyama K, Hashimoto T, Sekine S, Ishii G, Ochiai A, Fukagawa T, Katai H, Sakai Y, Ushijima T. Cancer cell niche factors secreted from cancer-associated fibroblast by loss of H3K27me3. Gut, 69:243-251, 2020

4. Sakata KI, Maeda K, Sakurai N, Liang S, Nakazawa S, Yanagihara K, Kubo T, Yoshiyama H, Kitagawa Y, Hamada JI, Iizasa H. ADAR2 Regulates Malignant Behaviour of Mesothelioma Cells Independent of RNA-editing Activity. Anticancer Res, 40:1307-1314, 2020

5. Ishikawa A, Sakamoto N, Honma R, Taniyama D, Fukada K, Hattori T, Sentani K, Oue N, Yanagihara K, Tanabe K, Ohdan H, Yasui W. Annexin A10 is involved in the induction of pancreatic duodenal homeobox?1 in gastric cancer tissue, cells and organoids. Oncol Rep, 43:581-590, 2020

6. Higashibata T, Tagami K, Miura T, Okizaki A, Watanabe YS, Matsumoto Y, Morita T, Kinoshita H. Usefulness of painDETECT and S-LANSS in identifying the neuropathic component of mixed pain among patients with tumor-related cancer pain. Support Care Cancer, 28:279-285, 2020

7. Sunami K, Ichikawa H, Kubo T, Kato M, Fujiwara Y, Shimomura A, Koyama T, Kakishima H, Kitami M, Matsushita H, Furukawa E, Narushima D, Nagai M, Taniguchi H, Motoi N, Sekine S, Maeshima A, Mori T, Watanabe R, Yoshida M, Yoshida A, Yoshida H, Satomi K, Sukeda A, Hashimoto T, Shimizu T, Iwasa S, Yonemori K, Kato K, Morizane C, Ogawa C, Tanabe N, Sugano K, Hiraoka N, Tamura K, Yoshida T, Fujiwara Y, Ochiai A, Yamamoto N, Kohno T. Feasibility and utility of a panel testing for 114 cancer-associated genes in a clinical setting: A hospital-based study. Cancer Sci, 110:1480-1490, 2019

8. Naito Y, Yamamoto Y, Sakamoto N, Shimomura I, Kogure A, Kumazaki M, Yokoi A, Yashiro M, Kiyono T, Yanagihara K, Takahashi RU, Hirakawa K, Yasui W, Ochiya T. Cancer extracellular vesicles contribute to stromal heterogeneity by inducing chemokines in cancer-associated fibroblasts. Oncogene, 38:5566-5579, 2019

9. Koga Y, Ochiai A. Systematic Review of Patient-Derived Xenograft Models for Preclinical Studies of Anti-Cancer Drugs in Solid Tumors. Cells, 8:418, 2019

10. Uzu M, Nonaka M, Miyano K, Sato H, Kurebayashi N, Yanagihara K, Sakurai T, Hisaka A, Uezono Y. A novel strategy for treatment of cancer cachexia targeting xanthine oxidase in the brain. J Pharmacol Sci, 140:109-112, 2019

11. Tonouchi A, Sugano M, Tokunaga M, Sugita S, Watanabe M, Sato R, Kaito A, Akimoto T, Ochiai A, Kinoshita T, Kuwata T. Extra-perigastric Extranodal Metastasis is a Significant Prognostic Factor in Node-Positive Gastric Cancer. World J Surg, 43:2499-2505, 2019

12. Oki T, Aokage K, Ueda T, Sugano M, Tane K, Miyoshi T, Kojima M, Fujii S, Kuwata T, Ochiai A, Funai K, Tsuboi M, Ishii G. Proportion of goblet cell is associated with malignant potential in invasive mucinous adenocarcinoma of the lung. Pathol Int, 69:526-535, 2019

13. Sukeda A, Nakamura Y, Nishida Y, Kojima M, Gotohda N, Akimoto T, Ochiai A. Expression of Monocarboxylate Transporter 1 Is Associated With Better Prognosis and Reduced Nodal Metastasis in Pancreatic Ductal Adenocarcinoma. Pancreas, 48:1102-1110, 2019

14. Hisamitsu S, Miyashita T, Hashimoto H, Neri S, Sugano M, Nakamura H, Yamazaki S, Ochiai A, Goto K, Tsuboi M, Ishii G. Interaction between cancer cells and cancer-associated fibroblasts after cisplatin treatment promotes cancer cell regrowth. Hum Cell, 32:453-464, 2019

15. Suzuki E, Yamazaki S, Naito T, Hashimoto H, Okubo S, Udagawa H, Goto K, Tsuboi M, Ochiai A, Ishii G. Secretion of high amounts of hepatocyte growth factor is a characteristic feature of cancer-associated fibroblasts with EGFR-TKI resistance-promoting phenotype: A study of 18 cases of cancer-associated fibroblasts. Pathol Int, 69:472-480, 2019

16. Kuwata T, Yanagihara K, Iino Y, Komatsu T, Ochiai A, Sekine S, Taniguchi H, Katai H, Kinoshita T, Ohtsu A. Establishment of Novel Gastric Cancer Patient-Derived Xenografts and Cell Lines: Pathological Comparison between Primary Tumor, Patient-Derived, and Cell-Line Derived Xenografts. Cells, 8:585, 2019

17. Omori T, Aokage K, Nakamura H, Katsumata S, Miyoshi T, Sugano M, Kojima M, Fujii S, Kuwata T, Ochiai A, Ikeda N, Tsuboi M, Ishii G. Growth patterns of small peripheral squamous cell carcinoma of the lung and their impacts on pathological and biological characteristics of tumor cells. J Cancer Res Clin Oncol, 145:1773-1783, 2019

18. Matsunaga R, Kojima M, Nishizawa Y, Yokota M, Hasegawa H, Saito N, Ito M, Ochiai A. The utility of longitudinal slicing method for rectal specimen: pathological analysis of circumferential resection margin of intersphincteric resection for low-lying rectal cancer. Pathol Int, 69:272-281, 2019

19. Nakamura H, Sugano M, Miyashita T, Hashimoto H, Ochiai A, Suzuki K, Tsuboi M, Ishii G. Organoid culture containing cancer cells and stromal cells reveals that podoplanin-positive cancer-associated fibroblasts enhance proliferation of lung cancer cells. Lung Cancer, 134:100-107, 2019

20. Suzuki J, Kojima M, Aokage K, Sakai T, Nakamura H, Ohara Y, Tane K, Miyoshi T, Sugano M, Fujii S, Kuwata T, Ochiai A, Ito M, Suzuki K, Tsuboi M, Ishii G. Clinicopathological characteristics associated with necrosis in pulmonary metastases from colorectal cancer. Virchows Arch, 474:569-575, 2019

21. Spaety ME, Gries A, Badie A, Venkatasamy A, Romain B, Orvain C, Yanagihara K, Okamoto K, Jung AC, Mellitzer G, Pfeffer S, Gaiddon C. HDAC4 Levels Control Sensibility toward Cisplatin in Gastric Cancer via the p53-p73/BIK Pathway. Cancers (Basel), 11:1747, 2019

22. Ohmoto A, Suzuki M, Takai E, Rokutan H, Fujiwara Y, Morizane C, Yanagihara K, Shibata T, Yachida S. Correction: Establishment of preclinical chemotherapy models for gastroenteropancreatic neuroendocrine carcinoma. Oncotarget, 10:5494, 2019

23. Kubo T, Nishimura Y, Hatori Y, Akagi R, Mihara K, Yanagihara K, Seyama T. Antitumor effect of palmitic acid-conjugated DsiRNA for colon cancer in a mouse subcutaneous tumor model. Chem Biol Drug Des, 93:570-581, 2019

24. Miura S, Naito T, Mitsunaga S, Omae K, Mori K, Inano T, Yamaguchi T, Tatematsu N, Okayama T, Morikawa A, Mouri T, Tanaka H, Kimura M, Imai H, Mizukami T, Imoto A, Kondoh C, Shiotsu S, Okuyama H, Ueno M, Takahashi T, Tsuji T, Aragane H, Inui A, Higashiguchi T, Takayama K. A randomized phase II study of nutritional and exercise treatment for elderly patients with advanced non-small cell lung or pancreatic cancer: the NEXTAC-TWO study protocol. BMC Cancer, 19:528, 2019

25. Terashima T, Umemoto K, Takahashi H, Hosoi H, Takai E, Kondo S, Sakamoto Y, Mitsunaga S, Ohno I, Hashimoto Y, Sasaki M, Ikeda M, Shimada K, Kaneko S, Yachida S, Sugano K, Okusaka T, Morizane C. Germline mutations in cancer-predisposition genes in patients with biliary tract cancer. Oncotarget, 10:5949-5957, 2019

26. Iizumi S, Kuchiba A, Okusaka T, Ikeda M, Sakamoto Y, Kondo S, Morizane C, Ueno H, Osame K, Mitsunaga S, Ohno I, Imaoka H, Hashimoto Y, Takahashi H, Sasaki M, Ohashi K. Impact of the Duration of Diabetes Mellitus on the Outcome of Metastatic Pancreatic Cancer Treated with Gemcitabine: A Retrospective Study. Intern Med, 58:2435-2441, 2019

Book

1. Ochiai A. Digestive System Tumours. In: WHO Classification of Tumours (ed), WHO Classification of Tumours, 5th Edition, Volume 1, Lyon, IARC, 2019

2. Ochiai A. Breast Tumours. In: WHO Classification of Tumours (ed), WHO Classification of Tumours, 5th Edition, Volume 2, Lyon, IARC, 2019