Division of Biomarker Discovery (Kashiwa Campus)

Atsushi Ochiai, Akiko Nagatsuma, Yuka Nakamura, Chisako Yamauchi, Syuichi Mitsunaga, Tomofumi Miura, Kazuyoshi Yanagihara, Ayumi Iwaya, Aya Endo, Yuki Iino, Teruo Komatsu, Sumiyo Itsukushima, Takahiro Mukaide, Sachiko Fukuda, Motoko Suzaki

Introduction

Our goal is to research new biomarkers and establish companion diagnostics, exploration of new biomarkers based on new concept of cancer stromal interaction, and co-development with pharmaceutical companies in association with the early phase of drug development.

Our team and what we do

The Division of Biomarker Discovery consists of three research groups, 1. Research for new targets and biomarkes for cancer treatment, 2. Research for predictive therapy response and early detection of cachexia, and 3. Support for biobank and pathological research service.

Research activities

1. Research for new targets for cancer treatment

The development of companion diagnosis is important for the molecular targeted drugs. Many collaborative researches on promising molecules with other departments and companies were performed. In recent years, cancer microenvironments are assumed to play a critical role for cancer proliferation, invasion and metastasis. To elucidate the interaction between cancer cells and fibroblasts which are main components in cancer microenvironment, a comprehensive screening of the genes that express on activated fibroblasts is currently in progress using cDNA microarray technology. Actin crosslink and ECM related genes were picked up as candidate genes associated with cancer malignancy, and further study about the genes'functions within cancer tissue is currently being carried out.

2. Research for predictive therapy response and early detection of cachexia

Exploring the biomarkers for predictive therapy response and early detection of cachexia is important in management of cancer patients. Systemic inflammatory reaction is in relation with chemotherapy refractory and cachexia, and is a good candidate for the biomarker to evaluate anti-tumor response and cachexia. We found that CRP is a good index for systemic inflammatory reaction in clinics, and is assessed for predicting prognosis and cachexia. In patients with 1st line systemic chemotherapy for advanced pancreatic cancer, high serum level of CRP was a poor prognostic factor, and was associated with cachexia.

3. Support for biobank and pathological research service

We have provided support to the DEF (Discovery and Establishment of new biomarkers For gastric cancer) study, in which 80 gastric cancer samples were registered in 2016 for xenograft model and new cell lines establishment (please refer to the "Division of Innovative Pathology and Laboratory Medicine") (Table 1).

Table 1. 2016/Pathological sections

List of papers published in 2016

Journal

1.Ikeda K, Kojima M, Saito N, Sakuyama N, Koushi K, Watanabe T, Sugihara K, Akimoto T, Ito M, Ochiai A. Current status of the histopathological assessment, diagnosis, and reporting of colorectal neuroendocrine tumors: A Web survey from the Japanese Society for Cancer of Colon and Rectum. Pathol Int, 66:94-101, 2016

2.Yokota M, Kojima M, Higuchi Y, Nishizawa Y, Kobayashi A, Ito M, Saito N, Ochiai A. Gene expression profile in the activation of subperitoneal fibroblasts reflects prognosis of patients with colon cancer. Int J Cancer, 138:1422-1431, 2016

3.Mitsunaga S, Ikeda M, Shimizu S, Ohno I, Takahashi H, Okuyama H, Ueno H, Morizane C, Kondo S, Sakamoto Y, Okusaka T, Ochiai A. C-Reactive Protein Level Is an Indicator of the Aggressiveness of Advanced Pancreatic Cancer. Pancreas, 45:110-116, 2016

4.Shoji H, Morizane C, Sakamoto Y, Kondo S, Ueno H, Takahashi H, Ohno I, Shimizu S, Mitsunaga S, Ikeda M, Okusaka T. Phase I clinical trial of oral administration of S-1 in combination with intravenous gemcitabine and cisplatin in patients with advanced biliary tract cancer. Jpn J Clin Oncol, 46:132-137, 2016

5.Kuboki Y, Yamashita S, Niwa T, Ushijima T, Nagatsuma A, Kuwata T, Yoshino T, Doi T, Ochiai A, Ohtsu A. Comprehensive analyses using next-generation sequencing and immunohistochemistry enable precise treatment in advanced gastric cancer. Ann Oncol, 27:127-133, 2016

6.Matsusaka S, Nashimoto A, Nishikawa K, Miki A, Miwa H, Yamaguchi K, Yoshikawa T, Ochiai A, Morita S, Sano T, Kodera Y, Kakeji Y, Sakamoto J, Saji S, Yoshida K. Clinicopathological factors associated with HER2 status in gastric cancer: results from a prospective multicenter observational cohort study in a Japanese population (JFMC44-1101). Gastric Cancer, 19:839-851, 2016

7.Matsusaka S, Nashimoto A, Nishikawa K, Miki A, Miwa H, Yamaguchi K, Yoshikawa T, Ochiai A, Morita S, Sano T, Kodera Y, Kakeji Y, Sakamoto J, Saji S, Yoshida K. Erratum to: Clinicopathological factors associated with HER2 status in gastric cancer: results from a prospective multicenter observational cohort study in a Japanese population (JFMC44-1101). Gastric Cancer, 19:1026, 2016

8.Yamanaka T, Oki E, Yamazaki K, Yamaguchi K, Muro K, Uetake H, Sato T, Nishina T, Ikeda M, Kato T, Kanazawa A, Kusumoto T, Chao C, Lopatin M, Krishnakumar J, Bailey H, Akagi K, Ochiai A, Ohtsu A, Ohashi Y, Yoshino T. 12-Gene Recurrence Score Assay Stratifies the Recurrence Risk in Stage II/III Colon Cancer With Surgery Alone: The SUNRISE Study. J Clin Oncol, 34:2906-2913, 2016

9.Katada C, Yokoyama T, Yano T, Kaneko K, Oda I, Shimizu Y, Doyama H, Koike T, Takizawa K, Hirao M, Okada H, Yoshii T, Konishi K, Yamanouchi T, Tsuda T, Omori T, Kobayashi N, Shimoda T, Ochiai A, Amanuma Y, Ohashi S, Matsuda T, Ishikawa H, Yokoyama A, Muto M. Alcohol Consumption and Multiple Dysplastic Lesions Increase Risk of Squamous Cell Carcinoma in the Esophagus, Head, and Neck. Gastroenterology, 151:860-869 e867, 2016

10.Higaki E, Kuwata T, Nagatsuma AK, Nishida Y, Kinoshita T, Aizawa M, Nitta H, Nagino M, Ochiai A. Gene copy number gain of EGFR is a poor prognostic biomarker in gastric cancer: evaluation of 855 patients with bright-field dual in situ hybridization (DISH) method. Gastric Cancer, 19:63-73, 2016

11.Fuse N, Kuboki Y, Kuwata T, Nishina T, Kadowaki S, Shinozaki E, Machida N, Yuki S, Ooki A, Kajiura S, Kimura T, Yamanaka T, Shitara K, Nagatsuma AK, Yoshino T, Ochiai A, Ohtsu A. Prognostic impact of HER2, EGFR, and c-MET status on overall survival of advanced gastric cancer patients. Gastric Cancer, 19:183-191, 2016

12.Yoshida T, Mihara K, Takei Y, Yanagihara K, Kubo T, Bhattacharyya J, Imai C, Mino T, Takihara Y, Ichinohe T. All-trans retinoic acid enhances cytotoxic effect of T cells with an anti-CD38 chimeric antigen receptor in acute myeloid leukemia. Clin Transl Immunology, 5:e116, 2016

13.Hirashita Y, Tsukamoto Y, Yanagihara K, Fumoto S, Hijiya N, Nakada C, Uchida T, Matsuura K, Kodama M, Okimoto T, Daa T, Seike M, Iha H, Shirao K, Murakami K, Moriyama M. Reduced phosphorylation of ribosomal protein S6 is associated with sensitivity to MEK inhibition in gastric cancer cells. Cancer Sci, 107:1919-1928, 2016

14.Kurashige J, Hasegawa T, Niida A, Sugimachi K, Deng N, Mima K, Uchi R, Sawada G, Takahashi Y, Eguchi H, Inomata M, Kitano S, Fukagawa T, Sasako M, Sasaki H, Sasaki S, Mori M, Yanagihara K, Baba H, Miyano S, Tan P, Mimori K. Integrated Molecular Profiling of Human Gastric Cancer Identifies DDR2 as a Potential Regulator of Peritoneal Dissemination. Sci Rep, 6:22371, 2016

15.Kubo H, Kitajima Y, Kai K, Nakamura J, Miyake S, Yanagihara K, Morito K, Tanaka T, Shida M, Noshiro H. Regulation and clinical significance of the hypoxia-induced expression of ANGPTL4 in gastric cancer. Oncol Lett, 11:1026-1034, 2016

16.Sato Y, Kubo T, Morimoto K, Yanagihara K, Seyama T. High mannose-binding Pseudomonas fluorescens lectin (PFL) downregulates cell surface integrin/EGFR and induces autophagy in gastric cancer cells. BMC Cancer, 16:63, 2016

17.Shida M, Kitajima Y, Nakamura J, Yanagihara K, Baba K, Wakiyama K, Noshiro H. Impaired mitophagy activates mtROS/HIF-1alpha interplay and increases cancer aggressiveness in gastric cancer cells under hypoxia. Int J Oncol, 48:1379-1390, 2016

18.Kubo T, Yanagihara K, Seyama T. In vivo RNAi efficacy of palmitic acid-conjugated dicer-substrate siRNA in a subcutaneous tumor mouse model. Chem Biol Drug Des, 87:811-823, 2016

19.Nohara S, Kato K, Fujiwara D, Sakuragi N, Yanagihara K, Iwanuma Y, Kajiyama Y. Aminopeptidase N (APN/CD13) as a target molecule for scirrhous gastric cancer. Clin Res Hepatol Gastroenterol, 40:494-503, 2016

20.Oo HZ, Sentani K, Mukai S, Hattori T, Shinmei S, Goto K, Sakamoto N, Naito Y, Anami K, Trang PTB, Yanagihara K, Oue N, Yasui W. Fukutin, identified by the Escherichia coli ampicillin secretion trap (CAST) method, participates in tumor progression in gastric cancer. Gastric Cancer, 19:443-452, 2016

21.Ikeda M, Sato A, Mochizuki N, Toyosaki K, Miyoshi C, Fujioka R, Mitsunaga S, Ohno I, Hashimoto Y, Takahashi H, Hasegawa H, Nomura S, Takahashi R, Yomoda S, Tsuchihara K, Kishino S, Esumi H. Phase I trial of GBS-01 for advanced pancreatic cancer refractory to gemcitabine. Cancer Sci, 107:1818-1824, 2016

22.Okusaka T, Otsuka T, Ueno H, Mitsunaga S, Sugimoto R, Muro K, Saito I, Tadayasu Y, Inoue K, Loembe A-B, Ikeda M. Phase I study of nintedanib in Japanese patients with advanced hepatocellular carcinoma and liver impairment. Cancer Sci, 107:1791-1799, 2016

23.Ikeda M, Yamamoto H, Kaneko M, Oshima H, Takahashi H, Umemoto K, Watanabe K, Hashimoto Y, Ohno I, Mitsunaga S, Okusaka T. Screening rate for hepatitis B virus infection in patients undergoing chemotherapy in Japan. Int J Clin Oncol, 21:1162-1166, 2016

24.Ikeda M, Okusaka T, Mitsunaga S, Ueno H, Tamai T, Suzuki T, Hayato S, Kadowaki T, Okita K, Kumada H. Safety and Pharmacokinetics of Lenvatinib in Patients with Advanced Hepatocellular Carcinoma. Clin Cancer Res, 22:1385-1394, 2016

25.Amano K, Maeda I, Morita T, Miura T, Inoue S, Ikenaga M, Matsumoto Y, Baba M, Sekine R, Yamaguchi T, Hirohashi T, Tajima T, Tatara R, Watanabe H, Otani H, Takigawa C, Matsuda Y, Nagaoka H, Mori M, Kinoshita H. Clinical Implications of C-Reactive Protein as a Prognostic Marker in Advanced Cancer Patients in Palliative Care Settings. J Pain Symptom Manage, 51:860-867, 2016

26.Tagami K, Miura T, Suzuki M, Matoba M. Analgesic Effectiveness of Systemic Lidocaine Administration for Abdominal Cancer Pain Caused by Peritoneal Carcinomatosis: A Case Series of 10 Patients. J Palliat Med, 19:1247-1248, 2016

27.Hatogai K, Kitano S, Fujii S, Kojima T, Daiko H, Nomura S, Yoshino T, Ohtsu A, Takiguchi Y, Doi T, Ochiai A. Comprehensive immunohistochemical analysis of tumor microenvironment immune status in esophageal squamous cell carcinoma. Oncotarget, 7:47252-47264, 2016

28.Sekine S, Yamashita S, Tanabe T, Hashimoto T, Yoshida H, Taniguchi H, Kojima M, Shinmura K, Saito Y, Hiraoka N, Ushijima T, Ochiai A. Frequent PTPRK-RSPO3 fusions and RNF43 mutations in colorectal traditional serrated adenoma. J Pathol, 239:133-138, 2016

29.Tanabe Y, Ichikawa H, Kohno T, Yoshida H, Kubo T, Kato M, Iwasa S, Ochiai A, Yamamoto N, Fujiwara Y, Tamura K. Comprehensive screening of target molecules by next-generation sequencing in patients with malignant solid tumors: guiding entry into phase I clinical trials. Mol Cancer, 15:73, 2016

30.Aramaki N, Ishii G, Yamada E, Morise M, Aokage K, Kojima M, Hishida T, Yoshida J, Ikeda N, Tsuboi M, Ochiai A. Drastic morphological and molecular differences between lymph node micrometastatic tumors and macrometastatic tumors of lung adenocarcinoma. J Cancer Res Clin Oncol, 142:37-46, 2016

31.Neri S, Hashimoto H, Kii H, Watanabe H, Masutomi K, Kuwata T, Date H, Tsuboi M, Goto K, Ochiai A, Ishii G. Cancer cell invasion driven by extracellular matrix remodeling is dependent on the properties of cancer-associated fibroblasts. J Cancer Res Clin Oncol, 142:437-446, 2016

32.Ishii G, Ochiai A, Neri S. Phenotypic and functional heterogeneity of cancer-associated fibroblast within the tumor microenvironment. Adv Drug Deliv Rev, 99:186-196, 2016

33.Hisakane K, Saruwatari K, Fujii S, Kirita K, Umemura S, Matsumoto S, Yoh K, Niho S, Ohmatsu H, Kuwata T, Ochiai A, Gemma A, Tsuboi M, Goto K, Ishii G. Unique intravascular tumor microenvironment predicting recurrence of lung squamous cell carcinoma. J Cancer Res Clin Oncol, 142:593-600, 2016

34.Sekihara K, Hishida T, Ikemura S, Saruwatari K, Morise M, Kuwata T, Fujii S, Kojima M, Ochiai A, Funai K, Aokage K, Yoshida J, Tsuboi M, Ishii G. The association of intravascular stromal cells with prognosis in high-grade neuroendocrine carcinoma of the lung. J Cancer Res Clin Oncol, 142:905-912, 2016

35.Saruwatari K, Ikemura S, Sekihara K, Kuwata T, Fujii S, Umemura S, Kirita K, Matsumoto S, Yoh K, Niho S, Ohmatsu H, Ochiai A, Kohrogi H, Tsuboi M, Goto K, Ishii G. Aggressive tumor microenvironment of solid predominant lung adenocarcinoma subtype harboring with epidermal growth factor receptor mutations. Lung Cancer, 91:7-14, 2016

36.Matsuzawa R, Kirita K, Kuwata T, Umemura S, Matsumoto S, Fujii S, Yoh K, Kojima M, Niho S, Ohmatsu H, Ochiai A, Tsuboi M, Goto K, Ishii G. Factors influencing the concordance of histological subtype diagnosis from biopsy and resected specimens of lung adenocarcinoma. Lung Cancer, 94:1-6, 2016

37.Hata K, Yoshida J, Udagawa H, Hashimoto H, Fujii S, Hishida T, Kuwata T, Aokage K, Kojima M, Ochiai A, Suzuki K, Tsuboi M, Ishii G. The difference in Ezrin-pAkt signaling axis between lepidic and papillary predominant invasive adenocarcinomas of the lung. J Cancer Res Clin Oncol, 142:1421-1430, 2016

38.Suzuki S, Aokage K, Hishida T, Yoshida J, Kuwata T, Yamauchi C, Tsuboi M, Ishii G. Interstitial growth as an aggressive growth pattern in primary lung cancer. J Cancer Res Clin Oncol, 142:1591-1598, 2016

39.Suda Y, Neri S, Hashimoto H, Higuchi Y, Ishibashi M, Sugano M, Masutomi K, Tsuboi M, Ochiai A, Ishii G. Clonal heterogeneity in osteogenic potential of lung cancer-associated fibroblasts: promotional effect of osteogenic progenitor cells on cancer cell migration. J Cancer Res Clin Oncol, 142:1487-1498, 2016

40.Naito M, Aokage K, Saruwatari K, Hisakane K, Miyoshi T, Hishida T, Yoshida J, Masato S, Kojima M, Kuwata T, Fujii S, Ochiai A, Sato Y, Tsuboi M, Ishii G. Microenvironmental changes in the progression from adenocarcinoma in situ to minimally invasive adenocarcinoma and invasive lepidic predominant adenocarcinoma of the lung. Lung Cancer, 100:53-62, 2016

41.Osera S, Fujii S, Ikematsu H, Miyamoto H, Oono Y, Yano T, Ochiai A, Yoshino T, Ohtsu A, Kaneko K. Clinicopathological, endoscopic, and molecular characteristics of the "skirt" - a new entity of lesions at the margin of laterally spreading tumors. Endoscopy, 48:448-455, 2016

42.Koushi K, Nishizawa Y, Kojima M, Fujii S, Saito N, Hayashi R, Ochiai A, Ito M. Association between pathologic features of peripheral nerves and postoperative anal function after neoadjuvant therapy for low rectal cancer. Int J Colorectal Dis, 31:1845-1852, 2016

43.Kojima M, Ikeda K, Saito N, Sakuyama N, Koushi K, Kawano S, Watanabe T, Sugihara K, Ito M, Ochiai A. Neuroendocrine Tumors of the Large Intestine: Clinicopathological Features and Predictive Factors of Lymph Node Metastasis. Front Oncol, 6:173, 2016

44.Mimaki S, Totsuka Y, Suzuki Y, Nakai C, Goto M, Kojima M, Arakawa H, Takemura S, Tanaka S, Marubashi S, Kinoshita M, Matsuda T, Shibata T, Nakagama H, Ochiai A, Kubo S, Nakamori S, Esumi H, Tsuchihara K. Hypermutation and unique mutational signatures of occupational cholangiocarcinoma in printing workers exposed to haloalkanes. Carcinogenesis, 37:817-826, 2016

45.Sakuyama N, Kojima M, Kawano S, Akimoto T, Saito N, Ito M, Ochiai A. Histological differences between preoperative chemoradiotherapy and chemotherapy for rectal cancer: a clinicopathological study. Pathol Int, 66:273-280, 2016