Annual Report 2017
Division of Biomarker Discovery (Kashiwa Campus)
Atsushi Ochiai, Akiko Nagatsuma, Chisako Yamauchi, Shuichi Mitsunaga, Satoshi Miura, Yuka Nakamura, Ken Hatogai, Aya Endo, Misato Ohashi, Kazuyoshi Yanagihara, Yuki Iino, Teruo Komatsu, Sachiko Fukuda, Motoko Suzaki
Introduction
In the translational research field for the exploration of biomarkers, we have been performing cancer diagnosis based on the elucidation of cancer patients and biological figure of cancer, exploring biomarkers that relate to the prognosis of cancer, and constructing companion diagnostics that relate to clinical studies with an aim to achieve the personalized (optimized) medicine.
Our team and what we do
In order to explore cancer biomarkers and predictive factors, the following three teams work on their objectives:
1) The exploration of new targets in cancer
2) The exploration of predictive factors on an effective treatment and progression of cancer
3) The supportive team for the exploring cancer biomarkers in the National Cancer Center (NCC)
Research activities
The research achievements of this year are summarized into the following three points:
1) In the research and development of molecular targeted drugs, it is important to develop the target that is characteristic of cancer. We have been exploring molecules which could be drug targets and conducting clinicopathological analyses thereof. Additionally, we particularly have been focusing on the role of the microenvironment which establishes the cancer, in the growth, invasion and metastasis of the cancer. We particularly focused on the interaction between the fibroblast cells that are the major constituents of the cancer microenvironment and the cancer cells. We have been analyzing the gene expression of the activated fibroblast cells using cDNA microarrays, and conducting comparative study on the changes in the interaction with interstitial cells and changes in the expression of genes that are involved in the grade of cancer based on the classification of the gastric carcinoma whose interaction with interstitial cells is gathering attention. We believe that these research results may not only clarify the role of the microenvironment formed by the stromal fibroblasts but also may form the foundation of the development of new therapy for the microenvironment of cancer.
2) The biomarkers, which are useful for the evaluation of the effectiveness of treatment and early detection of the aggravation of diseases, may enhance the efficacy of systemic chemotherapy and supportive care. We transplanted a cultured human pancreatic cancer cell to the sciatic nerve of immunodeficient mice. As a result, we found that the inflammation in dorsal root ganglia (DRG) changes the pain threshold resulting in strong pain felt by cancer patients. We confirmed that this pain in an animal model is actually taking place in human patients by comparing the degrees of abdominal perception and nerve infiltration in 43 patients of pancreatic cancer who received the operation. As a result, it was shown that in cases which the nerve infiltration was obviously observed, the pain threshold thereof was changing; thus, a likelihood that the nerve inflammation strongly correlates to pain. Since this pain is considered to relate strongly to the performance status, it was thought that the suppression of nerve inflammation has an important meaning in the clinical study on the safety and efficacy of systemic chemotherapy and supportive care that may alleviate the aggravation of condition also has a great importance.
3) We have supported a total of 250 cases of establishments of xenografts and novel cell lines in cooperation with the biobank, studies on the establishment of xenografts and novel cell lines (the DEF Study) that are performed in collaboration with the NCC Hospital East (NCCHE). We collected serums from patients with multiple cancers for establishing the meth-od of serum screening system by miRNAs to cooperate with the NCC Research Institute (NCCRI). Additionally, regarding the preparation of PDX from tissues of pathological specimens which has been conducted, we prepared pathological slices from PDX specimens and instructed researchers immunostaining procedures and how to evaluate the immuno-staining for the purpose of supporting the DEF study. In order to support the study using pathological specimens that is conducted in the Exploratory Oncology Research and Clinical Trial Center (EPOC), we supported the preparation of specimens.
Future prospects
Since the personalized medicine requires the best biomarkers indicating the target in cancer and the prediction of the effectiveness of treatment and patients' survival, the Division of Biomarker Discovery will provide new cancer targets and biomarkers for cancer patients and treatments.
List of papers published in January 2017 - March 2018
Journal
1. Abe A, Nagatsuma AK, Higuchi Y, Nakamura Y, Yanagihara K, Ochiai A. Site-specific fibroblasts regulate site-specific inflammatory niche formation in gastric cancer. Gastric cancer, 20:92-103, 2017
2. Ichikawa W, Terashima M, Ochiai A, Kitada K, Kurahashi I, Sakuramoto S, Katai H, Sano T, Imamura H, Sasako M. Impact of insulin-like growth factor-1 receptor and amphiregulin expression on survival in patients with stage II/III gastric cancer enrolled in the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer. Gastric cancer, 20:263-273, 2017
3. Yoshino T, Uetake H, Tsuchihara K, Shitara K, Yamazaki K, Oki E, Sato T, Naitoh T, Komatsu Y, Kato T, Yamanaka K, Iwasaki K, Soeda J, Hihara M, Yamanaka T, Ochiai A, Muro K. Rationale for and Design of the PARADIGM Study: Randomized Phase III Study of mFOLFOX6 Plus Bevacizumab or Panitumumab in Chemotherapy-naive Patients With RAS (KRAS/NRAS) Wild-type, Metastatic Colorectal Cancer. Clin Colorectal Cancer, 16:158-163, 2017
4. Sunagawa H, Kinoshita T, Kaito A, Shibasaki H, Kaneko K, Ochiai A, Ohtsu A, Nishida T. Additional surgery for non-curative resection after endoscopic submucosal dissection for gastric cancer: a retrospective analysis of 200 cases. Surg Today, 47:202-209, 2017
5. Amano K, Maeda I, Morita T, Baba M, Miura T, Hama T, Mori I, Nakajima N, Nishi T, Sakurai H, Shimoyama S, Shinjo T, Shirayama H, Yamada T, Ono S, Ozawa T, Yamamoto R, Yamamoto N, Shishido H, Kinoshita H. C-reactive protein, symptoms and activity of daily living in patients with advanced cancer receiving palliative care. J Cachexia Sarcopenia Muscle, 8:457-465, 2017
6. Terawaki K, Kashiwase Y, Sawada Y, Hashimoto H, Yoshimura M, Ohbuchi K, Sudo Y, Suzuki M, Miyano K, Shiraishi S, Higami Y, Yanagihara K, Hattori T, Kase Y, Ueta Y, Uezono Y. Development of ghrelin resistance in a cancer cachexia rat model using human gastric cancer-derived 85As2 cells and the palliative effects of the Kampo medicine rikkunshito on the model. PLoS One, 12:e0173113, 2017
7. Higaki E, Yanagi S, Gotohda N, Kinoshita T, Kuwata T, Nagino M, Ochiai A, Fujii S. Intraoperative peritoneal lavage cytology offers prognostic significance for gastric cancer patients with curative resection. Cancer Sci, 108:978-986, 2017
8. Nakayama M, Sakai E, Echizen K, Yamada Y, Oshima H, Han TS, Ohki R, Fujii S, Ochiai A, Robine S, Voon DC, Tanaka T, Taketo MM, Oshima M. Intestinal cancer progression by mutant p53 through the acquisition of invasiveness associated with complex glandular formation. Oncogene, 36:5885-5896, 2017
9. Tamaki R, Kanai-Mori A, Morishige Y, Koike A, Yanagihara K, Amano F. Effects of 5-fluorouracil, adriamycin and irinotecan on HSC-39, a human scirrhous gastric cancer cell line. Oncol Rep, 37:2366-2374, 2017
10. Ichikawa T, Saruwatari K, Mimaki S, Sugano M, Aokage K, Kojima M, Hishida T, Fujii S, Yoshida J, Kuwata T, Ochiai A, Suzuki K, Tsuboi M, Goto K, Tsuchihara K, Ishii G. Immunohistochemical and genetic characteristics of lung cancer mimicking organizing pneumonia. Lung Cancer, 113:134-139, 2017
11. Neri S, Miyashita T, Hashimoto H, Suda Y, Ishibashi M, Kii H, Watanabe H, Kuwata T, Tsuboi M, Goto K, Menju T, Sonobe M, Date H, Ochiai A, Ishii G. Fibroblast-led cancer cell invasion is activated by epithelial-mesenchymal transition through platelet-derived growth factor BB secretion of lung adenocarcinoma. Cancer Lett, 395:20-30, 2017
12. Ikemura S, Aramaki N, Fujii S, Kirita K, Umemura S, Matsumoto S, Yoh K, Niho S, Ohmatsu H, Kuwata T, Kojima M, Ochiai A, Betsuyaku T, Tsuboi M, Goto K, Ishii G. Changes in the tumor microenvironment during lymphatic metastasis of lung squamous cell carcinoma. Cancer Sci, 108:136-142, 2017
13. Shimizu K, Kirita K, Aokage K, Kojima M, Hishida T, Kuwata T, Fujii S, Ochiai A, Funai K, Yoshida J, Tsuboi M, Ishii G. Clinicopathological significance of caveolin-1 expression by cancer-associated fibroblasts in lung adenocarcinoma. J Cancer Res Clin Oncol, 143:321-328, 2017
14. Kojima M, Shimazaki H, Iwaya K, Nakamura T, Kawachi H, Ichikawa K, Sekine S, Ishiguro S, Shimoda T, Kushima R, Yao T, Fujimori T, Hase K, Watanabe T, Sugihara K, Lauwers GY, Ochiai A. Intramucosal colorectal carcinoma with invasion of the lamina propria: a study by the Japanese Society for Cancer of the Colon and Rectum. Hum Pathol, 66:230-237, 2017
15. Hashimoto H, Suda Y, Miyashita T, Ochiai A, Tsuboi M, Masutomi K, Kiyono T, Ishii G. A novel method to generate single-cell-derived cancer-associated fibroblast clones. J Cancer Res Clin Oncol, 143:1409-1419, 2017
16. Yoshida H, Yamashita Y, Shimazu T, Cosatto E, Kiyuna T, Taniguchi H, Sekine S, Ochiai A. Automated histological classification of whole slide images of colorectal biopsy specimens. Oncotarget, 8:90719-90729, 2017
17. Itoh G, Chida S, Yanagihara K, Yashiro M, Aiba N, Tanaka M. Cancer-associated fibroblasts induce cancer cell apoptosis that regulates invasion mode of tumours. Oncogene, 36:4434-4444, 2017
18. Tanaka M, Kuriyama S, Itoh G, Maeda D, Goto A, Tamiya Y, Yanagihara K, Yashiro M, Aiba N. Mesothelial Cells Create a Novel Tissue Niche That Facilitates Gastric Cancer Invasion. Cancer Res, 77:684-695, 2017
19. Hatogai K, Fujii S, Kojima T, Daiko H, Nomura S, Doi T, Kitano S, Ohtsu A, Takiguchi Y, Yoshino T, Ochiai A. Large-scale comprehensive immunohistochemical biomarker analyses in esophageal squamous cell carcinoma. J Cancer Res Clin Oncol, 143:2351-2361, 2017
20. Han TS, Hur K, Choi B, Lee JY, Byeon SJ, Min J, Yu J, Cho JK, Hong J, Lee HJ, Kong SH, Kim WH, Yanagihara K, Song SC, Yang HK. Improvement of anti-cancer drug efficacy via thermosensitive hydrogel in peritoneal carcinomatosis in gastric cancer. Oncotarget, 8:108848-108858, 2017
21. Ishibashi M, Neri S, Hashimoto H, Miyashita T, Yoshida T, Nakamura Y, Udagawa H, Kirita K, Matsumoto S, Umemura S, Yoh K, Niho S, Tsuboi M, Masutomi K, Goto K, Ochiai A, Ishii G. CD200-positive cancer associated fibroblasts augment the sensitivity of Epidermal Growth Factor Receptor mutation-positive lung adenocarcinomas to EGFR Tyrosine kinase inhibitors. Sci Rep, 7:46662, 2017
22. Miyashita T, Higuchi Y, Kojima M, Ochiai A, Ishii G. Single cell time-lapse analysis reveals that podoplanin enhances cell survival and colony formation capacity of squamous cell carcinoma cells. Sci Rep, 7:39971, 2017
23. Hatogai K, Fujii S, Kojima T, Daiko H, Doi T, Ohtsu A, Ochiai A, Takiguchi Y, Yoshino T. Concordance between PIK3CA mutations in endoscopic biopsy and surgically resected specimens of esophageal squamous cell carcinoma. BMC Cancer, 17:36, 2017
24. Kawazoe A, Kuwata T, Kuboki Y, Shitara K, Nagatsuma AK, Aizawa M, Yoshino T, Doi T, Ohtsu A, Ochiai A. Clinicopathological features of programmed death ligand 1 expression with tumor-infiltrating lymphocyte, mismatch repair, and Epstein-Barr virus status in a large cohort of gastric cancer patients. Gastric Cancer, 20:407-415, 2017
25. Baba K, Kitajima Y, Miyake S, Nakamura J, Wakiyama K, Sato H, Okuyama K, Kitagawa H, Tanaka T, Hiraki M, Yanagihara K, Noshiro H. Hypoxia-induced ANGPTL4 sustains tumour growth and anoikis resistance through different mechanisms in scirrhous gastric cancer cell lines. Sci Rep, 7:11127, 2017
26. Terashima M, Ichikawa W, Ochiai A, Kitada K, Kurahashi I, Sakuramoto S, Katai H, Sano T, Imamura H, Sasako M. TOP2A, GGH, and PECAM1 are associated with hematogenous, lymph node, and peritoneal recurrence in stage II/III gastric cancer patients enrolled in the ACTS-GC study. Oncotarget, 8:57574-57582, 2017
27. Hashimoto T, Yamashita S, Yoshida H, Taniguchi H, Ushijima T, Yamada T, Saito Y, Ochiai A, Sekine S, Hiraoka N. WNT Pathway Gene Mutations Are Associated With the Presence of Dysplasia in Colorectal Sessile Serrated Adenoma/Polyps. Am J Surg Pathol, 41:1188-1197, 2017
28. Mitsunaga S, Okusaka T, IkedaM, Ozaka M, Ohkawa S, Ioka T, Shimura T, Sato K, Terao K, Ochiai A, Furuse J. Multicenter, Open-Label, Phase I/II Study of Tocilizumab, an Anti-Interleukin-6 Receptor Monoclonal Antibody, Combined with Gemcitabine in Patients with Advanced Pancreatic Cancer. J Med Diagn Meth, 6:234, 2017
29. Takei Y, Suzuki A, Mihara K, Yanagihara K. The microRNA miR-516a-3p regulates the Wnt pathway by targeting extracellular sulfatase 1 in human scirrhous gastric cancers: Anti-metastatic therapy via miRNA-based medicine. Medical Research Archives, 5:1-19, 2017
30. Takeuchi S, Fukuda K, Yamada T, Arai S, Takagi S, Ishii G, Ochiai A, Iwakiri S, Itoi K, Uehara H, Nishihara H, Fujita N, Yano S. Podoplanin promotes progression of malignant pleural mesothelioma by regulating motility and focus formation. Cancer Sci, 108:696-703, 2017
31. Sekine S, Ogawa R, Hashimoto T, Motohiro K, Yoshida H, Taniguchi H, Saito Y, Yasuhiro O, Ochiai A, Hiraoka N. Comprehensive characterization of RSPO fusions in colorectal traditional serrated adenomas. Histopathology, 71:601-609, 2017
32. Sekine S, Mori T, Ogawa R, Tanaka M, Yoshida H, Taniguchi H, Nakajima T, Sugano K, Yoshida T, Kato M, Furukawa E, Ochiai A, Hiraoka N. Mismatch repair deficiency commonly precedes adenoma formation in Lynch Syndrome-Associated colorectal tumorigenesis. Mod Pathol, 30:1144-1151, 2017
33. Wakiyama K, Kitajima Y, Tanaka T, Kaneki M, Yanagihara K, Aishima S, Nakamura J, Noshiro H. Low-dose YC-1 combined with glucose and insulin selectively induces apoptosis in hypoxic gastric carcinoma cells by inhibiting anaerobic glycolysis. Sci Rep, 7:12653, 2017
34. Goto M, Naito M, Saruwatari K, Hisakane K, Kojima M, Fujii S, Kuwata T, Ochiai A, Nomura S, Aokage K, Hishida T, Yoshida J, Yokoi K, Tsuboi M, Ishii G. The ratio of cancer cells to stroma after induction therapy in the treatment of non-small cell lung cancer. J Cancer Res Clin Oncol, 143:215-223, 2017
35. Sakuyama N, Kojima M, Kawano S, Matsuda Y, Mino-Kenudson M, Ochiai A, Ito M. Area of residual tumor is a robust prognostic marker for patients with rectal cancer undergoing preoperative therapy. Cancer Sci, 109:871-878, 2018
36. Hirooka K, Otani H, Morita T, Miura T, Fukahori H, Aoyama M, Kizawa Y, Shima Y, Tsuneto S, Miyashita M. End-of-life experiences of family caregivers of deceased patients with cancer: A nation-wide survey. Psychooncology, 27:272-278, 2018
37. Miyamoto S, Nagamura Y, Nakabo A, Okabe A, Yanagihara K, Fukami K, Sakai R, Yamaguchi H. Aberrant alternative splicing of RHOA is associated with loss of its expression and activity in diffuse-type gastric carcinoma cells. Biochem Biophys Res Commun, 495:1942-1947, 2018
38. Sakai E, Nakayama M, Oshima H, Kouyama Y, Niida A, Fujii S, Ochiai A, Nakayama KI, Mimori K, Suzuki Y, Hong CP, Ock CY, Kim SJ, Oshima M. Combined Mutation of Apc, Kras, and Tgfbr2 Effectively Drives Metastasis of Intestinal Cancer. Cancer Res, 78:1334-1346, 2018
39. Nakamura H, Ichikawa T, Nakasone S, Miyoshi T, Sugano M, Kojima M, Fujii S, Ochiai A, Kuwata T, Aokage K, Suzuki K, Tsuboi M, Ishii G. Abundant tumor promoting stromal cells in lung adenocarcinoma with hypoxic regions. Lung Cancer, 115:56-63, 2018
40. Yoshida H, Shimazu T, Kiyuna T, Marugame A, Yamashita Y, Cosatto E, Taniguchi H, Sekine S, Ochiai A. Automated histological classification of whole-slide images of gastric biopsy specimens. Gastric cancer, 21:249-257, 2018