Annual Report 2017
Division of Pathology
Genichiro Ishii, Satoshi Fujii, Motohiro Kojima, Hiroko Hashimoto, Yoshiko Onuma, Tomoyuki Miyashita, Syota Yamazaki, Erika Suzuki, Hojong Lee, Shoshi Hisamitsu, Daiki Maruyama
Introduction
Our aim is to make evidence to support "precision medicine" for cancer patients. To this end, our members perform basic and translational research based on the clinicopathological characteristics of cancer. Our missions are to 1) explore cancer biology, 2) explore cancer microenvironment which could affect drug sensitivity, and 3) develop novel therapeutic and diagnostic methods.
Routine activities
Team members are involved in routine diagnosis with the collaboration of staff pathologists of the Department of Pathology and Clinical Laboratories of the National Cancer Center Hospital East (NCCHE). As routine activities, we perform 1) pathological and cytological diagnoses in the NCCHE, 2) education of clinical residents for diagnosis and translational research, 3) education of doctoral and master course students for basic and translational research, and 4) support for the biobank platform (tissue preparation and tissue microarray construction).
Moreover, team members participate in clinicopathological conferences and research meetings between the NCCHE and the Exploratory Oncology Research & Clinical Trial Center (EPOC).
Research activities
The aims of our team are to 1) explore cancer biology, 2) explore cancer microenvironment which could affect drug sensitivity, and 3) develop novel therapeutic and diagnostic methods. Therefore, team members are responsible for basic and translational research using pathological samples and clinicopathological information. During this process, we generated novel in vitro models and also confirmed our hypothesis by using human samples.
Notably, most of our research products were generated through collaborative investigation with clinicians. Followings are major research results of this year.
1) We found the smaller the total area of residual cancer cells, the higher residual tumor contained non-cancerous components in the induction therapy group, which may be the characteristic histological feature of NSCLC after induction therapy.
2) Single cell time-lapse analysis revealed that high clonal expansion capacity of podoplanin positive cancer stem cell populations was the result of reduced cell death by podoplanin-mediated signaling.
3) By using novel in vitro invasion assay, we found cancer cells undergoing epithelial-mesenchymal transition accelerate their own ability to invade local tissues via PDGF-BB secretion to promote cancer associated fibroblast matrix remodeling.
4) We reported that CD200-positive cancer associated fibroblasts can augment the sensitivity of EGFR-mutated lung adenocarcinoma cells to EGFR-TKIs and may possess far reaching applications in the therapeutic use of EGFR-TKIs.
5) We identified the KRT4 gene expression as a prognostic predictor of advanced tongue squamous cell carcinoma and identified DNA methylation of HSD17B4 gene promoter as a predictive factor of efficacy of trastuzumab treatment for HER2-positive breast cancer.
6) We established the cytological criteria that should be judged as positive for gastric cancer cells as a poor prognostic factor from microscopic observation of peritoneal lavage fluids during surgery of more than 1,000 patients with gastric cancer.
7) In superficial esophageal squamous cell carcinoma, we found the measured value of submucosal invasive depth was a prognostic factor. Moreover, we cleared that the effect of neo-adjuvant chemotherapy on metastatic lymph nodes of esophageal squamous cell carcinoma was a prognostic factor.
8) Using genomic DNA extracted from FFPE colorectal cancer specimens collected from multi-institutions, we revealed BRAFnon-V600E mutation found by executing next generation sequencing was a predictive factor for the efficacy of anti-EGFR antibody therapy.
9) On behalf of the Japanese Society for Cancer of the Colon and Rectum, we collected invasive intramucosal colorectal cancer from multiple institutions. We performed clinicopathological study and proposed pathological pit-falls for accurate diagnosis. We propose that invasive intramucosal colorectal cancer should be categorized into pT1a. Our proposal was accepted as an original article in this year.
10) Preoperative therapy has been increasing in many cancers. Regression grades after preoperative therapy are known as an important prognostic factors. On the other hand, a standardized assessment method has not been established. We have been proposing "area of residual tumor (ART)" as an objective and useful prognostic factor. In this year, we examined its utility and association with immunological features.
11) Through the assessment of the association between physical property of human tissue and clinicopathological features, we are trying to develop medical devices. In this year, we reported the association between pancreas tissue stiffness and pancreas fistula after pancreatectomy.
12) In collaboration with clinicians, we published clinicopathological researches and case reports of lung, esophagus, breast, head and neck, colon and hepato-biliary-pancreatic tumors.
Education
Our members give lectures of diagnostic training and pathological research for clinical residents in the NCCHE. Moreover, staff members give professional guidance for doctoral students of Juntendo University, Keio University. Some members are faculty of the Tokyo Medical and Dental University and Graduate School of Frontier Sciences, the University of Tokyo and perform instruction to students in master and doctoral courses. We have two visiting research fellows (from Juntendo University) and one international student (the University of Tokyo).
Future prospects
We should understand distinctive biological characteristics of cancer arising in various organs. To promote basic and translational research for precision medicine, we examine not only cancer cell biology but microenvironmental biology which is closely associated with clinical use. Moreover, we develop novel diagnostic methods to support precision medicine. We will develop automated support tools for immunohistochemical diagnosis by using artificial intelligence (AI)-powered computer system in collaboration with clinicians and industrial members.
List of papers published in January 2017 - March 2018
Journal
1. Takahashi S, Ohno I, Ikeda M, Kobayashi T, Akimoto T, Kojima M, Konishi M, Uesaka K. Neoadjuvant S-1 with concurrent radiotherapy followed by surgery for borderline resectable pancreatic cancer: study protocol for an open-label, multicentre, prospective phase II trial (JASPAC05). BMJ Open, 7:e018445, 2017
2. Kadota T, Yano T, Fujita T, Daiko H, Fujii S. Submucosal Invasive Depth Predicts Lymph Node Metastasis and Poor Prognosis in Submucosal Invasive Esophageal Squamous Cell Carcinoma. Am J Clin Pathol, 148:416-426, 2017
3. Miyoshi T, Umemura S, Matsumura Y, Mimaki S, Tada S, Makinoshima H, Ishii G, Udagawa H, Matsumoto S, Yoh K, Niho S, Ohmatsu H, Aokage K, Hishida T, Yoshida J, Nagai K, Goto K, Tsuboi M, Tsuchihara K. Genomic Profiling of Large-Cell Neuroendocrine Carcinoma of the Lung. Clinical Cancer Research, 23:757-765, 2017
4. 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
5. Aokage K, Miyoshi T, Ishii G, Kusumoto M, Nomura S, Katsumata S, Sekihara K, Hishida T, Tsuboi M. Clinical and Pathological Staging Validation in the Eighth Edition of the TNM Classification for Lung Cancer: Correlation between Solid Size on Thin-Section Computed Tomography and Invasive Size in Pathological Findings in the New T Classification. J Thorac Oncol, 12:1403-1412, 2017
6. 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
7. 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
8. Ishii G. Crosstalk Between Cancer Associated Fibroblasts and Cancer Cells in the Tumor Microenvironment After Radiotherapy. EBioMedicine, 17:7-8, 2017
9. Suzuki S, Aokage K, Yoshida J, Ishii G, Matsumura Y, Haruki T, Hishida T, Nagai K. Thin-section computed tomography findings of lung adenocarcinoma with inherent metastatic potential. Surg Today, 47:619-626, 2017
10. 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
11. Sasaki M, Izumi H, Yokoyama T, Kojima M, Hosono A. Follicular dendritic cell sarcoma treated with a variety of chemotherapy. Hematol Oncol, 35:905-908, 2017
12. Hashimoto K, Hayashi R, Mukaigawa T, Yamazaki M, Fujii S. Concomitant expression of ezrin and HER2 predicts distant metastasis and poor prognosis of patients with salivary gland carcinomas. Hum Pathol, 63:110-119, 2017
13. 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
14. 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
15. 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
16. 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
17. 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
18. Yamazaki N, Koga Y, Taniguchi H, Kojima M, Kanemitsu Y, Saito N, Matsumura Y. High expression of miR-181c as a predictive marker of recurrence in stage II colorectal cancer. Oncotarget, 8:6970-6983, 2017
19. 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
20. 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
21. 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
22. Sugimoto M, Takahashi S, Kojima M, Kobayashi T, Gotohda N, Konishi M. In Patients with a Soft Pancreas, a Thick Parenchyma, a Small Duct, and Fatty Infiltration Are Significant Risks for Pancreatic Fistula After Pancreaticoduodenectomy. J Gastrointest Surg, 21:846-854, 2017
23. Yoh K, Seto T, Satouchi M, Nishio M, Yamamoto N, Murakami H, Nogami N, Matsumoto S, Kohno T, Tsuta K, Tsuchihara K, Ishii G, Nomura S, Sato A, Ohtsu A, Ohe Y, Goto K. Vandetanib in patients with previously treated RET-rearranged advanced non-small-cell lung cancer (LURET): an open-label, multicentre phase 2 trial. Lancet Respir Med, 5:42-50, 2017
24. Fujii S, Yamashita S, Yamaguchi T, Takahashi M, Hozumi Y, Ushijima T, Mukai H. Pathological complete response of HER2-positive breast cancer to trastuzumab and chemotherapy can be predicted by HSD17B4 methylation. Oncotarget, 8:19039-19048, 2017
25. Osera S, Ikematsu H, Fujii S, Hori K, Oono Y, Yano T, Kaneko K. Endoscopic treatment outcomes of laterally spreading tumors with a skirt (with video). Gastrointest Endosc, 86:533-541, 2017
26. 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
27. Sekine S, Ogawa R, Hashimoto T, Kojima M, Yoshida H, Taniguchi H, Saito Y, Ohno Y, Ochiai A, Hiraoka N. Comprehensive characterization of RSPO fusions in colorectal traditional serrated adenomas.. Histopathology, 71:601-609, 2017
28. Shinozaki E, Yoshino T, Yamazaki K, Muro K, Yamaguchi K, Nishina T, Yuki S, Shitara K, Bando H, Mimaki S, Nakai C, Matsushima K, Suzuki Y, Akagi K, Yamanaka T, Nomura S, Fujii S, Esumi H, Sugiyama M, Nishida N, Mizokami M, Koh Y, Abe Y, Ohtsu A, Tsuchihara K. Clinical significance of BRAF non-V600E mutations on the therapeutic effects of anti-EGFR monoclonal antibody treatment in patients with pretreated metastatic colorectal cancer: the Biomarker Research for anti-EGFR monoclonal Antibodies by Comprehensive Cancer genomics (BREAC) study. Br J Cancer, 117:1450-1458, 2017
29. Enokida T, Fujii S, Takahashi M, Higuchi Y, Nomura S, Wakasugi T, Yamazaki T, Hayashi R, Ohtsu A, Tahara M. Gene expression profiling to predict recurrence of advanced squamous cell carcinoma of the tongue: discovery and external validation. Oncotarget, 8:61786-61799, 2017
30. 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
31. 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
32. Nakaoku T, Kohno T, Araki M, Niho S, Chauhan R, Knowles PP, Tsuchihara K, Matsumoto S, Shimada Y, Mimaki S, Ishii G, Ichikawa H, Nagatoishi S, Tsumoto K, Okuno Y, Yoh K, McDonald NQ, Goto K. A secondary RET mutation in the activation loop conferring resistance to vandetanib. Nat Commun, 9:625, 2018
33. Ueda T, Aokage K, Nishikawa H, Neri S, Nakamura H, Sugano M, Tane K, Miyoshi T, Kojima M, Fujii S, Kuwata T, Ochiai A, Kusumoto M, Suzuki K, Tsuboi M, Ishii G. Immunosuppressive tumor microenvironment of usual interstitial pneumonia-associated squamous cell carcinoma of the lung. J Cancer Res Clin Oncol, 144:835-844, 2018
34. Nakasone S, Mimaki S, Ichikawa T, Aokage K, Miyoshi T, Sugano M, Kojima M, Fujii S, Kuwata T, Ochiai A, Tsuboi M, Goto K, Tsuchihara K, Ishii G. Podoplanin-positive cancer-associated fibroblast recruitment within cancer stroma is associated with a higher number of single nucleotide variants in cancer cells in lung adenocarcinoma. J Cancer Res Clin Oncol, 144:893-900, 2018
35. Ichikawa T, Aokage K, Sugano M, Miyoshi T, Kojima M, Fujii S, Kuwata T, Ochiai A, Suzuki K, Tsuboi M, Ishii G. The ratio of cancer cells to stroma within the invasive area is a histologic prognostic parameter of lung adenocarcinoma. Lung Cancer, 118:30-35, 2018
36. Kadota T, Hatogai K, Yano T, Fujita T, Kojima T, Daiko H, Fujii S. Pathological tumor regression grade of metastatic tumors in lymph node predicts prognosis in esophageal cancer patients. Cancer Sci, 109:2046-2055, 2018
37. Sakai T, Tane K, Usui Y, Miyoshi T, Matsumoto S, Aokage K, Goto K, Suzuki M, Ishii G, Tsuboi M. Utility of Site-Specific Biopsy for Diagnosis of Desmoplastic Malignant Mesothelioma. Ann Thorac Surg, 2018
38. Aokage K, Miyoshi T, Ishii G, Kusumoto M, Nomura S, Katsumata S, Sekihara K, Tane K, Tsuboi M. Influence of Ground Glass Opacity and the Corresponding Pathological Findings on Survival in Patients with Clinical Stage I Non-Small Cell Lung Cancer. J Thorac Oncol, 13:533-542, 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