Hironori Takagi1, Songji Zhao2, Satoshi Muto1, Hiroshi Yokouchi3, Hiroshi Nishihara4, Toshiyuki Harada5, Hikaru Yamaguchi1, Hayato Mine1, Masayuki Watanabe1, Yuki Ozaki1, Takuya Inoue1, Takumi Yamaura1, Mitsuro Fukuhara1, Naoyuki Okabe1, Yuki Matsumura1, Takeo Hasegawa1, Jun Osugi1, Mika Hoshino1, Mitsunori Higuchi1, Yutaka Shio1, Ryuzo Kanno6, Miho Aoki2, Chengbo Tan2, Saki Shimoyama2, Shigeo Yamazaki7, Hajime Kikuchi8, Jun Sakakibara-Konishi9, Satoshi Oizumi3, Masao Harada3, Kenji Akie10, Fumiko Sugaya11, Yuka Fujita12, Kei Takamura13, Tetsuya Kojima14, Osamu Honjo15, Yoshinori Minami16, Masaharu Nishimura9, Hirotoshi Dosaka-Akita17, Koji Nakamura18, Akihiro Inano2, Hiroshi Isobe14, Hiroyuki Suzuki19. 1. Department of Chest Surgery, Fukushima Medical University, Fukushima, Japan. 2. Advanced Clinical Research Center, Fukushima Medical University, Fukushima, Japan. 3. Department of Respiratory Medicine, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan. 4. Department of Translational Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan; Genomics Unit, Keio Cancer Center, Keio University School of Medicine, Tokyo, Japan. 5. Center for Respiratory Diseases, JCHO Hokkaido Hospital, Sapporo, Japan. 6. Department of Thoracic Surgery, Fukushima Red Cross Hospital, Fukushima, Japan. 7. Department of Thoracic Surgery, Keiyukai Sapporo Hospital, Sapporo, Japan. 8. First Department of Medicine, Hokkaido University Hospital, Sapporo, Japan; Department of Respiratory Medicine, Obihiro Kosei Hospital, Obihiro, Japan. 9. First Department of Medicine, Hokkaido University Hospital, Sapporo, Japan. 10. Department of Respiratory Disease, Sapporo City General Hospital, Sapporo, Japan. 11. Department of Respiratory Medicine, Teine Keijinkai Hospital, Sapporo, Japan. 12. Department of Respiratory Medicine, National Hospital Organization Asahikawa Medical Center, Asahikawa, Japan. 13. Department of Respiratory Medicine, Obihiro Kosei Hospital, Obihiro, Japan. 14. Department of Medical Oncology, KKR Sapporo Medical Center, Sapporo, Japan. 15. Department of Respiratory Medicine, Sapporo-Kosei General Hospital, Sapporo, Japan; Department of Respiratory Medicine, Sapporo Minami Sanjo Hospital, Sapporo, Japan. 16. Respiratory Center, Asahikawa Medical University, Asahikawa, Japan. 17. Department of Medical Oncology, Hokkaido University Graduate School of Medicine, Sapporo, Japan. 18. Chiome Bioscience Inc., Kawasaki, Japan. 19. Department of Chest Surgery, Fukushima Medical University, Fukushima, Japan. Electronic address: hiro@fmu.ac.jp.
Abstract
OBJECTIVES: Delta-like 1 homolog (DLK1) is a non-canonical Notch ligand known to be expressed in several cancers but whose role in lung cancer is not yet fully understood. We sought to confirm DLK1 expression in small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), and to examine DLK1's clinical significance. Furthermore, we examined the possible utility of DLK1 as a novel target in radioimmunotherapy (RIT). METHODS: We retrospectively assessed the correlation between clinical features and DLK1 expression by immunohistochemistry in resected specimens from 112 patients with SCLC and 101 patients with NSCLC. Moreover, we performed cell and animal experiments, and examined the possibility of RIT targeting DLK1 in SCLC using iodine-125 (125I) -labeled anti-DLK1 antibody, knowing that 125I can be replaced with the alpha-particle-emitter astatine-211 (211At). RESULTS: In SCLC and NSCLC, 20.5 % (23/112) and 16.8 % (17/101) of patients (respectively) had DLK1-positive tumors. In NSCLC, DLK1 expression was associated with recurrence-free survival (P < 0.01) but not with overall survival. In SCLC, there was no association between DLK1 expression and survival. In addition, 125I-labeled anti-DLK1 antibody specifically targeted DLK1 on human SCLC tumor cell lines. Furthermore, 125I-labeled anti-DLK1 antibody was incorporated into tumor tissue in a mouse model. CONCLUSION: A proportion of SCLC and NSCLC exhibits DLK1 expression. As a clinical feature, DLK1 expression could be a promising prognostic factor for recurrence in patients with resected NSCLC. In addition, DLK1 could serve as a new therapeutic target, including RIT, as suggested by our pilot study using a radiolabeled anti-DLK1 antibody in SCLC.
OBJECTIVES:Delta-like 1 homolog (DLK1) is a non-canonical Notch ligand known to be expressed in several cancers but whose role in lung cancer is not yet fully understood. We sought to confirm DLK1 expression in small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), and to examine DLK1's clinical significance. Furthermore, we examined the possible utility of DLK1 as a novel target in radioimmunotherapy (RIT). METHODS: We retrospectively assessed the correlation between clinical features and DLK1 expression by immunohistochemistry in resected specimens from 112 patients with SCLC and 101 patients with NSCLC. Moreover, we performed cell and animal experiments, and examined the possibility of RIT targeting DLK1 in SCLC using iodine-125 (125I) -labeled anti-DLK1 antibody, knowing that 125I can be replaced with the alpha-particle-emitter astatine-211 (211At). RESULTS: In SCLC and NSCLC, 20.5 % (23/112) and 16.8 % (17/101) of patients (respectively) had DLK1-positive tumors. In NSCLC, DLK1 expression was associated with recurrence-free survival (P < 0.01) but not with overall survival. In SCLC, there was no association between DLK1 expression and survival. In addition, 125I-labeled anti-DLK1 antibody specifically targeted DLK1 on humanSCLC tumor cell lines. Furthermore, 125I-labeled anti-DLK1 antibody was incorporated into tumor tissue in a mouse model. CONCLUSION: A proportion of SCLC and NSCLC exhibits DLK1 expression. As a clinical feature, DLK1 expression could be a promising prognostic factor for recurrence in patients with resected NSCLC. In addition, DLK1 could serve as a new therapeutic target, including RIT, as suggested by our pilot study using a radiolabeled anti-DLK1 antibody in SCLC.