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High Delta-Like Ligand 4 Expression Correlates with a Poor Clinical Journal of Cancer 2019, Vol. 10 3172 Ivyspring International Publisher Journal of Cancer 2019; 10(14): 3172-3178. doi: 10.7150/jca.30257 Research Paper High delta-like ligand 4 expression correlates with a poor clinical outcome in gastric cancer Youjin Kim1,2*, Sun-ju Byeon3,4*, Joonyoung Hur1, Kangkook Lee1, Dongin Kim5, Jin-Hyung Ahn5, Sang Hoon Lee5, Weon-Kyoo You5, Seung Tae Kim1, Se Hoon Park1, Won Ki Kang1, Kyoung-Mee Kim3, Jeeyun Lee1 1. Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2. Division of Hematology-Oncology, Department of Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea 3. Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 4. Department of Pathology, Hallym University Dongtan Sacred Heart Hospital, Korea 5. ABL Bio, Korea *Equal contributing authors Corresponding authors: Jeeyun Lee, MD, Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351 (Korea). Tel. +82 2 3410 1779; Fax +82 2 3410 1754; Email: [email protected] and Kyoung-Mee Kim, MD, Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351 (Korea). Tel. +82 2 3410 2807; Fax +82 2 3410 1754; Email: [email protected] © Ivyspring International Publisher. This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions. Received: 2018.09.28; Accepted: 2019.04.30; Published: 2019.06.02 Abstract Background: Emerging evidence suggests that delta-like ligand 4 (DLL4) and other members of the Notch pathway may offer new targets for development of anti-angiogenesis drugs for the treatment of several tumor types. However, the role of DLL4 in gastric cancer (GC) remains unclear. In this study, we investigated the impact of DLL4 overexpression on recurrence and survival in gastric cancer (GC) patients. Methods: DLL4 expression levels were evaluated by immunohistochemistry in tissue samples from 336 GC patients. Samples were classified into high and low DLL4 expression according to a cut-off of 50% positively stained cells. The correlation between DLL4 expression and clinicopathological parameters, disease-free survival (DFS), and overall survival (OS) were statistically analyzed. Results: High DLL4 expression was observed in 67 (19.9%) of the 336 GC patients. After a median follow-up duration of 54.97 months [95% confidence interval (CI), 52.40–57.55 months), patients at stage II-IV with high DLL4 expression showed significantly poorer DFS compared with those at the same stage but with low DLL4 expression [not reached (NR) for both cohorts, hazard ratio (HR) 0.73 (95% CI, 0.38–1.40); p = 0.007]. Likewise, GC patients with high DLL4 expression had a significantly shorter OS following curative surgery compared to those with low DLL4 expression [NR for both groups, HR 0.56 (95% CI, 0.32–0.96; p = 0.002]. High DLL4 expression had a greater influence on DFS in stage IIIb/IV patients than in patients at early stages [34.87 vs. 10.1 months; HR, 0.44 (95% CI, 0.19–0.96); p = 0.004]. Moreover, stage IIIb/IV patients with high DLL4 expression had a significantly shorter OS after surgery than those with low DLL4 expression [58.87 vs. 16.93 months, HR 0.39 (95% CI, 0.16–0.99), p = 0.001). Conclusion: High DLL4 expression was observed in 19.9% of GC patients and was significantly associated with poor survival following curative surgery. Given its prevalence in the GC cohort with a poor prognosis, DLL4 is a potential therapeutic target. Key words: DLL4, Gastric cancer, anti-angiogenesis Introduction In 2012, approximately 951,000 individuals were death of 723,000 individuals worldwide [1]. Most diagnosed with gastric cancer (GC), which led to the patients are diagnosed with GC at a late stage when http://www.jcancer.org Journal of Cancer 2019, Vol. 10 3173 symptoms appear, and thus the prognosis is poor [2]: Materials and Methods the median survival time for recurrent or metastatic GC remains less than 1 year. Recently, Patients anti-angiogenesis agents have emerged as efficacious We used the ARTIST trial results for our anti-tumor drugs against several tumor types, analysis. The complete details of the ARTIST trial are including colorectal cancer and GC. The RAINBOW published elsewhere [13]. In brief, 458 patients with trial, which compared the effects of paclitaxel with or pathological stage Ib–IV (M0) GC, according to the without the anti-vascular endothelial factor receptor 2 American Joint Committee on Cancer 2002 staging (VEGFR2) monoclonal antibody ramucirumab in system, were randomly assigned to receive the second-line chemotherapy for metastatic GC resulted adjuvant XP (n = 228) or XPRT (n = 230) treatment. in improved survival in the paclitaxel/ramucirumab The treatment regimen administered in the XP arm arm [3]. Accordingly, the paclitaxel/ramucirumab included six cycles of 1,000 mg/m2 capecitabine combination is the current standard chemotherapy administered twice daily on days 1–14 and 60 mg/m2 regimen for GC in a second-line setting. Because the cisplatin on day 1. The treatment regimen prognosis remains poor after recurrence following administered in the XPRT arm included concomitant curative surgery, identification of prognostic administration of a total radiotherapy dose of 45 Gy biomarkers associated with pivotal signaling and 825 mg/m2 capecitabine twice daily after pathways is crucial for enhancing survival for GC completion of two cycles of XP, followed by patients {Kim, 2018 #2680}. The most widely administration of two additional cycles of XP. Written prescribed anti-angiogenesis inhibitor is informed consent was obtained from all participating bevacizumab, which is a monoclonal antibody against patients before they were randomly assigned to the human VEGF ligand approved for use in the groups. A total of 336 specimens were available for treatment colorectal and ovarian cancers. further analysis in the present study. VEGF/VEGFR signaling inhibitors block VEGF-driven angiogenesis and thus regress IHC analysis VEGF-dependent tumor vessels. Nevertheless, VEGF Representative tumor areas were selected for all inhibitors alone do not destroy all of the blood vessels available samples, and a tissue microarray was in tumors. Indeed, clinical studies have demonstrated constructed after reviewing a hematoxylin and the emergence of resistance to anti-VEGF eosin-stained section from the donor block. Using this monotherapy [4, 5]. slide for guidance, two representative regions of the A few studies have identified the Notch tumor were sampled from the donor block, and signaling pathway as a newly emerging therapeutic 2-mm-diameter cores were extracted and embedded tumor angiogenesis target [6-8]. Five ligands in the in the array block. Tumor sections from the array Notch signaling pathway (Jagged 1 and 2 and blocks were freshly cut into 3-µm slices, and dried at delta-like ligands 1, 3, and 4) are involved in 60°C for 30 min. For DLL4 IHC, the slides were tumorigenesis, tumor progression, tumor deparaffinized, and endogenous peroxidase was angiogenesis, and chemo-resistance. Among these, blocked for 5 min. Antigen retrieval was performed in delta-like ligand 4 (DLL4) has received the most an autoimmunostainer at 97°C for 20 min with ER1 attention, and DLL4 inhibitors have been developed buffer (pH 6.0). The slides were incubated with mouse that show potent anti-tumor effects in a broad DLL4 monoclonal antibody (HPA023392, 1:150, spectrum of VEGF therapy-resistant xenograft models Sigma-Aldrich) at room temperature for 15 min using [9-12]. Nevertheless, the prevalence of DLL4 a BOND-MAX autoimmunostainer (Leica expression in tumor specimens and its clinical Microsystems, Wetzlar, Germany) and BOND implication in GC has not been extensively studied. Polymer Refine Detection kit (DS9800; Vision Since this information is essential for identifying the BioSystems, Melbourne, Australia). potential target population for anti-DLL4 inhibitor Two well-experienced pathologists examined the treatment, in the present study, we surveyed the IHC slides without prior information about the expression level of DLL4 using immunohistochemical clinicopathological features of the patients. (IHC) analysis in samples obtained from a large and Semiquantitative estimates were achieved using a well-defined cohort from the Adjuvant composite score comprised of the sum of the staining Chemoradiotherapy in Stomach Tumors (ARTIST) intensity values and the relative abundance of trial [13], and evaluated the association of DLL4 positive cells. The intensities were graded as 0 expression with patient survival. (negative), 1 (weakly positive), 2 (moderately positive), and 3 (strongly positive). The abundance of positive cells was graded from 0 to 4 (0<5 % positive http://www.jcancer.org Journal of Cancer 2019, Vol. 10 3174 cells; 1, 5–24 %; 2, 25–49 %; 3, 50–74 %; 4, 75–100 %). Table 1. Patients and disease characteristics in the gastric cancer Based on the distribution of results, low and high and according to DLL4 status. DLL4 expression was defined if <50% or ≥50% of the Characteristic N=336 (%) DLL 4 (low) DLL 4 (high) p value cells were stained with DLL4 monoclonal antibody, n=269 (80.1%) n=67 (19.9%) Age respectively (Fig. 1). Median (range), years 57 (28-77) 56 (28-77) 59 (33-77) 0.104 < 60 195 (58.0) 162 (60.2) 33 (49.3) Statistical analyses >60 141 (42.0) 107 (39.8) 34 (50.7) Sex The correlations between DLL4 expression and Male 217 (64.6) 172 (63.9) 45 (67.2) 0.622 clinical characteristics were analyzed using the χ2 test Female 119 (35.4) 97 (36.1) 22 (32.8) or t-test as appropriate.
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