Glycan expression profile of signet ring cell gastric cancer cells and potential applicability of rBC2LCN-targeted lectin drug conjugate therapy
Glycan expression profile of signet ring cell gastric cancer cells and potential applicability of rBC2LCN-targeted lectin drug conjugate therapy
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DOI：
10.1007/s10120-022-01312-x
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发表时间：
2022-06-17
期刊：
影响因子：
7.4
通讯作者：
Oda，Tatsuya
中科院分区：
文献类型：
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作者：
Yang，Yu;Akashi，Yoshimasa;Oda，Tatsuya
背景印戒细胞癌（SRC）是胃癌（GC）的一种独特亚型；然而，癌细胞表面聚糖和糖基化的具体特征仍不清楚。在本研究中，我们使用凝集素微阵列研究了 SRC 特异性聚糖，并评估了聚糖靶向治疗的潜在适用性。方法对 SRC 细胞系（NUGC-4 和 KATO-III）和非 SRC (NSRC) 细胞系（NCI-N87、SNU-1 和 MKN-45）进行凝集素微阵列分析，以鉴定 SRC 特异性聚糖。此外，我们还进行了免疫组织化学凝集素染色，并使用高亲和力凝集素对 SRC 评估了凝集素药物缀合物 (LDC) 的抗肿瘤作用。结果在测试的 96 种凝集素中，鉴定出 11 种高亲和力凝集素和 8 种低亲和力凝集素可用于 SRC。高亲和力凝集素中的聚糖结合基序有所不同，但 5 种 (62.5%) 低亲和力凝集素结合相同的聚糖结构，即 α2-6 连接的唾液酸。 SRC 与 NSRC 的信号强度比 (SRC/NSRC) 在 rBC2LCN 凝集素中最高（1.930 倍），其次是 BPL 凝集素（1.786 倍）。 rBC2LCN 凝集素对两种 SRC 细胞系和三种 NSRC 细胞系之一 (NCI-N87) 显示出高亲和力。 LDC、rBC2LCN-PE38（rBC2LCN 和假单胞菌外毒素 A）的治疗效果在体外显示出杀细胞作用，在体内小鼠异种移植模型中显示出肿瘤消退作用。结论我们报告了 SRC 细胞中的特定聚糖谱，显示 α2-6 连接唾液酸减少。此外，我们发现使用 rBC2LCN 凝集素的靶向治疗可能适用于 SRC 患者的替代治疗选择。
BackgroundSignet ring cell carcinoma (SRC) is a distinct subtype of gastric cancer (GC); however, the specific characteristics of cancer cell surface glycans and glycosylation remain unclear. In this study, we investigated SRC-specific glycans using lectin microarray and evaluated the potential applicability of a glycan-targeting therapy.MethodsSRC cell lines (NUGC-4 and KATO-III) and non-SRC (NSRC) cell lines (NCI-N87, SNU-1, and MKN-45) were subjected to lectin microarray analysis to identify the SRC-specific glycans. Additionally, we performed immunohistochemical lectin staining and evaluated the anti-tumor effects of lectin drug conjugates (LDCs) using high-affinity lectins for SRC.ResultsAmong the 96 lectins tested, 11 high-affinity and 8 low-affinity lectins were identified for SRC. Glycan-binding motifs varied in the high-affinity lectins, but 5 (62.5%) low-affinity lectins bound the same glycan structure, α2–6-linked sialic acids. The ratio of signal intensity in SRC to NSRC (SRC/NSRC) was highest in the rBC2LCN lectin (1.930-fold), followed by the BPL lectin (1.786-fold). rBC2LCN lectin showed high affinity for both SRC cell lines and one of the three NSRC cell lines (NCI-N87). The therapeutic effects of the LDC, rBC2LCN-PE38 (rBC2LCN, andPseudomonasexotoxin A), showed cytocidal effects in vitro and tumor regression in in vivo mouse xenograft models.ConclusionWe reported specific glycan profiles in SRC cells, showing reduced α2–6-linked sialic acids. Additionally, we found a targeted therapy using rBC2LCN lectin might be applicable as an alternative treatment option for patients with SRC.