Leiden University Medical Center, Center for Proteomics and Metabolomics, Postbus 9600, 2300 RC Leiden, The Netherlands.
Department of Chemical Biology and Drug Discovery, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
Theranostics. 2022 May 26;12(10):4498-4512. doi: 10.7150/thno.72818. eCollection 2022.
Cells are covered with a dense layer of carbohydrates, some of which are solely present on neoplastic cells. The so-called tumor-associated carbohydrate antigens (TACAs) are increasingly recognized as promising targets for immunotherapy. These carbohydrates differ from those of the surrounding non-cancerous tissues and contribute to the malignant phenotype of the cancer cells by promoting proliferation, metastasis, and immunosuppression. However, due to tumor tissue heterogeneity and technological limitations, TACAs are insufficiently explored. A workflow was established to decode the colorectal cancer (CRC)-associated -linked glycans from approximately 20,000 cell extracts. Extracts were obtained through laser capture microdissection of formalin fixed paraffin embedded tissues of both primary tumors and metastatic sites, and compared to healthy colon mucosa from the same patients. The released -glycans were analyzed by porous graphitized carbon liquid chromatography-tandem mass spectrometry in negative ion mode. Distinctive -glycosylation features were found in cancerous, stromal and normal colon mucosal regions. Over 100 -linked glycans were detected in cancerous regions with absence in normal mucosa. From those, six core 2 -glycans were exclusively found in more than 33% of the cancers, carrying the terminal (sialyl-)Lewis antigen. Moreover, two -glycans were present in 72% of the analyzed cancers and 94% of the investigated cancers expressed at least one of these two -glycans. In contrast, normal colon mucosa predominantly expressed core 3 -glycans, carrying α2-6-linked sialylation, (sulfo-)Lewis and Sda antigens. In this study, we present a novel panel of highly specific TACAs, based upon differences in the glycomic profiles between CRC and healthy colon mucosa. These TACAs are promising new targets for development of innovative cancer immune target therapies and lay the foundation for the targeted treatment of CRC.
细胞表面覆盖着一层密集的碳水化合物，其中一些仅存在于肿瘤细胞上。所谓的肿瘤相关碳水化合物抗原（TACA）越来越被认为是免疫治疗的有前途的靶点。这些碳水化合物与周围正常组织的碳水化合物不同，通过促进增殖、转移和免疫抑制作用，促进癌细胞的恶性表型。然而，由于肿瘤组织的异质性和技术限制，TACA 的研究还不够充分。
建立了一种工作流程，从大约 20000 个细胞提取物中解码结直肠癌（CRC）相关的连接聚糖。提取物通过对原发肿瘤和转移部位的福尔马林固定石蜡包埋组织进行激光捕获微切割获得，并与来自同一患者的健康结肠黏膜进行比较。通过负离子模式的多孔石墨化碳液相色谱-串联质谱分析释放的-聚糖。
在癌性、基质和正常结肠黏膜区域发现了独特的-糖基化特征。在癌性区域检测到 100 多种-连接聚糖，而在正常黏膜中不存在。其中，六种核心 2-聚糖仅在超过 33%的癌症中发现，携带末端（唾液酸-）Lewis 抗原。此外，两种-聚糖存在于 72%的分析癌症中，94%的研究癌症表达至少其中一种-聚糖。相比之下，正常结肠黏膜主要表达携带α2-6 连接唾液酸化、（磺基-）Lewis 和 Sda 抗原的核心 3-聚糖。
在这项研究中，我们提出了一组基于 CRC 和健康结肠黏膜之间糖基化谱差异的新型高度特异性 TACA。这些 TACA 是开发创新癌症免疫靶向治疗的有前途的新靶点，并为 CRC 的靶向治疗奠定了基础。
