BACKGROUND In colorectal cancer, hPG80 (progastrin) is released from tumor cells, promotes cancer stem cells (CSC) self-renewal and is detected in the blood of patients. Because the gene GAST that encodes hPG80 is a target gene of oncogenic pathways that are activated in many tumor types, we hypothesized that hPG80 could be expressed by tumors from various origins other than colorectal cancers, be a drug target and be detectable in the blood of these patients. METHODS hPG80 expression was monitored by fluorescent immunohistochemistry and mRNA expression in tumors from various origins. Cancer cell lines were used in sphere forming assay to analyze CSC self-renewal. Blood samples were obtained from 1546 patients with 11 different cancer origins and from two retrospective kinetic studies in patients with peritoneal carcinomatosis or hepatocellular carcinomas. These patients were regularly sampled during treatments and assayed for hPG80. FINDINGS We showed that hPG80 was present in the 11 tumor types tested. In cell lines originating from these tumor types, hPG80 neutralization decreased significantly CSC self-renewal by 28 to 54%. hPG80 was detected in the blood of patients at significantly higher concentration than in healthy blood donors (median hPG80: 4.88 pM versus 1.05 pM; p < 0.0001) and shown to be correlated to GAST mRNA levels in the matched tumor (i.e., lung cancers, Spearman r = 0.8; p = 0.0023). Furthermore, we showed a strong association between longitudinal hPG80 concentration changes and anti-cancer treatment efficacy in two independent retrospective studies. In the peritoneal carcinomatosis cohort, median hPG80 from inclusion to the post-operative period decreased from 5.36 to 3.00 pM (p < 0.0001, n = 62) and in the hepatocellular carcinoma cohort, median hPG80 from inclusion to remission decreased from 11.54 pM to 1.99 pM (p < 0.0001, n = 63). INTERPRETATION Because oncogenic hPG80 is expressed in tumor cells from different origins and because circulating hPG80 in the blood is related to the burden/activity of the tumor, it is a promising cancer target for therapy and for disease monitoring. FUNDINGS ECS-Progastrin.

中文翻译：

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致癌和可药物化的 hPG80（前胃泌素）在多种癌症中过度表达，并在患者血液中检测到。

背景技术在结直肠癌中，hPG80（前胃泌素）从肿瘤细胞中释放出来，促进癌症干细胞（CSC）自我更新，并在患者血液中检测到。因为编码 hPG80 的基因 GAST 是在许多肿瘤类型中被激活的致癌途径的靶基因，我们假设 hPG80 可以在结直肠癌以外的各种来源的肿瘤中表达，成为药物靶点并且可以在血液中检测到。这些病人。方法 hPG80 表达通过荧光免疫组织化学和不同来源肿瘤中的 mRNA 表达进行监测。癌细胞系用于球体形成测定以分析 CSC 自我更新。血液样本来自 11 种不同癌症起源的 1546 名患者，以及腹膜癌病或肝细胞癌患者的两项回顾性动力学研究。在治疗期间定期对这些患者进行取样并测定 hPG80。结果 我们发现 hPG80 存在于测试的 11 种肿瘤类型中。在源自这些肿瘤类型的细胞系中，hPG80 中和作用显着降低了 CSC 自我更新 28% 至 54%。在患者血液中检测到的 hPG80 浓度显着高于健康献血者（中位 hPG80：4.88 pM 对 1.05 pM；p < 0.0001），并显示与匹配肿瘤（即肺癌、斯皮尔曼 r = 0.8；p = 0.0023）。此外，我们在两项独立的回顾性研究中显示了纵向 hPG80 浓度变化与抗癌治疗效果之间的强关联。在腹膜癌病队列中，从纳入到术后期间的中位 hPG80 从 5.36 pM 下降到 3.00 pM（p < 0.0001，n = 62），在肝细胞癌队列中，从纳入到缓解的中位 hPG80 从 11.54 pM 下降到 1.99 pM (p < 0.0001, n = 63)。解释 因为致癌的 hPG80 在不同来源的肿瘤细胞中表达，并且血液中的循环 hPG80 与肿瘤的负荷/活动有关，所以它是治疗和疾病监测的有希望的癌症靶点。资金 ECS-前胃泌素。从纳入到术后期间的中位 hPG80 从 5.36 pM 下降到 3.00 pM（p < 0.0001，n = 62），在肝细胞癌队列中，从纳入到缓解的中位 hPG80 从 11.54 pM 下降到 1.99 pM（p < 0.0001， n = 63)。解释 因为致癌的 hPG80 在不同来源的肿瘤细胞中表达，并且血液中的循环 hPG80 与肿瘤的负荷/活动有关，所以它是治疗和疾病监测的有希望的癌症靶点。资金 ECS-前胃泌素。从纳入到术后期间的中位 hPG80 从 5.36 pM 下降到 3.00 pM（p < 0.0001，n = 62），在肝细胞癌队列中，从纳入到缓解的中位 hPG80 从 11.54 pM 下降到 1.99 pM（p < 0.0001， n = 63)。解释 因为致癌的 hPG80 在不同来源的肿瘤细胞中表达，并且血液中的循环 hPG80 与肿瘤的负荷/活动有关，所以它是治疗和疾病监测的有希望的癌症靶点。资金 ECS-前胃泌素。解释 因为致癌的 hPG80 在不同来源的肿瘤细胞中表达，并且血液中的循环 hPG80 与肿瘤的负荷/活动有关，所以它是治疗和疾病监测的有希望的癌症靶点。资金 ECS-前胃泌素。解释 因为致癌的 hPG80 在不同来源的肿瘤细胞中表达，并且血液中的循环 hPG80 与肿瘤的负荷/活动有关，所以它是治疗和疾病监测的有希望的癌症靶点。资金 ECS-前胃泌素。