The role of the Wnt5a/Frizzled5 signaling axis in the development and therapy of helicobacter-associated gastric cancer arising from epithelial stem cells

Wnt5a/Frizzled5信号轴在上皮干细胞产生的螺杆菌相关胃癌的发生和治疗中的作用

• 批准号: 455565488
• 负责人: Dr. Henrik Nienhüser
• 金额: --
• 依托单位: Division of Digestive and Liver Diseases
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/455565488?language=en
• 关键词: role; Wnt5a; Frizzled5; signaling; axis

Gastric cancer is one of the most frequent types of gastrointestinal cancer worldwide and the outcome is still poor. The surgical resection is the only curative treatment but the majority of the patients receives preoperative chemotherapy. The response rates to this therapy vary in each patient and until today, there is no reliable parameter predicting the response to preoperative therapy. One potential reason for this different response are tumor stem cells. In the last years several potential stem cell population in the gastric epithelium have been described. In this project we aim to investigate the relevance of the FZD5/Wnt5a signaling axis on the development of gastric cancer. In a first step we will stain human tissue for FZD5 and perform in-situ hybridisation for Wnt5a since immunhistochemical detection of Wnt5a is quite challenging. Previous studies have shown innate lymphoid cells type 2 (ILC-2) as a major source of Wnt5a in the stomach so that we will perform staining for these cells as well. These parameters will correlated with the clinical patient data to evaluate the potential progonostic value of the expression of these markers in human gastric cancer. In a next step we will investigate this signaling axis in different murine models in detail. For these experiments, different mouse models are available in which these genes can be knocked out. These animals will be infected with Helicobacter ssp. that induce an inflammation. Chronic infection with Helicobacter represents one of the major risks factors for the development of gastric cancer in humans. Using FACS-isolation we will analyse FZD5+ stem cells and investigate the stemness using organoids. Additionally, we aim to identify potential therapeutic targets using RNA-sequencing. The results from these experiment will be validated and tested for the prognostic relevance using the human samples. This project will help to improve the understanding of gastric cancer development following chronic infection with Helicobacter and will provide important knowledge for the improvement of therapy in gastric cancer patients.

胃癌是世界上最常见的胃肠道癌症之一，其预后仍然很差。手术切除是唯一有效的治疗方法，但大多数患者术前接受化疗。每个患者对这种疗法的反应率各不相同，直到今天，还没有可靠的参数预测对术前治疗的反应。这种不同反应的一个潜在原因是肿瘤干细胞。在过去的几年中，已经描述了胃上皮中几种潜在的干细胞群。在本项目中，我们旨在研究FZD5/Wnt5a信号轴在胃癌发生发展中的相关性。第一步，我们将对人体组织进行FZD5染色，并对Wnt5a进行原位杂交，因为Wnt5a的免疫组化检测相当具有挑战性。先前的研究表明，先天淋巴样细胞2型（ILC-2）是胃中Wnt5a的主要来源，因此我们也将对这些细胞进行染色。这些参数将与临床患者数据相关联，以评估这些标志物在人胃癌中的表达的潜在预后价值。下一步，我们将在不同的小鼠模型中详细研究这个信号轴。对于这些实验，有不同的小鼠模型，这些基因可以被敲除。这些动物会感染幽门螺杆菌。会引起炎症。幽门螺杆菌的慢性感染是人类胃癌发生的主要危险因素之一。使用facs分离，我们将分析FZD5+干细胞，并使用类器官研究干性。此外，我们的目标是利用rna测序来确定潜在的治疗靶点。这些实验的结果将通过人类样本进行验证和预后相关性测试。本项目将有助于提高对幽门螺杆菌慢性感染后胃癌发展的认识，为改善胃癌患者的治疗提供重要的知识。