Interaction between Hh/Ptch and Wnt5a Signaling Pathways in Regression of Basal Cell Carcinoma

Hh/Ptch 和 Wnt5a 信号通路在基底细胞癌消退中的相互作用

• 批准号: 52875439
• 负责人: Professorin Dr. Heidi Hahn
• 金额: --
• 依托单位: Institut für Humangenetik
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/52875439?language=en
• 关键词: Interaction; between; Hh; Ptch; Wnt5a

In conditional Patchedflox/floxERT2+/- knock-out mice, basal cell carcinoma (BCC) regress with time and show a more differentiated phenotype. Interestingly, this is accompanied by upregulation of Wnt5a in the tumor-stroma. In vitro experiments revealed that Wnt5a is upregulated in tumor-adjacent macrophages by soluble signals derived from BCC cells. In turn Wnt5a induces the expression of the differentiation marker K10 in tumor cells, which is mediated by Wnt/Ca2+ signaling in a CaMKII-dependent manner. These data suggest that, in contrast to many other tumors, Wnt5a upregulation in the stroma of BCC is a tumor-defense mechanism leading to BCC regression and differentiation. The current aim is to verify the role of Wnt5a in differentiation and regression of BCC in vivo. Wnt5a levels will be either decreased (genetic approach, adoptive transfer of Wnt5a-deficient haematopoietic stem cells, depletion of Wnt5a-expressing macrophages) or increased (application of a Wnt5a expression plasmid) in BCC-bearing skin. Other aims are to a) investigate the role of Ca2+ and CaMKII-dependent Wnt/Ca2+ signaling in BCC-defense-mechanisms, b) determine the Wnt5a receptor responsible for activation of CaMKII-dependent Wnt/Ca2+ signaling in BCC, c) identify the soluble signals of BCC cells responsible for induction of Wnt5a in tumor-associated macrophages and d) identify other components of the Wnt signaling cascade involved in BCC regression.

在条件性 Patchedflox/floxERT2+/- 基因敲除小鼠中，基底细胞癌 (BCC) 随着时间的推移而消退，并显示出更加分化的表型。有趣的是，这伴随着肿瘤间质中 Wnt5a 的上调。体外实验表明，来自 BCC 细胞的可溶性信号使肿瘤邻近巨噬细胞中的 Wnt5a 上调。反过来，Wnt5a 诱导肿瘤细胞中分化标志物 K10 的表达，这是由 Wnt/Ca2+ 信号以 CaMKII 依赖性方式介导的。这些数据表明，与许多其他肿瘤相比，BCC 基质中 Wnt5a 的上调是导致 BCC 消退和分化的肿瘤防御机制。目前的目的是验证Wnt5a在体内BCC分化和消退中的作用。在携带 BCC 的皮肤中，Wnt5a 水平会降低（遗传方法、Wnt5a 缺陷型造血干细胞的过继转移、表达 Wnt5a 的巨噬细胞的耗竭）或升高（应用 Wnt5a 表达质粒）。其他目标是 a) 研究 Ca2+ 和 CaMKII 依赖性 Wnt/Ca2+ 信号传导在 BCC 防御机制中的作用，b) 确定 BCC 中负责激活 CaMKII 依赖性 Wnt/Ca2+ 信号传导的 Wnt5a 受体，c) 鉴定负责在肿瘤相关巨噬细胞中诱导 Wnt5a 的 BCC 细胞的可溶性信号，以及 d) 鉴定 BCC 中负责诱导 Wnt5a 的 BCC 细胞的可溶性信号。 Wnt 信号级联参与 BCC 回归。