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

在条件性Patchedflox/p53 ERT 2 +/-基因敲除小鼠中，基底细胞癌（BCC）随时间推移而消退，并显示出更分化的表型。有趣的是，这伴随着肿瘤间质中Wnt 5a的上调。体外实验表明，Wnt 5a在肿瘤相邻的巨噬细胞中通过来自BCC细胞的可溶性信号上调。反过来，Wnt 5a诱导肿瘤细胞中分化标志物K10的表达，这是由Wnt/Ca 2+信号以CaMK II依赖性方式介导的。这些数据表明，与许多其他肿瘤相比，BCC基质中的Wnt 5a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Wnt 5a在体内BCC分化和消退中的作用。在携带BCC的皮肤中，Wnt 5a水平将降低（遗传方法，Wnt 5a缺陷型造血干细胞的过继转移，Wnt 5a表达巨噬细胞的消耗）或增加（应用Wnt 5a表达质粒）。其他目的是a）研究Ca 2+和CaMK II依赖性Wnt/Ca 2+信号传导在BCC防御机制中的作用，B）确定负责BCC中CaMK II依赖性Wnt/Ca 2+信号传导激活的Wnt 5a受体，c）鉴定负责肿瘤相关巨噬细胞中Wnt 5a诱导的BCC细胞的可溶性信号，和d）鉴定参与BCC消退的Wnt信号传导级联的其他组分。

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.