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

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，并表现出更多的分化表型。有趣的是，这伴随着Wnt5a在肿瘤间质中的上调。体外实验表明，Wnt5a在肿瘤周围的巨噬细胞中通过来自BCC细胞的可溶性信号上调。反过来，Wnt5a诱导肿瘤细胞中分化标记K10的表达，这是由Wnt/Ca~(2+)信号以CaMKII依赖的方式介导的。这些数据表明，与许多其他肿瘤相比，基底细胞癌间质中WNT5a的上调是导致基底细胞癌退化和分化的一种肿瘤防御机制。目前的目的是在体内验证Wnt5a在BCC分化和消退中的作用。在BCC皮肤中，Wnt5A水平要么降低(遗传途径、过继转移Wnt5a缺陷的造血干细胞、去除表达Wnt5a的巨噬细胞)，要么升高(应用Wnt5a表达质粒)。其他目的是：a)研究钙离子和CaMKII依赖的Wnt/Ca~(2+)信号在BCC防御机制中的作用；b)确定在BCC中激活依赖CaMKII的WNT/Ca~(2+)信号的Wnt5a受体；c)确定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)确定参与BCC回归的Wnt信号级联的其他成分。

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.