Embryonic Stem Cell Properties in Cancer

描述（由申请人提供）：Wnt信号蛋白--连环蛋白的不适当激活导致广泛器官的癌症，包括约90%的结直肠癌。连环蛋白也被证明可以促进成体干细胞和胚胎干细胞的自我更新。一些研究表明，<$-catenin对干细胞的影响与其致癌能力直接相关;然而，Tcf-<$-catenin对干细胞和肿瘤形成的影响的下游机制仍然是该领域的一个重要问题。为了-catenin刺激肿瘤形成和干细胞自我更新，它结合Tcf蛋白家族的成员，作为Wnt-catenin信号传导的DNA结合效应物。一种Tcf蛋白Tcf 3在几种不同类型的干细胞（造血干细胞、神经干细胞、胚胎干细胞、毛囊干细胞）中表达，这些干细胞对β-连环蛋白水平敏感。我们的初步研究表明，Tcf 3在干细胞中作为<$-catenin的抑制剂发挥作用，这表明Tcf 3可能具有肿瘤抑制剂样功能。该提案的重点是Tcf 3在小鼠中的作用，特别是因为它们与干细胞自我更新和肿瘤形成有关。我们提出两个具体目标：（1）确定Tcf 3在预防其高度表达的器官（前列腺、结肠）和我们发现在TCF 3 +/-小鼠中发生肿瘤的器官（子宫）中的癌症方面的功能，以及（2）阐明Tcf 3调节干细胞自我更新的下游分子机制。TCF 3条件性基因敲除小鼠（Aim 1）中下游机制（Aim 2）的检查将用于确定小鼠缺陷的根本原因。这些实验将对干细胞自我更新和肿瘤形成的潜在分子控制产生重要的新认识。如果他们证明Tcf 3的缺失导致肿瘤形成，他们将鉴定出一种潜在的新型肿瘤抑制基因。如果他们发现Tcf 3的丢失不会导致癌症易感性，他们将确定安全的基于细胞的治疗方法的新途径，以促进干细胞自我更新。公共卫生相关性：这项拟议中的研究将阐明干细胞中的基因决定干细胞是否会产生更多的干细胞、产生不同的细胞类型或停止分裂的基本机制。此外，使用小鼠进行的强大遗传实验将确定影响成体干细胞中这些基本机制的分子控制的缺陷如何导致子宫，结肠和前列腺等器官的恶性肿瘤。

DESCRIPTION (provided by applicant): Inappropriate activation of the Wnt-signaling protein, ¿-catenin causes cancer in a wide range of organs, including ~90% of colorectal cancers. ¿ -catenin has also been shown to promote self-renewal of adult stem cells and embryonic stem cells. Several studies suggest that effects of ¿ -catenin on stem cells are directly linked to its ability to cause cancer; however the downstream mechanisms connecting Tcf- ¿ -catenin effects on stem cells and tumor formation remain a significant question in the field. In order for ¿ -catenin to stimulate tumor formation and stem cell self-renewal, it binds to members of the Tcf family of proteins, which function as the DNA-binding effectors of Wnt- ¿ -catenin signaling. One Tcf protein, Tcf3, is expressed in several different types of stem cells (hematopoietic, neural, embryonic, hair follicle) that are sensitive to ¿-catenin levels. Our preliminary studies demonstrate that Tcf3 functions as an inhibitor of ¿ -catenin in stem cells, suggesting the possibility that Tcf3 has tumor suppressor-like functions. This proposal focuses on the effects of Tcf3 in mice specifically as they relate to stem cell self renewal and tumor formation. We propose two specific aims: (1) to determine the function of Tcf3 in preventing cancer in organs where it is highly expressed (prostate, colon) and in an organ (uterus) that we found to develop tumors in TCF3+/- mice, and (2) to elucidate the downstream molecular mechanisms used by Tcf3 that regulate stem cell self renewal. Examination of the downstream mechanisms (Aim 2) in TCF3 conditional knockout mice (Aim 1) will be used to determine the underlying cause of defects in mice. The proposed experiments will generate important new understanding into the underlying molecular controls of stem cell self renewal and tumor formation. Should they demonstrate that loss of Tcf3 leads to tumor formation, they will identify a potentially novel tumor suppressor gene. Should they reveal that loss of Tcf3 does not confer a susceptibility to cancer, they will identify new avenues for safe cell-based therapeutics to promote stem cell self renewal. PUBLIC HEALTH RELEVANCE: The proposed research will elucidate fundamental mechanisms by which genes in stem cells determine whether stem cells will make more stem cells, make different cell types, or stop dividing. In addition, powerful genetic experiments using mice will determine how defects affecting the molecular control of these fundamental mechanisms in adult stem cells could lead to malignancies in organs such as the uterus, colon and prostate.