Regulation of Oncogene-Induced Senescence by Wnt-Signaling

Wnt 信号传导调控癌基因诱导的衰老

基本信息

批准号：
7464069
负责人：
PETER D. ADAMS
金额：
$ 32.32万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-01 至 2008-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7464069
关键词：
Aberrant crypt foci Adult Affect Automobile Driving Benign CDKN2A gene Cancerous Cell Aging Cell Line Cell Proliferation Cells Coculture Techniques Colon Colon Carcinoma DNA biosynthesis DNA chemical synthesis Data Development Epigenetic Process Epithelial Cells Event Frequencies Genes Genetic Genus Cola Growth Heterochromatin Human In Vitro K-ras Oncogene Lead Lesion Ligands Malignant - descriptor Malignant Neoplasms Malignant neoplasm of prostate Mammalian Cell Mammals Melanocytic nevus Melanoma Cell Mole the mammal Molecular Mus Mutation Nevus Nuclear Numbers Oncogenes Oncogenic Pathway interactions Patients Population Process Prostate Protein p53 Public Health Ras Signaling Pathway Regulation Repression Retinoblastoma Protein Signal Pathway Signal Transduction Stem cells T-Cell Lymphoma TP53 gene Testing Thinking Tissues Transducers Tumor Suppression Tumor Suppressor Genes United States base cell transformation daughter cell extracellular gene repression in vivo keratinocyte killings melanocyte melanoma mouse model neoplastic neoplastic cell prevent programs ras Oncogene research study senescence tumor tumor progression tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Development of cancer is typically a multi-step process that depends on many genetic and epigenetic alterations in the tumor cells. In addition, cancer progression is modulated by interactions between the tumor cells and extracellular growth signals. This application investigates how genetic alterations and specific extracellular growth signals interact to modulate tumor progression. Mammalian cells that acquire a single activated oncogene frequently enter a state of irreversible proliferation arrest, called senescence. This "oncogene-induced senescence" acts an important tumor suppression process, by arresting proliferation of nascent tumor cells and therefore preventing their progression along a tumorigenic pathway. Formation of several cancers is suppressed by this mechanism, including human melanomas, human prostate cancer, T-cell lymphomas in mice and, likely, colon cancers. Most strikingly, benign human nevi (moles) are pre-neoplastic lesions comprised of melanocytes, made senescent by oncogenic activation of the Ras-signaling pathway. In mammalian tissues, the canonical Wnt-signaling pathway typically maintains cell proliferation, for example of adult tissue stem cells. This pathway is activated by extracellular Wnt ligands that trigger a cascade of cytoplasmic and nuclear events, culminating in expression of proliferative genes. Recently, we found that Wnt-signaling antagonizes oncogene-induced senescence, and vice versa. This points to a previously unappreciated cross-talk between these two very important cell proliferation- control processes, both of great significance to cancer. In particular, these results suggest that extracellular growth signals, such as canonical Wnt ligands, can modulate cancer progression by affecting the efficiency of oncogene-induced senescence and its resultant tumor suppression activity. We will test these ideas through the following Specific Aims: Specific Aim 1. Define how Wnt-signaling suppresses oncogene-induced senescence. Specific Aim 2. Investigate whether Wnt-signaling drives melanoma formation by inhibiting oncogene- induced senescence in melanocytes. Specific Aim 3. Investigate whether Wnt-signaling drives colon cancer by inhibiting oncogene-induced senescence in colonic epithelial cells. PUBLIC HEALTH RELEVANCE: Recently, we found that Wnt signaling (tumor-promoting) suppresses oncogene-induced senescence (tumor-suppressing). We will test whether this new-found functional interaction contributes to tumor progression in vivo. Specifically, we will focus on melanoma and colon cancer, two cancers which between them kill about 60,000 people a year in the United States.

描述（由申请人提供）：癌症的发展通常是一个多步过程，取决于肿瘤细胞中许多遗传和表观遗传学的改变。此外，癌症的进展是由肿瘤细胞与细胞外生长信号之间的相互作用调节的。该应用研究了遗传改变和特定的细胞外生长信号如何相互作用以调节肿瘤进展。获得单个激活癌基的哺乳动物细胞经常进入一种不可逆的增生停滞状态，称为衰老。这种“癌基因诱导的衰老”起着重要的肿瘤抑制过程，它通过阻止了新生肿瘤细胞的增殖，从而防止其沿肿瘤途径的进展。这种机制抑制了几种癌症的形成，包括人类黑色素瘤，人前列腺癌，小鼠中的T细胞淋巴瘤以及可能的结肠癌。最引人注目的是，良性人Nevi（痣）是由黑素细胞组成的塑性病变，通过对RAS信号途径的致癌激活使衰老。在哺乳动物组织中，规范的WNT信号途径通常保持细胞增殖，例如成人组织干细胞。该途径是由触发一系列细胞质和核事件的细胞外Wnt配体激活的，最终导致增殖基因的表达。最近，我们发现，Wnt信号会拮抗癌基因引起的衰老，反之亦然。这表明，这两个非常重要的细胞增殖控制过程之间先前未经批准的串扰，这对癌症都有意义。特别是，这些结果表明，细胞外生长信号（例如典型的Wnt配体）可以通过影响癌基因诱导的衰老的效率及其所致的肿瘤抑制活性来调节癌症的进展。我们将通过以下特定目的来测试这些想法：特定目标1。定义WNT信号如何抑制癌基因引起的衰老。具体目的2。研究Wnt信号是否通过抑制癌基因诱导的黑素细胞衰老来驱动黑色素瘤形成。具体目标3。研究WNT信号是否通过抑制癌基因诱导的结肠上皮细胞衰老来驱动结肠癌。公共卫生相关性：最近，我们发现Wnt信号传导（促进肿瘤）抑制了癌基因引起的衰老（肿瘤抑制）。我们将测试这种新发现的功能相互作用是否有助于体内肿瘤进展。具体来说，我们将专注于黑色素瘤和结肠癌，两种癌症在美国每年杀死约60,000人。