The effects of Age on Cancer Signaling Pathways in Mice

描述（申请人提供）：癌症是一种与年龄相关的疾病。在人类和老鼠身上，癌症发病率随着年龄的增长呈指数增长。然而，衰老如何影响癌症发展的机制仍然知之甚少。这项研究的主要目的是探索衰老增加癌症易感性的潜在机制。我们将在衰老的背景下研究致癌信号的组成部分，这些信号可能对癌症的发展很重要。首先，我们将分析肿瘤抑制因子p53在不同年龄丢失对小鼠的影响，表明衰老组织中的p53丢失比年轻组织中的p53丢失更有害。其次，我们将比较不同年龄的致癌基因激活对小鼠肺部的影响。我们假设，细胞在衰老的组织环境中更容易发生致癌转化，而在同样的衰老环境中，对抗转化事件的细胞防御系统变得不那么有效。在本提案中，我们将使用基因工程小鼠模型在不同年龄激活突变的K-Ras癌基因或灭活p53肿瘤抑制基因，以确定癌症信号和应激反应途径中是否存在与年龄相关的差异，以及这些差异是否影响癌症发生和进展的生物学。提出了两个目标。在第一个目标中，我们将在全球范围内删除不同年龄的p53肿瘤抑制基因，并比较在年轻和老年年龄失去p53功能的肿瘤的动力学、生物学和基因表达模式特征。我们还将通过实验探索p53抗癌功能的新模型：p53不仅作为晚期看门人阻止恶性进展，而且在早期发育过程中作为早期看门人抑制基因组不稳定。在第二个目标中，我们将在3、12和24个月大时激活肺中的突变K-Ras癌基因。我们将监测这些K- ras激活小鼠的肿瘤发生进展，并检查致癌信号通路和细胞抗致癌应激通路是否受到年龄的影响。从这些实验中，我们希望对衰老组织如何影响癌症易感性获得重要的新机制见解。

DESCRIPTION (provided by applicant): Cancer is an age-related disease. In humans and mice, cancer incidence increases exponentially with age. However, the mechanisms for how aging affects cancer development remain poorly understood. The primary goal of the proposed research is to explore potential mechanisms by which aging increases cancer susceptibility. We will examine components of oncogenic signaling in the context of aging likely to be important in cancer development. First, we will analyze the effects of tumor suppressor p53 loss at different ages in the mouse to show that p53 loss in aged tissues is more deleterious than in young tissues. Second, we will compare the effects of oncogene activation at various ages in the lungs of mice. We hypothesize that cells become more susceptible to oncogenic transformation in the aged tissue environment and that the cellular defense systems to counteract transformation events become less effective in that same aged environment. In this proposal, we will use genetically engineered mouse models to activate the mutant K-Ras oncogene or inactivate the p53 tumor suppressor gene at different ages to determine whether age-associated differences in cancer signaling and stress response pathways exist and whether these differences affect the biology of cancer development and progression. Two aims are proposed. In the first aim, we will globally delete the p53 tumor suppressor gene at different ages and compare the kinetics,biology, and gene expression patterns characteristic of tumors losing p53 function at young and old ages. We will also perform experiments to explore a novel model of p53 anti-cancer function: that p53 not only acts as a late gatekeeper to prevent malignant progession, but also as an early caretaker to suppress genomic instability during early development. In the second aim, we will activate a mutant K-Ras oncogene in the lung at 3, 12, and 24 months of age. We will monitor the progression of tumorigenesis in these K- Ras-activated mice and also examine whether oncogenic signaling pathways and cellular anti-oncogenic stress pathways are affected by age. From these experiments we hope to gain important new mechanistic insights into how aging tissues affect cancer susceptibility. PUBLIC HEALTH RELEVANCE: Cancer incidence rates are greatly elevated in the final third of the human lifespan. The median age for cancer diagnosis in industrialized countries is near 70 and will increase in the coming years, placing enormous burdens on health care systems. Having a better understanding of how and why aging tissues become cancer susceptible may provide oncologists with better tools for fighting cancer in the elderly.