Uncovering the Mechanisms by which Aged Stroma Impacts Tumor Initiation

揭示老化基质影响肿瘤发生的机制

基本信息

  • 批准号:
    8461250
  • 负责人:
  • 金额:
    $ 29.65万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-07-01 至 2016-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Age-related changes in the tumor microenvironment are hypothesized to significantly impact tumorigenesis. Investigation into how age contributes to increased cancer incidence has focused on accumulation of autonomous mutations within incipient cancer cells. While it is clear that these mutations are integral to the transformation process, it is now well accepted that the surrounding stroma collaborates in the process and thus contributes to age-dependent increases in cancer incidence. Indeed, "normal" fibroblasts within a tumor secrete factors that promote tumor cell growth. Like genetic mutations, senescent fibroblasts accumulate with age, and recent data suggests that they promote tumorigenesis. We hypothesize that as the number of senescent fibroblasts increase within the stromal compartment with age, they create a pro-tumorigenic environment that promotes tumorigenesis. To test this hypothesis, we created the "FASST" (fibroblasts accelerate stromal-supported tumorigenesis) mouse, which is a novel model that allows us to temporally and spatially control the activation of senescence in the stromal compartment of a young mouse and ask how this impacts tumor latency, penetrance and progression. Using the FASST model, we show that the presence of senescent stroma in young animals accelerates the appearance of papillomas following a classic two-step skin carcinogenesis protocol. The goal of this proposal is to elucidate the mechanisms by which senescent stroma promotes tumorigenesis. First, we will determine if senescence accelerates tumorigenesis by acting locally and/or systemically. Because we have already demonstrated that osteopontin (OPN) is an important senescent stromal-derived factor in the skin, we will focus on OPN and its ability to stimulate preneoplastic cell proliferation directly and its ability elicit a pro-tumor inflammatory response and determine how this impacts tumorigenesis in the FASST model. Finally, we expand these studies to include analysis of tumorigenesis in the breast, which allows us to ask a critical question; does senescence create a general pro-tumorigenic state or is its activities tissue and oncogene specific? The data provided by these questions will shape our general understanding of tumorigenesis and may lead to the identification of novel stromal-specific therapeutic targets. The specific aims of this proposal are: Aim 1: Determine whether cancer promotion by senescent stromal cells acts locally or systemically in a well-characterized two-step skin carcinogenesis model Aim 2: Identify the OPN dependent and independent mechanisms by which senescent stroma accelerate tumorigenesis Aim 3: Determine the tumor-promoting abilities of senescent stroma on breast tumorigenesis.
描述(由申请人提供):肿瘤微环境中与年龄相关的变化被假设为显著影响肿瘤发生。关于年龄如何导致癌症发病率上升的研究,一直集中在早期癌细胞中自主突变的积累上。虽然很明显,这些突变是转化过程中不可或缺的,但现在人们普遍认为,周围的间质在转化过程中相互协作,从而导致癌症发病率的年龄相关性增加。事实上,肿瘤内的“正常”成纤维细胞会分泌促进肿瘤细胞生长的因子。就像基因突变一样,衰老的成纤维细胞会随着年龄的增长而积累,最近的数据表明,它们促进了肿瘤的发生。我们假设,随着间质中衰老成纤维细胞的数量随着年龄的增长而增加,它们创造了促进肿瘤发生的促肿瘤环境。为了验证这一假设,我们创建了“FASST”(成纤维细胞加速间质支持的肿瘤发生)小鼠,这是一个新的模型,允许我们在时间和空间上控制年轻小鼠间质间衰老的激活,并询问这如何影响肿瘤的潜伏期、外显率和进展。使用FASST模型,我们发现幼年动物衰老间质的存在加速了乳头状瘤的出现,遵循经典的两步皮肤癌发生方案。这项建议的目的是阐明衰老间质促进肿瘤发生的机制。首先,我们将确定衰老是否通过局部和/或全身作用来加速肿瘤的发生。由于我们已经证明了骨桥蛋白(OPN)是皮肤中一种重要的衰老基质衍生因子,所以我们将重点介绍OPN及其直接刺激癌前细胞增殖的能力,以及它引发促肿瘤炎症反应的能力,并在FASST模型中确定这如何影响肿瘤的发生。最后,我们将这些研究扩展到包括对乳房肿瘤发生的分析,这使我们能够提出一个关键问题:衰老是否创造了一般的促肿瘤状态,或者它的活动是组织和癌基因特有的吗?这些问题提供的数据将塑造我们对肿瘤发生的一般理解,并可能导致识别新的间质特异性治疗靶点。该建议的具体目的是:目的1:确定衰老间质细胞在两步皮肤癌模型中是否局部或系统地发挥促癌作用。目的2:确定OPN依赖和独立的机制,衰老间质促进肿瘤的发生。目的3:确定衰老间质在乳腺肿瘤发生中的促癌能力。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Sheila A Stewart其他文献

Sheila A Stewart的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Sheila A Stewart', 18)}}的其他基金

MICROENVIRONMENTAL CONTROLS OF TUMOR DORMANCY
肿瘤休眠的微环境控制
  • 批准号:
    9897506
  • 财政年份:
    2018
  • 资助金额:
    $ 29.65万
  • 项目类别:
MICROENVIRONMENTAL CONTROLS OF TUMOR DORMANCY
肿瘤休眠的微环境控制
  • 批准号:
    10376279
  • 财政年份:
    2018
  • 资助金额:
    $ 29.65万
  • 项目类别:
SENESCENT STROMA STIMULATES INFLAMMATION TO PROMOTE TUMORIGENESIS
衰老基质刺激炎症促进肿瘤发生
  • 批准号:
    10057360
  • 财政年份:
    2017
  • 资助金额:
    $ 29.65万
  • 项目类别:
SENESCENT STROMA STIMULATES INFLAMMATION TO PROMOTE TUMORIGENESIS
衰老基质刺激炎症促进肿瘤发生
  • 批准号:
    10310473
  • 财政年份:
    2017
  • 资助金额:
    $ 29.65万
  • 项目类别:
Uncovering the Mechanisms by which Aged Stroma Impacts Tumor Initiation
揭示老化基质影响肿瘤发生的机制
  • 批准号:
    8658021
  • 财政年份:
    2011
  • 资助金额:
    $ 29.65万
  • 项目类别:
Uncovering the Mechanisms by which Aged Stroma Impacts Tumor Initiation
揭示老化基质影响肿瘤发生的机制
  • 批准号:
    8835061
  • 财政年份:
    2011
  • 资助金额:
    $ 29.65万
  • 项目类别:
Uncovering the Mechanisms by which Aged Stroma Impacts Tumor Initiation
揭示老化基质影响肿瘤发生的机制
  • 批准号:
    8286861
  • 财政年份:
    2011
  • 资助金额:
    $ 29.65万
  • 项目类别:
Uncovering the Mechanisms by which Aged Stroma Impacts Tumor Initiation
揭示老化基质影响肿瘤发生的机制
  • 批准号:
    8184104
  • 财政年份:
    2011
  • 资助金额:
    $ 29.65万
  • 项目类别:
HDNA2 IN DNA REPLICATION AND TELOMERE STABILITY
HDNA2 在 DNA 复制和端粒稳定性中的作用
  • 批准号:
    8678946
  • 财政年份:
    2011
  • 资助金额:
    $ 29.65万
  • 项目类别:
HDNA2 IN DNA REPLICATION AND TELOMERE STABILITY
HDNA2 在 DNA 复制和端粒稳定性中的作用
  • 批准号:
    8500390
  • 财政年份:
    2011
  • 资助金额:
    $ 29.65万
  • 项目类别:

相似海外基金

Hormone therapy, age of menopause, previous parity, and APOE genotype affect cognition in aging humans.
激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
  • 批准号:
    495182
  • 财政年份:
    2023
  • 资助金额:
    $ 29.65万
  • 项目类别:
Investigating how alternative splicing processes affect cartilage biology from development to old age
研究选择性剪接过程如何影响从发育到老年的软骨生物学
  • 批准号:
    2601817
  • 财政年份:
    2021
  • 资助金额:
    $ 29.65万
  • 项目类别:
    Studentship
RAPID: Coronavirus Risk Communication: How Age and Communication Format Affect Risk Perception and Behaviors
RAPID:冠状病毒风险沟通:年龄和沟通方式如何影响风险认知和行为
  • 批准号:
    2029039
  • 财政年份:
    2020
  • 资助金额:
    $ 29.65万
  • 项目类别:
    Standard Grant
Neighborhood and Parent Variables Affect Low-Income Preschool Age Child Physical Activity
社区和家长变量影响低收入学龄前儿童的身体活动
  • 批准号:
    9888417
  • 财政年份:
    2019
  • 资助金额:
    $ 29.65万
  • 项目类别:
The affect of Age related hearing loss for cognitive function
年龄相关性听力损失对认知功能的影响
  • 批准号:
    17K11318
  • 财政年份:
    2017
  • 资助金额:
    $ 29.65万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
  • 批准号:
    9320090
  • 财政年份:
    2017
  • 资助金额:
    $ 29.65万
  • 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
  • 批准号:
    10166936
  • 财政年份:
    2017
  • 资助金额:
    $ 29.65万
  • 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
  • 批准号:
    9761593
  • 财政年份:
    2017
  • 资助金额:
    $ 29.65万
  • 项目类别:
How age dependent molecular changes in T follicular helper cells affect their function
滤泡辅助 T 细胞的年龄依赖性分子变化如何影响其功能
  • 批准号:
    BB/M50306X/1
  • 财政年份:
    2014
  • 资助金额:
    $ 29.65万
  • 项目类别:
    Training Grant
Inflamm-aging: What do we know about the effect of inflammation on HIV treatment and disease as we age, and how does this affect our search for a Cure?
炎症衰老:随着年龄的增长,我们对炎症对艾滋病毒治疗和疾病的影响了解多少?这对我们寻找治愈方法有何影响?
  • 批准号:
    288272
  • 财政年份:
    2013
  • 资助金额:
    $ 29.65万
  • 项目类别:
    Miscellaneous Programs
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了