(PQB-4) Opposing Effects of the SASP in Cancer Progression

(PQB-4) SASP 在癌症进展中的相反作用

• 批准号: 9059048
• 负责人: Utz Herbig
• 金额: $ 32.99万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9059048
• 关键词: Address; Age; Aging; Animal Model; Animals; Benign; Biological; Biological Models; Cell Aging; Cell Fractionation; Cell Proliferation; Cells; Data; Dermal; Development; Elderly; Enzymes; Fibroblasts; Functional disorder; Growth; Health; Human; IL6 gene; Incidence; Individual; Knowledge; Laboratories; Life; Malignant - descriptor; Malignant Neoplasms; Mammalian Cell; Mammals; Mass Spectrum Analysis; Mediating; Molecular; Mus; Neoplasms; Papio; Paracrine Communication; Pathway interactions; Phenotype; Premalignant; Primates; Proliferating; Property; Publishing; Reporting; Resistance; Risk Factors; Signal Pathway; Signal Transduction; Signaling Molecule; Skin; Somatic Cell; Stromal Cells; Stromal Neoplasm; System; TP53 gene; Telomerase; Testing; Therapeutic; Tissues; Transplantation; Tumorigenicity; Work; Xenograft Model; age related; aging population; cancer cell; combat; extracellular; human tissue; in vivo; melanocyte; nonhuman primate; paracrine; response; senescence; telomere; tumor; tumor progression

DESCRIPTION (provided by applicant): Even though it has been evident for decades that aging is a fundamental risk factor in cancer development, we still don't fully understand the causes for this increase. A primary reason for this incomplete understanding is because we still don't know a significant amount about progressive changes that occur in our tissues on the cellular and molecular levels as we get older. To address this critical and unresolved issue, we have been working towards characterizing these changes for several years. Published and ongoing studies in our laboratory have demonstrated an aging associated, and sometime dramatic, accumulation of senescent cells displaying dysfunctional telomeres in various tissues of long lived mammals, including humans. Significantly, cells that had undergone Telomere Dysfunction Induced cellular Senescence (TDIS) also secrete a large number of signaling molecules and matrix remodeling enzymes, suggesting that these cells not only increasing alter structural components of the tissue, but also generate a tissue microenvironment that may promote growth of inactive cancer cells. Indeed, components of this Senescence Associated Secretory Phenotype (SASP) have been demonstrated to promote growth of cancers in animal model systems, although antiproliferative properties of this SASP have also been reported. We have uncovered the reasons for the opposing effects of the SASP on cell proliferation. In this application we will therefore explore whether and to what extent TDIS and the accompanying SASP of stromal and pre- malignant human cells alters tissue microenvironment and therefore contributes to increasing cancer incidences in the aging population. We will 1) identify signaling molecules that trigger TDIS and SASP in somatic human cells, 2) characterize signaling pathways that mediate TDIS in response to extracellular factors, and 3) determine the biological significance of paracrine signaling mediated-TDIS in cancer development. Our comprehensive and multifaceted study will reveal the contributions of the stromal and tumor SASP to aging associated increases in cancer incidences and will therefore provide critical knowledge essential for combating aging associated cancer development.

描述（由申请人提供）：尽管数十年来，衰老是癌症发展的基本危险因素这一点已被证实，但我们仍然不完全了解这种增加的原因。这种不完全理解的主要原因是我们仍然不知道随着年龄的增长，我们的组织在细胞和分子水平上发生的渐进性变化。为了解决这个关键且尚未解决的问题，我们多年来一直致力于描述这些变化的特征。我们实验室已发表和正在进行的研究表明，在包括人类在内的长寿哺乳动物的各种组织中，衰老细胞的积累与衰老相关，有时甚至是戏剧性的，这些细胞表现出功能失调的端粒。值得注意的是，经历端粒功能障碍诱导的细胞衰老（TDIS）的细胞也会分泌大量信号分子和基质重塑酶，这表明这些细胞不仅增加了组织结构成分的改变，而且还产生了可能促进细胞衰老的组织微环境。不活跃的癌细胞的生长。事实上，这种衰老相关分泌表型 (SASP) 的成分已被证明可以促进动物模型系统中癌症的生长，尽管也有报道称这种 SASP 具有抗增殖特性。我们已经揭示了 SASP 对细胞增殖产生相反作用的原因。因此，在本申请中，我们将探讨 TDIS 以及伴随的基质细胞和癌前人类细胞的 SASP 是否以及在何种程度上改变组织微环境，从而导致老龄化人群中癌症发病率的增加。我们将 1) 鉴定在人体细胞中触发 TDIS 和 SASP 的信号分子，2) 表征响应细胞外因子介导 TDIS 的信号通路，以及 3) 确定旁分泌信号介导的 TDIS 在癌症发展中的生物学意义。我们全面、多方面的研究将揭示间质和肿瘤 SASP 对衰老相关癌症发病率增加的贡献，因此将为对抗衰老相关癌症的发展提供至关重要的知识。