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

描述(由申请人提供)：尽管几十年来很明显，衰老是癌症发展的一个基本风险因素，但我们仍然不完全了解这种增加的原因。这种不完全理解的一个主要原因是，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进行性变化的大量情况。为了解决这一关键和悬而未决的问题，我们多年来一直在努力确定这些变化的特征。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，与衰老相关的、有时甚至是戏剧性的衰老细胞积累显示出功能失调的端粒。值得注意的是，经历了端粒功能障碍诱导的细胞衰老(TDIS)的细胞还分泌了大量的信号分子和基质重塑酶，这表明这些细胞不仅增加了组织的结构成分，而且产生了可能促进非活性癌细胞生长的组织微环境。事实上，这种衰老相关分泌表型(SASP)的成分已经在动物模型系统中被证明可以促进癌症的生长，尽管这种SASP的抗增殖特性也有报道。我们已经发现了SASP对细胞增殖产生相反影响的原因。因此，在这项应用中，我们将探索TDIS和伴随的间质和癌前细胞的SASP是否以及在多大程度上改变组织微环境，从而导致老年人口癌症发病率的增加。我们将1)确定在人体细胞中触发TDIs和SASP的信号分子，2)表征介导TDIs响应细胞外因素的信号通路，3)确定旁分泌信号介导的TDIs在癌症发展中的生物学意义。我们的全面和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，因此将提供对抗衰老相关癌症发展所必需的关键知识。

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.