The role of senescent cells in late-life tumorigenesis

描述(申请人提供)：高龄是癌症，尤其是上皮癌的主要危险因素。然而，晚年恶性肿瘤急剧增加的基本机制仍然很大程度上尚不清楚，这阻碍了预防或减弱晚年肿瘤发生的干预措施的发展。长期以来，人们一直推测，随着年龄的增长，在许多组织和器官中积累的衰老细胞会刺激癌细胞的发展和扩散。乍一看，这似乎是自相矛盾的，因为细胞衰老被广泛认为是一种关键的抗癌机制，可以防止处于肿瘤转化风险的细胞的生长。然而，来自体外研究的最新证据支持这样的观点，即细胞衰老可能通过创造一个有利于肿瘤形成的环境来刺激肿瘤的发生。衰老细胞形成一种复杂的表型，称为衰老相关分泌表型(SASP)，在这种表型中，它们分泌大量的生长因子、细胞因子和蛋白水解酶。据认为，这种分泌体扰乱了组织中邻近细胞的结构和功能，并创造了一个允许肿瘤病变增殖和扩散的微环境。测试这一点的关键障碍是 体内的想法是缺乏一种允许选择性消除衰老细胞的小鼠模型。我们利用衰老的生物标记物p16INK4a，产生了一种新的转基因INK-ATTAC，它可以在给药后移除p16INK4a阳性的衰老细胞。利用这个和其他小鼠模型，我们将检验中心假设，即细胞衰老与肿瘤的发展有因果关系，移除衰老细胞，或它们分泌的关键恶性肿瘤相关因子，将具有深刻的肿瘤保护作用。我们提出了三个具体目标。在第一个目标中，我们将确定 哪些衰老细胞的晚期清除抑制了肺癌和乳腺癌的发展和转移。在第二个目标中，我们将确定衰老细胞的分泌表型随着年龄的增长在不同的小鼠组织中自然积累的性质和后果。在第三个目标中，我们将通过敲除衰老细胞中特定的促肿瘤SASP成分，然后测量其对小鼠乳腺肿瘤形成的影响，来剖析衰老细胞驱动肿瘤发生的机制。该项目的总体影响是，它将批判性地检验长期以来未经检验的假设，即衰老细胞促进肿瘤发生，解决关于自然发生的衰老细胞的关键基本问题，确定促进肿瘤发展和/或转移的SASP的关键成分，并测试以衰老细胞或SASP的关键成分为靶点的全新概念作为抗癌治疗策略。

DESCRIPTION (provided by applicant): Advanced age is the major risk factor for cancer, particularly epithelial cancers. However the fundamental mechanisms underlying the dramatic increase in malignancies later in life remain largely unknown, impeding the development of interventions that prevent or attenuate late-life tumorigenesis. It has long been speculated that senescent cells, which accumulate with aging in many tissues and organs, stimulate the development and dissemination of cancer cells. At first glance, this seems paradoxical because cellular senescence is widely recognized as a crucial anticancer mechanism that prevents the growth of cells at risk for neoplastic transformation. However, recent evidence from in vitro studies supports the idea that cellular senescence may stimulate tumorigenesis by creating a pro-tumorigenic milieu. Senescent cells develop a complex phenotype, termed the senescence-associated secretory phenotype (SASP), in which they secrete high levels of numerous growth factors, cytokines, and proteases. It is thought that this secretome disrupts the architecture and functionality of neighboring cells in the tissue and creates a microenvironment that is permissive for the proliferation and dissemination of neoplastic lesions. The critical barrier to testing this idea in vivo has been the lack of a mouse model that allows for selective elimination of senescent cells. We made use of a biomarker for senescence, p16Ink4a, to generate a novel transgene, INK-ATTAC, which removes p16Ink4a-positive senescent cells upon administration of a synthetic drug. Using this and other mouse models, we will test the central hypothesis that cellular senescence is causally implicated in tumor development and that removal of senescent cells, or key malignancy-associated factors that they secrete, will have a profound tumor protective effect. We propose three specific aims. In the first aim we will determine the extent to which late-life clearance of senescent cells inhibits the development and metastasis of lung and breast cancer. In the second aim, we will establish the nature and consequences of the secretory phenotypes of senescent cells accumulating naturally in different mouse tissues with aging. In the third aim, we will dissect the mechanism by which senescent cells drive tumorigenesis by knocking out individual pro-tumorigenic SASP components specifically in senescent cells and then measuring the effect on mouse mammary gland tumorigenesis. The overall impact of this project is that it will critically test the longstanding untested hypothesisthat senescent cells promote tumorigenesis, address key fundamental questions about naturally occurring senescent cells, identify key components of the SASP that promote tumor development and/or metastasis, and test the entirely novel concept of targeting senescent cells or key elements of the SASP as an anti-cancer therapeutic strategy.