The role of senescent cells in late-life tumorigenesis

描述（由申请人提供）：高龄是癌症，尤其是上皮性癌症的主要危险因素。然而，晚年恶性肿瘤急剧增加的基本机制在很大程度上仍然未知，这阻碍了预防或减轻晚年肿瘤发生的干预措施的发展。长期以来，人们一直推测，随着衰老在许多组织和器官中积累的衰老细胞刺激了癌细胞的发展和传播。乍一看，这似乎是矛盾的，因为细胞衰老被广泛认为是一种至关重要的抗癌机制，可以阻止肿瘤转化风险细胞的生长。然而，最近来自体外研究的证据支持细胞衰老可能通过创造促肿瘤发生的环境来刺激肿瘤发生的观点。衰老细胞产生一种复杂的表型，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、细胞因子和蛋白酶。据认为，这种分泌组破坏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传播的微环境。测试这一点的关键障碍

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.