Understanding how the aging hematopoietic system affects cancer progression

描述(由申请人提供)：我们研究计划的目标是了解衰老对造血系统的生理影响如何影响乳腺癌的进展。包括我们自己在内的许多研究已经证实，在各种癌症模型中，特定的造血骨髓来源细胞促进肿瘤进展；然而，年龄对这些促肿瘤细胞的影响尚不清楚。我们建立了模拟年龄依赖性乳腺癌进展的小鼠和人类异种移植模型。利用我们的人类异种移植模型，我们最近初步发现，来自老年小鼠的骨髓来源的细胞在支持乳腺癌生长方面的效果明显低于来自年轻小鼠的对应细胞，即使在年轻小鼠中也是如此。引人注目的是，年轻小鼠的骨髓来源细胞恢复了老年小鼠的肿瘤生长。这些发现表明，宿主造血系统的年龄是乳腺癌进展的一个强有力的决定因素。我们设计了实验，以了解年龄如何影响支持乳腺癌进展的骨髓细胞，并确定哪些骨髓细胞依赖的肿瘤支持过程，包括支持肿瘤的微环境的形成，在老年宿主中减弱。据我们所知，这将是此类研究的第一次。明确年轻和老年宿主中支持肿瘤的造血细胞的功能和分子差异，应该为这一相对未知的癌症研究领域的进一步工作奠定基础。了解年轻和老年宿主中存在的肿瘤支持机制应该会为乳腺癌年龄分层治疗的临床前开发提供新的思路。这些考虑是重要的，因为目前乳腺癌患者的治疗在有效性和耐受性方面都面临着年龄上的严重挑战。

DESCRIPTION (provided by applicant): The goal of our research proposal is to understand how the physiological effects of aging on the hematopoietic system affect breast cancer progression. A number of studies, including our own, have established that specific hematopoietic bone marrow derived cells facilitate tumor progression in various cancer models; however, the impact that age has upon these tumor-promoting cells is not known. We established murine and human xenograft models that mimic age-dependent breast cancer progression. Using our human xenograft model, we recently made the preliminary discovery that bone marrow derived cells from aged mice are significantly less effective in supporting breast cancer growth, even in young mice, than the counterpart cells from young mice. Strikingly, bone marrow derived cells from young mice restored tumor growth in aged mice. These findings suggest that the age of the host hematopoietic system is a powerful determinant of breast tumor progression. We have designed experiments to understand how age affects bone marrow cells that support breast tumor progression and to determine which bone marrow cell dependent tumor supportive processes, including formation of the tumor-supportive microenvironment, are attenuated in aged hosts. To our knowledge, these will be the first studies of this kind. Defining functional and molecular differences between tumor supportive hematopoietic cells in young and aged hosts should lay a foundation for further work in this relatively uncharted area of cancer research. Understanding tumor support mechanisms that exist in young and aged hosts should suggest new ideas for preclinical development of age-stratified breast cancer therapies. Such considerations are important because current treatment of breast cancer patients presents serious age-specific challenges with respect to both efficacy and tolerability.