Understanding how the aging hematopoietic system affects cancer progression

描述（由申请人提供）：我们的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。许多研究，包括我们自己的研究，已经确定特定的造血骨髓源性细胞促进各种癌症模型中的肿瘤进展;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鼠和人异种移植模型。使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，来自年轻小鼠的骨髓来源的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肿瘤进展的一个强有力的决定因素。我们设计了实验来了解年龄如何影响支持乳腺肿瘤进展的骨髓细胞，并确定哪些骨髓细胞依赖的肿瘤支持过程，包括肿瘤支持微环境的形成，在老年宿主中减弱。据我们所知，这将是此类研究的第一次。确定年轻和老年宿主中肿瘤支持造血细胞之间的功能和分子差异，应为这一相对未知的癌症研究领域的进一步工作奠定基础。了解存在于年轻和老年宿主中的肿瘤支持机制应该为年龄分层乳腺癌治疗的临床前开发提供新思路。这些考虑是重要的，因为目前乳腺癌患者的治疗在疗效和耐受性方面存在严重的年龄特异性挑战。

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.