Understanding how the aging hematopoietic system affects cancer progression

了解衰老的造血系统如何影响癌症进展

• 批准号: 8769009
• 负责人: Sandra S McAllister
• 金额: $ 21.4万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8769009
• 关键词: Accounting; Affect; Age; Aging; Area; Attenuated; Biological Assay; Bone Marrow; Bone Marrow Cells; Breast; Breast Cancer Model; Breast Cancer Treatment; Breast Carcinoma; Cancer Model; Cancer Patient; Cell Aging; Cells; Development; Disease; Disease Progression; Elderly; Foundations; Frequencies; Functional disorder; Gene Expression; Gene Expression Profile; Goals; Growth; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Human; Immune; Incidence; Investigation; Knowledge; Malignant Neoplasms; Mammary Neoplasms; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Mus; Neoplasm Metastasis; Patients; Physiological; Play; Process; Proteins; Research Proposals; Role; Series; Solid; Solid Neoplasm; Specimen; Stem cells; Testing; Validation; Work; Xenograft Model; Xenograft procedure; age effect; age related; aged; anticancer research; breast neoplasm diagnosis; cancer therapy; cell age; design; improved; insight; malignant breast neoplasm; mortality; older patient; pre-clinical; public health relevance; research clinical testing; research study; response; stem; tumor; tumor growth; tumor progression; tumor xenograft; tumorigenic

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.

描述（由申请人提供）：我们的研究建议的目的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衍生的细胞促进了各种癌症模型中的肿瘤进展。但是，年龄对这些促进肿瘤细胞的影响尚不清楚。我们建立了模仿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，我们最近提出了初步发现，即来自老年小鼠的骨髓衍生的细胞在支撑乳腺癌生长方面的有效性明显低于年轻小鼠的乳腺癌生长，而与年轻小鼠的对应细胞相比。令人惊讶的是，骨髓衍生出来自年轻小鼠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有力决定因素。我们设计了实验，以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性肿瘤的支撑过程，包括形成肿瘤支持性微环境的形成，在老年宿主中会减弱。据我们所知，这些将是对这种研究的第一项研究。定义年轻和老年宿主的肿瘤支持性造血细胞之间的功能和分子差异应为在这个相对未知的癌症研究领域进一步工作奠定基础。了解年轻宿主和老年宿主中存在的肿瘤支持机制应提出有关年龄分离乳腺癌疗法的临床前发展的新思想。此类考虑很重要，因为目前对乳腺癌患者的治疗在功效和耐受性方面都面临着严重的年龄特异性挑战。