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.
Bone marrow derived cells are known to play a critical role in breast cancer progression;however, the effects of aging on these bone marrow cells in the context of cancer are completely unknown. We propose to elucidate important aspects of breast cancer pathophysiology by building on our observations that bone marrow derived hematopoietic cells from aged hosts are less efficient at supporting tumor growth than are counterpart cells in young hosts. The knowledge we obtain from our proposed experiments should lay a foundation for improved pre-clinical testing and designing age-stratified therapies for breast cancer patients that improve tolerability and response to treatment.
|Marsh, Timothy; Wong, Irene; Sceneay, Jaclyn et al. (2016) Hematopoietic Age at Onset of Triple-Negative Breast Cancer Dictates Disease Aggressiveness and Progression. Cancer Res 76:2932-43|