Hypoxia-mediated changes in bone marrow microenvironment in breast cancer dormancy.

Abstract

Breast cancer (BC) remains a clinical challenge despite improved treatments and public awareness to ensure early diagnosis. A major issue is the ability of BC cells (BCCs) to survive as dormant cancer cells in the bone marrow (BM), resulting in the cancer surviving for decades with the potential to resurge as metastatic cancer. The experimental evidence indicates similarity between dormant BCCs and other stem cells, resulting in the preponderance of data to show dormant BCCs being cancer stem cells (CSCs). The BM niche and their secretome support BCC dormancy. Lacking in the literature is a comprehensive research to describe how the hypoxic environment within the BM may influence the behavior of BCCs. This information is relevant to understand the prognosis of BC in young and aged individuals whose oxygen levels differ in BM. This review discusses the changing information on vascularity in different regions of the BM and the impact on endogenous hematopoietic stem cells (HSCs). This review highlights the necessary information to provide insights on vascularity of different BM regions on the behavior of BCCs, in particular a dormant phase. For instance, how the transcription factor HIF1-α (hypoxia-inducible factor 1 alpha), functioning as first responder under hypoxic conditions, affects the expression of specific gene networks involved in energy metabolism, cell survival, tumor invasion and angiogenesis. This enables cell fate transition and facilitates tumor heterogeneity, which in turn favors tumor progression and resistance to anticancer treatments Thus, HIF1-α could be a potential target for cancer treatment. This review describes epigenetic mechanisms involved in hypoxic responses during cancer dormancy in the bone marrow. The varied hypoxic environment in the BM is relevant to understand the complex process of the aging bone marrow for insights on breast cancer outcome between the young and aged.