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

Highlights

• Hypoxia influence the survival of hematopoietic stem cells and cancer stem cells.

• Normal stem cells co-exist with cancer stem cells.

• Hypoxia induce molecular changes in the cancer cells to facilitate dormancy.

• Hypoxia and aged and young is important for breast cancer prognosis.

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.

Introduction

The literature indicates great strides in early diagnosis and treatment of breast cancer (BC). However, this cancer remains a public health issue [1]. There are several ongoing studies to understand the current landscape of BC. A major issue is the ability of BC cells (BCCs) to adapt a dormant phase at distant site where the cells can remain quiescent and resist current treatments. The dormant drug resistant BCCs can resurge as long as decades later into metastatic cancer [2]. In the advent of emerging technologies, there is a ‘race’ to find unidentified molecular events that are responsible for BCCs evading current treatments [3]. Functional studies on the role of lncRNAs on physiological functions, such as immune responses, could be extrapolated to BC pathogenesis. However, in order to understand the role of lncRNAs, there is a need for further investigations that dissect the molecular events, such as interaction between lncRNAs and other genes as well as with other non-coding RNAs.

Another area of experimental and clinical research that requires attention is immune therapy. Specifically, an individual with BC could show heterogeneity in among the cancer cells and this might be organ-specific. Such variation when compounded by different hormonal phenotype, adds to the difficulty in treating the tumor, even by precision medicine. An issue is that BC is presented with marked genomic diversity and few driver mutations [4]. Broadly, ER + BC might be less immunogenic as compared to other BC types. Also, within each type of BC, there is heterogeneity within the BCCs forming a developmental hierarchy in which the most primitive BCCs, termed cancer stem cells (CSCs), are place at the top of the list [[5], [6], [7]]. Thus, there are likely advantages to examine how each BCC subset responds to the microenvironment to elicit an immune response and, to identify if specific surface expression may dictate the response [[8], [9], [10]].

A major progress in BC treatment is the multi-institutional clinical trials that enroll females while ensuring ethnic diversity. This advantage underscores another problem for the growing male cohort of BC patients [11]. There is no strong clinical and scientific evidence that BC between males and females are similar despite epidemiological studies, which include risk factors on male cohorts of BC [12]. Thus, it is important for the scientific community to work closely with clinical oncologist to include male BC in basic and clinical research [13]. The large public database with Omics analyses contained valuable information for inclusion into mainstream functional studies [14]. There is an unmet need within the Omics data that incorporate BC samples from male patients. As we move into the 21st century with the evolving emphasis on precision medicine, treatment should not extrapolate on the outcome of clinical trials that enrolled only female BC cohorts.

This review article contributes to the unmet need in BC by discussing how the hypoxic gradient and specific regions within the bone marrow (BM) may influence the behavior of breast CSCs. We discuss the impact on prognosis, including differences in aged BM microenvironment with respect to the hypoxic niche. The articles focuses on the BM because it is a common site for BC metastasis, resulting in poor prognosis [15]. More importantly, the BM can facilitate long-term survival of BCCs as dormant cells [16,17]. There are several investigations into the mechanisms of dormancy in the context of BC within BM and the consequence to prognosis. However, there is little information on the role of a hypoxic environment in BM on dormancy/reverse dormancy [2,18,19]. We include the differences in the hypoxic niche between aged and young BM since the information is relevant to understanding age-linked BC pathogenesis in the BM.

BC in young individuals tend to be more aggressive, although there is increased mortality in the aged, which might be explained by other co-morbidities [20]. Although several factors could explain such differences, this article focuses on age-related differences with respect to changes in oxygen within the BM [21,22]. The information will expand to discuss how this might affect the survival of dormant BCCs within an aged microenvironment as compared to the young BM niche.