Parallels between hematopoietic stem cell and prostate cancer disseminated tumor cell regulation

Highlights

• Prostate cancer disseminated tumor cells (DTCs) and hematopoietic stem cells (HSCs) have analogous functions.

• Both home to the bone marrow, for which CXCL12 is critically important.

• HSCs and DTCs share a home or “niche” as shown in part by competition experiments.

• The niche regulates survival and dormancy vs. proliferation of both cell types.

Abstract

The bone marrow is the primary site of hematopoiesis and the home for hematopoietic stem cells (HSCs) in adult mammals. Prostate cancer commonly metastasizes to the bone and forms bone metastases in almost all patients who die of the disease. Prostate cancer bone metastases are thought to develop after rare bone marrow disseminated tumor cells (DTCs) escape a dormant state and reactivate. Prostate cancer DTCs and normal HSCs have been shown to compete for residence in the bone marrow and share many of same regulatory mechanisms for survival, proliferation and homing. In this review, we highlight these parallels in order to help our readers use the literature in HSC and DTC biology to inform their research and generate hypotheses in both fields.

Introduction

Prostate cancer (PCa) is a large public health problem with over 180,000 new cases and over 26,000 deaths per year in the United States alone [1]. Of PCa patients with distant metastases, 90% have metastases to bone [2]. PCa cells are thought to spread to the bone marrow early in the disease process, even at or before the time of curative intent surgery or radiation therapy to the prostate. At this time, they are termed disseminated tumor cells (DTCs) or micro-metastases. These cells are found in bone marrow or other tissues rather than circulating in peripheral blood, which most investigators term circulating tumor cells, or CTCs. The presence of bone marrow DTCs in PCa patients at the time of radical prostatectomy has been demonstrated by research groups at three institutions using various techniques including, RT-PCR for prostate specific antigen (PSA), immunohistochemistry for PSA and single cell selection of epithelial cell adhesion molecule (EPCAM) positive cells by single cell isolation after prior negative and positive selection [[3], [4], [5], [6], [7]]. Furthermore, their presence was shown by all three groups to correlate with PCa recurrence [5,8,9]. However, recently investigators reported being able to detect these cells in only a small minority of patients with localized PCa [10]. This report highlights the challenges in conducting this type of research and suggests further investigation.

PCa DTCs can remain viable but dormant for long time periods; as illustrated by the fact that about 20% of PCa recurrences after surgery occur greater than 5 years after patients were thought to be cured [11]. Reactivation or dormancy escape of bone marrow DTCs is thought to be a major cause of relapse in PCa and other malignancies [12]. Furthermore, an understanding of the biology of how DTCs or micrometastases are different from macroscopic tumors and how they interact with bone microenvironment has the potential to lend insight into later stages of the disease when metastases are visible on imaging. Therefore, understanding the biology of DTCs in the bone environment is crucial for prevention of relapse or treatment of relapsed disease.

There are two major models which have been invoked to describe tumor heterogeneity, either of which could describe the behavior of DTCs. The cancer stem cell (CSC) model suggests that subpopulations of cancer cells form a hierarchical cluster of tumor initiating cells [13]. These CSCs often feature parameters present in normal tissue stem cells, and like normal stem cells maintain themselves through self-renewal, but also differentiate into progenitor cell populations and ultimately into mature or non-stem cancer cells (NSCCs). The second major model for tumor development is the stochastic model. In the stochastic model, tumors develop by clonal evolution to progress into heterogeneous populations which are influenced by both intrinsic and extrinsic environmental factors [14].

Many tissues which harbor DTCs, including lung, liver and bone marrow, are also sites in which clinical relapse can eventually occur. Each of these organs support stem cell populations and tightly regulates proliferation as a component of normal function. This suggests that the normal activity of the host tissues to regulate stem cell function, be it the induction or maintenance of quiescence, ultimately becomes insufficient to enforce dormancy of DTCs. Yet, whether DTCs are primed for proliferation but constantly kept in check by suppressive signals or rather reprogrammed into a semi-permanent dormant state by the microenvironment remains unclear. In several experimental systems DTCs isolated directly from humans or from preclinical models are difficult to grow in vitro, and only proliferate after extended culture periods [12,15]. The implication from these studies is that DTCs, at least in these organs, are reprogrammed into a dormant state rather than held in check by the continual presence of negative regulators. Alternatively, there is ample evidence that immune regulation of DTCs plays a major role in controlling DTC proliferation [[16], [17], [18], [19]]. How the host is able to distinguish normal stem cells from tumor cells, be they CSCs or NSCCs, remains unclear.

We and others have hypothesized that DTCs reside in similar environments or “niches” as hematopoietic stem cells (HSCs) and compete for occupancy of the bone marrow microenvironment [20]. Likely because of shared interactions with stromal cell types, research over the past one or two decades has discovered shared regulatory mechanisms between DTCs and HSCs. In this review, we use HSC biology to frame a discussion of PCa bone marrow DTC regulation in hopes that we will help our readers gain intuition into DTC biology and help them generate new hypotheses by drawing on the more extensive HSC literature. We concentrate here on PCa, but note that many of the same concepts will apply to breast cancer and other malignancies which metastasize to bone. The mechanisms discussed below are summarized in Fig. 1.