Keeping an open mind: highlights and controversies of the breast cancer stem cell theory

Abstract

The discovery that breast cancers contain stem-like cells has fuelled exciting research in the last few years. These cells are referred to as breast cancer stem cells (BCSCs) and are thought to be involved in tumor initiation, progression, and metastasis. Being intrinsically resistant to chemo- and radiotherapy, they are also considered responsible for recurrence of the disease after treatment. BCSCs have been suggested to be at the basis of tumor complexity, as they have the ability to self-renew and give rise to highly proliferating and terminally differentiated cancer cells that comprise the heterogeneous bulk of the tumor. There has been much speculation on the BCSC model, and in this review we address some fundamental questions, such as the identity of BCSCs and their involvement in tumor intra- and interheterogeneity. As an alternative to the BCSC model, we discuss clonal evolution, as both theories show extensive evidence in support of their arguments. Finally, we discuss a unifying idea that reconciles both models, which is based on stem cell plasticity and epigenetic modifications induced by the tumor microenvironment. The implications of cancer stem cell plasticity for drug discovery and future therapeutic interventions are presented.

Keywords: cancer; clonal evolution; epigenetics; mammary stem cells; plasticity; therapy.

Figure 1

Models explaining the origins of tumor heterogeneity in breast cancer. Notes: Tumor heterogeneity (middle) is due to cancer cell types differing in genetic and phenotypic identities, as well as differing in terms of spatial and temporal existence within the tumor. These variations can depend on genetic insults and epigenetic alterations induced by microenvironmental changes. The two models explain the origin of this heterogeneity: the clonal evolution and the BCSC theory. The clonal evolution model (left) proposes that cancer clones compete with each other and the microenvironment to expand and dominate within the tumor (eg, Clone 1, 2, 3, and 4). Some clones may expand, but do not evolve fast enough to survive selective pressures and die off (Clone 5). A genetic drift of a single clone can generate a subclone (Clone 1.1). The BCSC model (right) proposes that BCSCs arise from transformed mammary cells. These BCSC self-renew (arced arrow), and give rise to highly proliferating progenitor cells that are responsible for generating differentiated cancer cells within the tumor. Abbreviation: BCSC, breast cancer stem cell.

Figure 2

Proposed model of the human MaSC differentiation hierarchy with corresponding surface markers for stem/progenitor cell identification and isolation. Note: A possible relationship to the cellular origin of breast cancer subtypes is shown in Table 1. Abbreviation: MaSC, mammary stem cell.

Figure 3

Unified theory of tumor heterogeneity. Notes: The dynamic nature of tumor initiation and progression is characterized by genetic and epigenetic insults on putative cancer cells and the microenvironment. The heterogeneity of the microenvironment includes varying densities of extracellular matrix, vasculature, immune cells, and oxygen concentration that places selective pressure on cancer cells. The genetic and epigenetic make-up of cells within tumors will vary from one region to the other. Some regions may be characterized by a BCSC hierarchy (A), stochastic plasticity (B), and clonal evolution (C) simultaneously, increasing its complexity. Abbreviations: BCSC, breast cancer stem cells; ECM, extracellular matrix.