The controversial clinicobiological role of breast cancer stem cells

Abstract

Breast cancer remains a leading cause of morbidity and mortality in women mainly because of the propensity of primary breast tumors to metastasize. Growing experimental evidence suggests that cancer stem cells (CSCs) may contribute to tumor progression and metastasis spread. However, despite the tremendous clinical potential of such cells and their possible therapeutic management, the real nature of CSCs remains to be elucidated. Starting from what is currently known about normal mammary stem/progenitor cells, to better define the cell that originates a tumor or is responsible for metastatic spread, this review will discuss experimental evidence of breast cancer stem cells and speculate about the clinical importance and implications of their evaluation.

Figure 1

Models of heterogeneity in solid cancer cells. (a) The clonal evolution model assumes that every cell in a tumor is potentially tumor-initiating. Progression is governed by rare stochastic events operating in all cells. Cells with mutations (yellow) that acquire growth advantage will dominate over all other cells in the tumor and will originate a new clone containing cells characterized by a different phenotype and having different proliferative potentials; in a clonogenicity or tumorigenicity assay, some of these cells (blue) would have a low probability of exhibiting this potential. (b) The cancer stem cell model states that a particular subset of tumor cells with stem cell-like properties, called “cancer stem cell” (CSC) (pink), drives tumor initiation, progression, and recurrence. CSCs are able to self-renew indefinitely and to differentiate, leading to the production of all cell types (blue) that make up the rest of the tumor. In clonogenic assays, CSCs have the potential to proliferate extensively and can form new tumors on transplantation.

Figure 2

Mixed model for the nature of sustained tumor growth. The tumor is originally driven by rare cells of one phenotype (CSC1, yellow), which may have stem/progenitor cell origin and give rise to the tumor bulk by producing terminally differentiated cells (blue). Subsequent mutations enhancing self-renewing capacity create a dominant subclone that is phenotypically different (CSC2, green) and more aggressive. If the CSC2 subclone does not display “stem-like” cell properties, such a subset will not be able to initiate tumors with a high frequency [30].

Figure 3

Metastatic evolution. Genetic and epigenetic mechanisms may cause the generation of a self-renewing metastatic cancer stem cell subclone (mCSC, yellow), phenotypically different from the CSC that is driving tumorigenesis (pink). Through a series of invasive processes, mCSC enters blood vessels and colonizes distant organs according to the seed and soil hypothesis. Blue cells represent bulk tumor cells [47].