Abstract
It is now widely believed that mammary epithelial cell plasticity, an important physiological process during the stages of mammary gland development, is exploited by the malignant cells for their successful disease progression. Normal mammary epithelial cells are heterogeneous and organized in hierarchical fashion, in which the mammary stem cells (MaSC) lie at the apex with regenerative capacity as well as plasticity. Despite the fact that the majority of studies supported the existence of multipotent MaSCs giving rise to both basal and luminal lineages, others proposed lineage restricted unipotent MaSCs. Consistent with the notion, the latest research has suggested that although normal MaSC subsets mainly stay in a quiescent state, they differ in their reconstituting ability, spatial localization, and molecular and epigenetic signatures in response to physiological stimuli within the respective microenvironment during the stages of mammary gland development. In this review, we will focus on current research on the biology of normal mammary stem cells with an emphasis on properties of cellular plasticity, self-renewal and quiescence, as well as the role of the microenvironment in regulating these processes. This will include a discussion of normal breast stem cell heterogeneity, stem cell markers, and lineage tracing studies.
Highlights
Normal tissues including the mammary gland consist of a cellular hierarchy; tissue specific stem cells (SC) at the apex with the ability to self-renew and generate all progeny, committed progenitors with a limited differentiation capacity, and terminally differentiated cells which constitute the functional gland
Adult SCs are distinguished from embryonic stem cells (ESC) in that their ability to generate progeny of distinct cell types is largely restricted to the particular organ from which SC originated
Long-Lived Quiescent mammary stem cells (MaSC) Which Are Activated in Response to Stimuli. Both lineage tracing and transplantation assays supported the existence of bipotent embryonic MaSCs, whether these bipotent embryonic stem cells are maintained in adult mammary gland remains controversial [19,20,41]
Summary
Normal tissues including the mammary gland consist of a cellular hierarchy; tissue specific (adult) stem cells (SC) at the apex with the ability to self-renew and generate all progeny, committed progenitors with a limited differentiation capacity, and terminally differentiated cells which constitute the functional gland. Other studies proposed that the adult mammary gland only contains unipotent stem cells, each of which generate only luminal or basal lineages [20–24] What these stem cells have in common though is that they have been shown to cross–communicate with their microenvironment to maintain homeostasis, which ensures the generation of mature functional cells throughout the life of organism without depletion of stem cell pools [12,25–28]. The example of “vasculogenic mimicry”, by which malignant cells express endothelial specific genes in order to create cells and structures resembling to vasculature [29–31], reinforces the concept for an increased stem-like plasticity under pathological conditions This is consistent with the notion that tumors may be not heterogeneous clonal populations, but are in effect “organ-like structures” composed of numerous cell types whose interaction promotes tumor progression and metastasis. We will focus on molecular mechanisms and clinical relevance of stem cell properties and their role during the organogenesis of mammary gland including the current state of stem cell markers
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