The Tumor Microenvironment as a Driving Force of Breast Cancer Stem Cell Plasticity

Abstract

Tumor progression involves the co-evolution of transformed cells and the milieu in which they live and expand. Breast cancer stem cells (BCSCs) are a specialized subset of cells that sustain tumor growth and drive metastatic colonization. However, the cellular hierarchy in breast tumors is rather plastic, and the capacity to transition from one cell state to another depends not only on the intrinsic properties of transformed cells, but also on the interplay with their niches. It has become evident that the tumor microenvironment (TME) is a major player in regulating the BCSC phenotype and metastasis. The complexity of the TME is reflected in its number of players and in the interactions that they establish with each other. Multiple types of immune cells, stromal cells, and the extracellular matrix (ECM) form an intricate communication network with cancer cells, exert a highly selective pressure on the tumor, and provide supportive niches for BCSC expansion. A better understanding of the mechanisms regulating these interactions is crucial to develop strategies aimed at interfering with key BCSC niche factors, which may help reducing tumor heterogeneity and impair metastasis.

Targeting HMGB1: An available Therapeutic Strategy for Breast Cancer Therapy

“…Tumor cells, together with various other cells, including immune cells, cancer-associated fibroblasts (CAFs), and MSCs, compose an intricate tumor microenvironment (TME), and the multiplex interactions between different cells in the TME are critical to tumor progression 100 . There are numerous experiments showing that HMGB1 executes the function that is widely engaged in dynamic interactions with other cells to remodel the TME, influencing cancer progression (Figure 3 ).…”

Cancer Stem Cells—Key Players in Tumor Relapse

“…It is worth mention that the CSC phenotype, in relation with therapy resistance and tumor recurrence, is further finely regulated by the tumor-surrounding microenvironment. Indeed, different cell types (i.e., stromal cells, immune cells, endothelial cells) and different contextures (i.e., perivascular or bone marrow niches) can actively promote tumor cell plasticity, thus adding further complexity to the field (for extensive reviews, see [240][241][242][243][244].…”

Messing Up the Cancer Stem Cell Chemoresistance Mechanisms Supported by Tumor Microenvironment

“…The induction of EMT and the over-expression of stem cell markers, such as CD90/Thy1 and EphA4, mediated the crosstalk between CSCs and TAMs. In addition, in different types of cancers and in particular in BC, the maintenance of a stem-like phenotype is also correlated to the presence of M2 macrophages in the TME (203,204). In osteosarcoma, Xue-jing Shao et al described the contribution of CD209 + M2 macrophages in tumor initiation and CSC maintenance, corroborating the possibility that the blockage of M2 macrophages depletes CSC subpopulation in the tumor bulk and, at the same time, inhibits tumor progression (205).…”

“…The induction of EMT and the over-expression of stem cell markers, such as CD90/Thy1 and EphA4, mediated the crosstalk between CSCs and TAMs. In addition, in different types of cancers and in particular in BC, the maintenance of a stem-like phenotype is also correlated to the presence of M2 macrophages in the TME ( 203 , 204 ). In osteosarcoma, Xue-jing Shao et al.…”