Abstract
Simple SummaryCXCL12 and its receptors have been extensively studied in cancer, including their influence on cancer stem cells (CSCs) and their niche. This intensive research has led to a better understanding of the crosstalk between CXCL12 and CSCs, which has aided in designing several drugs that are currently being tested in clinical trials. However, a comprehensive review has not been published to date. The aim of this review is to provide an overview on how CXCL12 axes are involved in the regulation and maintenance of CSCs, their presence and influence at different cellular levels within the CSC niche, and the current state-of-the-art of therapeutic approaches aimed to target the CXCL12 crossroads.Cancer stem cells (CSCs) are defined as a subpopulation of “stem”-like cells within the tumor with unique characteristics that allow them to maintain tumor growth, escape standard anti-tumor therapies and drive subsequent repopulation of the tumor. This is the result of their intrinsic “stem”-like features and the strong driving influence of the CSC niche, a subcompartment within the tumor microenvironment that includes a diverse group of cells focused on maintaining and supporting the CSC. CXCL12 is a chemokine that plays a crucial role in hematopoietic stem cell support and has been extensively reported to be involved in several cancer-related processes. In this review, we will provide the latest evidence about the interactions between CSC niche-derived CXCL12 and its receptors—CXCR4 and CXCR7—present on CSC populations across different tumor entities. The interactions facilitated by CXCL12/CXCR4/CXCR7 axes seem to be strongly linked to CSC “stem”-like features, tumor progression, and metastasis promotion. Altogether, this suggests a role for CXCL12 and its receptors in the maintenance of CSCs and the components of their niche. Moreover, we will also provide an update of the therapeutic options being currently tested to disrupt the CXCL12 axes in order to target, directly or indirectly, the CSC subpopulation.
Highlights
Cancer stem cells (CSCs) research largely focuses on trying to unravel the origin of these cells, the mechanisms that underlie their inherent plasticity, their precise role in metastasis and chemoresistance, and their suitability as a therapeutic target, the latter relying on the ability to identify, isolate, and target them based on markers or properties that set them apart from other cells
While the role of MSCs in the immunomodulation of the CSC niche has not been fully elucidated to date, it is well known that MSCs are involved in angiogenesis, as they produce factors that promote vasculature formation like angiopoietin-1 and VEGF and induce CSCs to secrete factors involved in neoangiogenesis [46]
cancer-associated fibroblasts (CAFs)-S1, has been associated with the accumulation of FOXP3+ T lymphocytes and CD4+ CD25+ T lymphocytes in the tumor, both populations related with cancer cell stemness as explained while CAF-S4 has been associated with an increase of stromal cells [67]
Summary
Several theories have been proposed to explain the origin of tumors, the cancer stem cell (CSC) concept has become a well-accepted model that accurately explains tumor origin, heterogeneity and hierarchy. Asymmetric division gives rise to a stem cell and a non-stem cell, the latter of which is usually referred to as progenitor or transient-amplifying daughter cell While these maintain certain stemlike properties, it is generally believed that their pluripotency is decreased compared to the parental CSC [6]. Similar to what has been shown for normal tissues such as the intestinal crypt [7], cancer cells in intermediate states of differentiation are believed to be plastic, i.e., to be capable of reverting to a more dedifferentiated CSC-like state if the correct signals are present This cellular reprogramming could be the result of signals exchanged between non-CSCs and the tumor microenvironment (TME) [8]. We will highlight a few of these important TME players
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