The CXCL12 Crossroads in Cancer Stem Cells and Their Niche

SIMPLE SUMMARY: CXCL12 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. ABSTRACT: 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.