The CXCL12 Crossroads in Cancer Stem Cells and Their Niche

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.

Chromosome instability induced by mutations in TAD anchors leads to tumors

“…All cells of tumor stroma originate from bone marrow and are recruited into stroma through blood and lymph vessels (Bianchi & Mezzapelle, 2020;Guo et al, 2016;Lopez-Gil et al, 2021;Mortezaee, 2020). There are two types of bone marrow cells: Hematopoietic stem cells and Bone Marrow Stem (Stromal) Cells (BMSC).…”

“…There are two types of bone marrow cells: Hematopoietic stem cells and Bone Marrow Stem (Stromal) Cells (BMSC). The later consist of pluripotent Mesenchymal Stem Cells (MSC) capable to differentiate into stromal fibroblasts, chondrocytes, adipocytes, osteoblasts and vascular cells (endothelial ones and pericytes) and others (Bianchi & Mezzapelle, 2020;Guo et al, 2016;Lopez-Gil et al, 2021;Mortezaee, 2020).…”

“…Thus, so-called "CXCL12/CXCR4 axis" is a prerequisite, i.e., is absolutely required, necessary and sometimes even sufficient for the formation of stroma in wounds and malignant tumors. For more detail see recent reviews and experimental papers (Bianchi & Mezzapelle, 2020;Guo et al, 2016;Lopez-Gil et al, 2021;Mortezaee, 2020;Xu et al, 2013).…”

Cancer Stem Cell for Tumor Therapy

“…All of the evidence shows the potential to eliminate CSCs by targeting CSC niches. As listed in Figure 3 , CXCR4 is a well-known CSC marker in many different cancer types, the crosstalk between CXCR4 and its ligand CXCL12 plays a crucial role in tumor development, also in CSC; it was summarized that CXCL12-CXCR4/CXCR7 axis could maintain CSCs stemness via modulating immune cell migration, recruitment of mesenchymal stem cells, formation of CAFs and vascular endothelial cells, thus, it’s a potential strategy to inhibit CSC niches via targeting CXCL12-CXCR4/CXCR7 axis [ 156 ]; some CXCR4/CXCR7 inhibitors listed in Table 5 have been evaluated in different clinical trials. Meanwhile, it may be another way to disrupt CSC niches via inhibiting HIF, a feedback loop composed of HIF-1α and SENP1 existed in the hepatocellular carcinoma, and it was indicated that the positive feedback loop was closely related to the increasing stemness of hepatocellular cancer stem cells and a potential target for HCC therapy [ 157 ].…”

Integrative Analysis to Identify Genes Associated with Stemness and Immune Infiltration in Glioblastoma

“…CXCR4, is a G protein coupled chemokine receptor, involved in invasion and metastasis, epithelial mesenchymal transition (EMT), chemotaxis, angiogenesis, and CSC survival and proliferation. It is also associated with the regulation of immune cell infiltration in the CSC microenvironment, Hematopoietic and Mesenchymal Stem Cell recruitment, and homing in tumours [11]. The two ligands for the receptor are SDF-1/CXCL12 and Macrophage Migration Inhibitory Factor (MIF).…”