CXCL12 modulation of CXCR4 and CXCR7 activity in human glioblastoma stem-like cells and regulation of the tumor microenvironment

Abstract

Chemokines are crucial autocrine and paracrine players in tumor development. In particular, CXCL12, through its receptors CXCR4 and CXCR7, affects tumor progression by controlling cancer cell survival, proliferation and migration, and, indirectly, via angiogenesis or recruiting immune cells. Glioblastoma (GBM) is the most prevalent primary malignant brain tumor in adults and despite current multimodal therapies it remains almost incurable. The aggressive and recurrent phenotype of GBM is ascribed to high growth rate, invasiveness to normal brain, marked angiogenesis, ability to escape the immune system and resistance to standard of care therapies. Tumor molecular and cellular heterogeneity severely hinders GBM therapeutic improvement. In particular, a subpopulation of chemo- and radio-therapy resistant tumorigenic cancer stem–like cells (CSCs) is believed to be the main responsible for tumor cell dissemination to the brain. GBM cells display heterogeneous expression levels of CXCR4 and CXCR7 that are overexpressed in CSCs, representing a molecular correlate for the invasive potential of GBM. The microenvironment contribution in GBM development is increasingly emphasized. An interplay exists between CSCs, differentiated GBM cells, and the microenvironment, mainly through secreted chemokines (e.g., CXCL12) causing recruitment of fibroblasts, endothelial, mesenchymal and inflammatory cells to the tumor, via specific receptors such as CXCR4. This review covers recent developments on the role of CXCL12/CXCR4–CXCR7 networks in GBM progression and the potential translational impact of their targeting. The biological and molecular understanding of the heterogeneous GBM cell behavior, phenotype and signaling is still limited. Progress in the identification of chemokine-dependent mechanisms that affect GBM cell survival, trafficking and chemo-attractive functions, opens new perspectives for development of more specific therapeutic approaches that include chemokine-based drugs.

The Role of Biomaterials on Cancer Stem Cell Enrichment and Behavior

“…In particular, it is believed that CSCs are especially efficient in modulating their microenvironment. 38,39 One specific way that CSCs may be involved in interacting with their microenvironment is during metastasis. 40 It has been suggested that they are particularly endowed with the capability to utilize the EMT mechanism.…”

Transplanted Dental Pulp Stem Cells Migrate to Injured Area and Express Neural Markers in a Rat Model of Cerebral Ischemia

“…Several studies have reported that stem cells mobilization mechanism may involve cytokines, chemokines, and growth factors released at the injured site and hypoxia environment [20]. Stromal cell-derived factor 1 (SDF-1), which is a strong chemoattractant, is widely expressed by a variety of tissues such as the bone marrow, heart, liver, lung, lymph nodes, kidney, and brain [21]. SDF-1 and its receptor CXCR4 play vital roles in the homing of stem cells [22].…”

Drug-repositioning opportunities for cancer therapy: novel molecular targets for known compounds

“…The existence of CSCs within tumors, together with the active pathological role currently recognized for the tumor microenvironment that influences acquired resistance, immune evasion and metastization [20,21], further favors the search for a combination of repurposed drugs against the whole tumor system, likely acting on intracellular mechanisms that differ from those targeted by standard anticancer agents [22].…”