CXCR4 Antagonists as Stem Cell Mobilizers and Therapy Sensitizers for Acute Myeloid Leukemia and Glioblastoma?

Vashendriya V.V Hira,Remco J Molenaar,Cornelis J.F Van Noorden

doi:10.3390/biology9020031

Vashendriya V.V Hira, Remco J Molenaar + Show 1 more

Open Access

https://doi.org/10.3390/biology9020031

Copy DOI

Abstract

Glioblastoma is the most aggressive and malignant primary brain tumor in adults and has a poor patient survival of only 20 months after diagnosis. This poor patient survival is at least partly caused by glioblastoma stem cells (GSCs), which are slowly-dividing and therefore therapy-resistant. GSCs are localized in protective hypoxic peri-arteriolar niches where these aforementioned stemness properties are maintained. We previously showed that hypoxic peri-arteriolar GSC niches in human glioblastoma are functionally similar to hypoxic peri-arteriolar hematopoietic stem cell (HSC) niches in human bone marrow. GSCs and HSCs express the receptor C-X-C receptor type 4 (CXCR4), which binds to the chemoattractant stromal-derived factor-1α (SDF-1α), which is highly expressed in GSC niches in glioblastoma and HSC niches in bone marrow. This receptor–ligand interaction retains the GSCs/HSCs in their niches and thereby maintains their slowly-dividing state. In acute myeloid leukemia (AML), leukemic cells use the SDF-1α–CXCR4 interaction to migrate to HSC niches and become slowly-dividing and therapy-resistant leukemic stem cells (LSCs). In this communication, we aim to elucidate how disruption of the SDF-1α–CXCR4 interaction using the FDA-approved CXCR4 inhibitor plerixafor (AMD3100) may be used to force slowly-dividing cancer stem cells out of their niches in glioblastoma and AML. Ultimately, this strategy aims to induce GSC and LSC differentiation and their sensitization to therapy.

Highlights

Glioblastoma is the most aggressive and malignant primary brain tumor in adults and has a poor patient survival of only 20 months after diagnosis
Glioblastoma (World Health Organization grade IV glioma) is the most aggressive and lethal primary brain tumor in adults, with a poor survival of only 20 months after diagnosis despite surgery, radiotherapy, temozolomide chemotherapy and magnetic tumor-treating fields (TTF) in the fittest patient population [1,2,3,4,5]. This poor patient survival is at least partly caused by glioblastoma stem cells (GSCs) that reside in protective niches where they are maintained as slowly-dividing and therapy-resistant cells [6,7,8,9]
We provided evidence that GSC niches in human glioblastoma tumors are functionally similar to hematopoietic stem cell (HSC) niches in normal human bone marrow [12,13]

Summary

The chemoattractant adjacent to the tunica adventitia of the arteriolar wall

The chemoattractant stromal-derived stromal-derived factor-1α (SDF-1α; known as CXCL12) is abundantly expressed in GSC/HSC factor-1α Hypoxia is crucial for [8,12,14,15]. Hypoxia is crucial for the maintenance of slowly-dividing GSCs/HSCs in niches. HIF-2α expression are highly expressed in niches upregulate expression of niches and in turn and upregulate of stem cell genes, and suchinasturn. CXCR4 in glioblastoma tumors and bone marrow via HIF-1α [9,15,16,17,18,19]. 1, a peri-arteriolar marrow via HIF-1α [9,15,16,17,18,19].

HSCs and GSCs express the stem cell marker

GSC niches

Karnofsky performance score