Similarities Between Stem Cell Niches in Glioblastoma and Bone Marrow: Rays of Hope for Novel Treatment Strategies

Abstract

Glioblastoma is the most aggressive primary brain tumor. Slowly dividing and therapy-resistant glioblastoma stem cells (GSCs) reside in protective peri-arteriolar niches and are held responsible for glioblastoma recurrence. Recently, we showed similarities between GSC niches and hematopoietic stem cell (HSC) niches in bone marrow. Acute myeloid leukemia (AML) cells hijack HSC niches and are transformed into therapy-resistant leukemic stem cells (LSCs). Current clinical trials are focussed on removal of LSCs out of HSC niches to differentiate and to become sensitized to chemotherapy. In the present study, we elaborated further on these similarities by immunohistochemical analyses of 17 biomarkers in paraffin sections of human glioblastoma and human bone marrow. We found all 17 biomarkers to be expressed both in hypoxic peri-arteriolar HSC niches in bone marrow and hypoxic peri-arteriolar GSC niches in glioblastoma. Our findings implicate that GSC niches are being formed in glioblastoma as a copy of HSC niches in bone marrow. These similarities between HSC niches and GSC niches provide a theoretic basis for the development of novel strategies to force GSCs out of their niches, in a similar manner as in AML, to induce GSC differentiation and proliferation to render them more sensitive to anti-glioblastoma therapies.

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

“…Both GSC niches and HSC niches are hypoxic and peri-arteriolar where the GSCs/HSCs are localized adjacent to the tunica adventitia of the arteriolar wall [8,12,14,15]. The chemoattractant stromal-derived factor-1α (SDF-1α; also known as CXCL12) is abundantly expressed in GSC/HSC niches for homing of C-X-C receptor type 4 (CXCR4)-positive GSCs/HSCs in their niches [8,12,14,15]. Hypoxia is crucial for the maintenance of slowly-dividing GSCs/HSCs in niches.…”

“…Hypoxia is crucial for the maintenance of slowly-dividing GSCs/HSCs in niches. The transcription factors hypoxia-inducible factor-1α (HIF-1α) and HIF-2α are highly expressed in niches and in turn upregulate expression of stem cell genes, such as CD133 and sex-determining region Y-box factor 2 (SOX2) for GSCs, and CD133 and CD150 for HSCs [12]. In addition, hypoxia upregulates the expression of SDF-1α and its receptor CXCR4 in glioblastoma tumors and bone marrow via HIF-1α [9,[15][16][17][18][19].…”

“…HSCs and GSCs express the stem cell marker CD133 and the SDF-1α receptor CXCR4. The GSCs/HSCs are localized around smooth muscle actin-positive arterioles in niches that contain extracellular SDF-1α [12]. Figure 1.…”

“…Because of the homology of the hypoxic peri-arteriolar HSC niches in bone marrow and the hypoxic peri-arteriolar GSC niches in glioblastoma tumors, we postulate the hypothesis that plerixafor treatment in combination with standard therapies is beneficial for glioblastoma patients as well. This hypothesis is based on the assumption that plerixafor treatment can mobilize GSCs out of their protective niches, which results in GSC differentiation and their sensitization to radiotherapy and chemotherapy [8,12,13,15]. In a single-arm phase I/II clinical trial including 29 glioblastoma patients, intravenous administration of plerixafor was combined with radiotherapy and temozolomide chemotherapy [35,36].…”

“…Besides chemoattraction and binding, the SDF-1α-CXCR4 axis is important for cell survival. GSCs express both SDF-1α and CXCR4 [12], which induces an autocrine loop, resulting in activation of the PI3K-MAPK-ERK1/2 signaling pathway for cell survival [75]. Thus, apart from mobilization of GSCs out of their niches, the abrogation of the SDF-1α-CXCR4 axis may also reduce GSC survival [75].…”