1. CXCR4 antagonists as stem cell mobilizers and therapy sensitizers for acute myeloid leukemia and glioblastoma?Vashendriya V. V. Hira, Cornelis J. F. van Noorden, Remco J. Molenaar, 2020, drugi znanstveni članki Povzetek: 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.
Ključne besede: glioblastoma, glioblastoma stem cells, niches, acute myeloid leukemia, hematopoietic stem cells, bone marrow, C-X-C receptor type 4, stromal-derived factor-1 ▫$[alpha]$▫, plerixafor
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2. Novel therapeutic strategies to target leukemic cells that hijack compartmentalized continuous hematopoietic stem cell nichesVashendriya V. V. Hira, Cornelis J. F. van Noorden, Hetty E. Carraway, Jaroslaw P. Maciejewski, Remco J. Molenaar, 2017, pregledni znanstveni članek Povzetek: Acute myeloid leukemia and acute lymphoblastic leukemia cells hijack hematopoietic stem cell (HSC) niches in the bone marrow and become leukemic stem cells (LSCs) at the expense of normal HSCs. LSCs are quiescent and resistant to chemotherapy and can cause relapse of the disease. HSCs in niches are needed to generate blood cell precursors that are committed to unilineage differentiation and eventually production of mature blood cells, including red blood cells, megakaryocytes, myeloid cells and lymphocytes. Thus far, three types of HSC niches are recognized: endosteal, reticular and perivascular niches. However, we argue here that there is only one type of HSC niche, which consists of a periarteriolar compartment and a perisinusoidal compartment. In the periarteriolar compartment, hypoxia and low levels of reactive oxygen species preserve the HSC pool. In the perisinusoidal compartment, hypoxia in combination with higher levels of reactive oxygen species enables proliferation of progenitor cells and their mobilization into the circulation. Because HSC niches offer protection to LSCs against chemotherapy, we review novel therapeutic strategies to inhibit homing of LSCs in niches for the prevention of dedifferentiation of leukemic cells into LSCs and to stimulate migration of leukemic cells out of niches. These strategies enhance differentiation and proliferation and thus sensitize leukemic cells to chemotherapy. Finally, we list clinical trials of therapies that tackle LSCs in HSC niches to circumvent their protection against chemotherapy.
Ključne besede: hematopoietic stem cell niche, hijacking, leukemic stem cells, bone marrow, therapy resistance, leukemia
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3. Morphological characteristics of young and old murine hematopoietic stem cell niches, as modeled in vitroMojca Justin, Ema Rogac Randl, Veno Kononenko, Matej Hočevar, Damjana Drobne, Primož Rožman, 2023, izvirni znanstveni članek Povzetek: The hematopoietic stem cell (HSC) niche undergoes detrimental changes with age. The molecular differences between young and
old niches are well studied and understood; however, young and old niches have not yet been extensively characterized in terms of
morphology. In the present work, a 2D stromal model of young and old HSC niches isolated from bone marrow was investigated
using light and scanning electron microscopy (SEM) to characterize cell density after one, two, or three weeks of culturing, cell
shape, and cell surface morphological features. Our work is aimed at identifying morphological differences between young and
old niche cells that could be used to discriminate between their respective murine HSC niches. The results show several age-
specific morphological characteristics. The old niches differ from the young ones in terms of lower cell proliferating capacity,
increased cell size with a flattened appearance, increased number of adipocytes, and the presence of tunneling nanotubes. In
addition, proliferating cell clusters are present in the young niches but not in the old niches. Together, these characteristics
could be used as a relatively simple and reliable tool to discriminate between young and old murine HSC niches and as a
complementary approach to imaging with specific cellular markers.
Ključne besede: bone marrow, hematoopetic stem cell niche, aging, adipocytes, scanning electron microscopy
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