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1.
Front Cell Dev Biol ; 9: 635189, 2021.
Article in English | MEDLINE | ID: mdl-33777944

ABSTRACT

Hematopoietic stem cells interact with bone marrow niches, including highly specialized blood vessels. Recent studies have revealed the phenotypic and functional heterogeneity of bone marrow endothelial cells. This has facilitated the analysis of the vascular microenvironment in steady state and malignant hematopoiesis. In this review, we provide an overview of the bone marrow microenvironment, focusing on refined analyses of the marrow vascular compartment performed in mouse studies. We also discuss the emerging role of the vascular niche in "inflamm-aging" and clonal hematopoiesis, and how the endothelial microenvironment influences, supports and interacts with hematopoietic cells in acute myeloid leukemia and myelodysplastic syndromes, as exemplar states of malignant myelopoiesis. Finally, we provide an overview of strategies for modulating these bidirectional interactions to therapeutic effect in myeloid malignancies.

2.
EMBO Mol Med ; 9(12): 1646-1659, 2017 12.
Article in English | MEDLINE | ID: mdl-29084756

ABSTRACT

Radiotherapy is an important anti-cancer treatment, but tumour recurrence remains a significant clinical problem. In an effort to improve outcomes further, targeted anti-cancer drugs are being tested in combination with radiotherapy. Here, we have studied the effects of Akt inhibition with AZD5363. AZD5363 administered as an adjuvant after radiotherapy to FaDu and PE/CA PJ34 tumours leads to long-term tumour control, which appears to be secondary to effects on the irradiated tumour microenvironment. AZD5363 reduces the downstream effectors VEGF and HIF-1α, but has no effect on tumour vascularity or oxygenation, or on tumour control, when administered prior to radiotherapy. In contrast, AZD5363 given after radiotherapy is associated with marked reductions in tumour vascular density, a decrease in the influx of CD11b+ myeloid cells and a failure of tumour regrowth. In addition, AZD5363 is shown to inhibit the proportion of proliferating tumour vascular endothelial cells in vivo, which may contribute to improved tumour control with adjuvant treatment. These new insights provide promise to improve outcomes with the addition of AZD5363 as an adjuvant therapy following radiotherapy.


Subject(s)
Head and Neck Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Pyrimidines/therapeutic use , Pyrroles/therapeutic use , Tumor Microenvironment , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Combined Modality Therapy , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Endothelial Cells/pathology , Female , Gamma Rays/therapeutic use , Head and Neck Neoplasms/pathology , Head and Neck Neoplasms/radiotherapy , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Mice , Mice, Nude , Positron Emission Tomography Computed Tomography , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Pyrimidines/pharmacology , Pyrroles/pharmacology , Transplantation, Heterologous , Tumor Microenvironment/drug effects , Vascular Endothelial Growth Factor A/metabolism
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