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Ferrata Storti Foundation
Haematologica 2019 Volume 104(10):1928-1934
Updates on the hematologic tumor microenvironment and its therapeutic targeting
Dorian Forte,1,2 Daniela S. Krause,3 Michael Andreeff,4 Dominique Bonnet5 and Simón Méndez-Ferrer1-2
1Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute and Department of Haematology, University of Cambridge, Cambridge, UK; 2National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, UK; 3Goethe University Frankfurt, Georg-Speyer-Haus, Frankfurt, Germany; 4Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA and 5Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, UK
ABSTRACT
In this review article, we present recent updates on the hematologic tumor microenvironment following the 3rd Scientific Workshop on the Haematological Tumour Microenvironment and its Therapeutic Targeting organized by the European School of Hematology, which took place at the Francis Crick Institute in London in February 2019. This review article is focused on recent scientific advances highlighted in the invited pre- sentations at the meeting, which encompassed the normal and malignant niches supporting hematopoietic stem cells and their progeny. Given the precise focus, it does not discuss other relevant contributions in this field, which have been the scope of other recent reviews. The content covers basic research and possible clinical applications with the major therapeutic angle of utilizing basic knowledge to devise new strategies to target the tumor microenvironment in hematologic cancers. The review is structured in the following sections: (i) regulation of normal hematopoietic stem cell niches during development, adulthood and aging; (ii) metabolic adaptation and reprogramming in the tumor microenvironment; (iii) the key role of inflammation in reshaping the normal microenvironment and driving hematopoietic stem cell proliferation; (iv) current understanding of the tumor microenvironment in different malignancies, such as chronic lym- phocytic leukemia, multiple myeloma, acute myeloid leukemia and myelodysplastic syndromes; and (v) the effects of therapies on the microen- vironment and some opportunities to target the niche directly in order to improve current treatments.
The normal niches in development, adulthood and aging
A maladapted vascular niche induces the generation and expansion of tumor-initiating cells
Work from Dr. Rafii’s laboratory, among others, has revealed the heterogeneity of endothelial cells, which comprise over 140 different types of endothelium in the human body. Each organ or tumor is vascularized by a specialized endothelium. It is believed that transcription factors belonging to the Ets family, such as Ets variant 2 (ETV2), Fli1 and the Ets-related gene (Erg), make endothelial cells organ-specific. Endothelial cells are important niche cells for hematopoietic stem cells (HSC) and their use as feeder cells in culture allows the expansion of HSC by ~150-fold.1 As a refinement, a combination of reprogramming factors, including FBJ murine osteosar- coma viral oncogene homolog B (FOSB), growth factor independent 1 transcriptional repressor (GFI1), runt-related transcription factor 1 (RUNX1) and SPI1 (which encodes PU.1), can be combined with sustained vascular niche induction to generate HSC that are endowed with secondary repopulating activity.
However, a maladapted vascular niche can facilitate the expansion of tumor-initi-
Correspondence:
DORIAN FORTE
dorian.forte2@unibo.it
SIMÓN MÉNDEZ-FERRER
sm2116@medschl.cam.ac.uk
Received: June 5, 2019.
Accepted: August 7, 2019. Pre-published: September 12, 2019.
doi:10.3324/haematol.2018.195396
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/10/1928
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