Publication
Title
Role of the hypoxic bone marrow microenvironment in 5T2MM murine myeloma tumor progression
Author
Abstract
Background and Objectives. Unlike most other tumors, multiple myeloma (MM) cells have to survive and to grow in a bone marrow (BM) microenvironment which is already hypoxic by nature. BM hypoxia is crucial for normal hematopoiesis. However, how BM hypoxia and MM affect each other is unknown. We addressed this topic in the 5T2MM mouse model. Design and Methods. Levels of hypoxia in the BM of control and tumor-bearing mice were analyzed by flow cytometric analysis of pimonidazole hypoxyprobe binding and hypoxia-inducible factor 1 alpha (HIF-1 alpha) expression. Micro-vessel density was measured by CD31 staining of BM sections for immunohistochemistry. Apoptosis sensitivity of CD45 5T2MM subsets in hypoxic conditions were analyzed by detection of active caspase-3. Results. Analysis of control and 5T2MM-diseased mice injected with pimonidazole hypoxyprobe indicated that both normal BM and myeloma-infiltrated BM are hypoxic. However, the hypoxia in the myelomatous BM was significantly decreased. Analysis of HIF-1 alpha expression, a surrogate marker of hypoxia, also demonstrated significantly lower levels of hypoxia in myeloma-infiltrated BM. HIF-1 alpha expression was inversely correlated with the micro-vessel density. In vitro culture of 5T2MM cells under hypoxic conditions indicated induction of apoptosis in the CD45(-) MM-fraction, but not in the CD45(+) 5T2MM cells. Interpretation and Conclusions. These data suggest that native BM hypoxia is advantageous for the tumor-initiating CD45(+) 5T2MM cells. Together with the decreased hypoxia in myeloma-infiltrated BM it also indicates that myeloma-associated angiogenesis is functional and permissive for the expansion of CD45(-) 5T2MM-cells. All together, the data raise the possibility of an important role of BM hypoxia in myeloma tumor progression.
Language
English
Source (journal)
Haematologica. - Roma
Publication
Roma : 2005
ISSN
0390-6078
Volume/pages
90:6(2005), p. 810-817
ISI
000230390700011
Full text (open access)
UAntwerpen
Faculty/Department
Research group
Publication type
Subject
External links
Web of Science
Record
Identification
Creation 03.01.2013
Last edited 26.06.2017