Page 266 - Vitamin D and Cancer

11 Vitamin D and Hematologic Malignancies 253

with interleukin (IL)-3, GM-CSF, and M-CSF. This cytokine is active in vivo,
stimulating an increase of peripheral blood granulocytes. The M-CSF stimulates the
formation of macrophage colonies in vitro. It maintains the survival of differentiated
macrophages and increases their antitumor activities and secretion of oxygen reduc-
tion products as well as plasminogen activators. This cytokine binds to a receptor
that is the product of the protooncogene c-fms. IL-3 has multilineage stimulating
activity and acts directly on the granulocyte-macrophage pathway, but also enhances
the development of erythroid, megakaryocytic, and mast cells, and possibly
T lymphocytes. In synergy with Epo, IL-3 stimulates the formation of early eryth-
roid stem cells, promoting the formation of colonies of red cells in soft gel culture
known as BFU-E. In addition, it supports the formation of early multilineage cells
in vitro. IL-3 also induces early progenitor cells to enter the cell cycle, and in
combination with other growth factors, stimulates the production of all the myeloid
cells in vivo. Stem cell factor (SCF) promotes survival, proliferation and differentia-
tion of hematopoietic progenitor cells. It synergizes with other growth factors
such as IL-3, GM-CSF, G-CSF and Epo to support the clonogenic growth in vitro.
SCF is a ligand for the c-kit receptor, a tyrosine kinase receptor that is expressed in
hematopoietic progenitor cells. The growth factor Epo stimulates the formation of
erythroid colonies (CFU-E) in vitro and is the primary hormone of erythropoiesis in
animals and humans. It binds to a specific receptor (Epo-R). Production of
erythroblasts is regulated by Epo which is modulated by the amount of tissue
oxygenation of Epo-producing cells in the kidney. Oxygen-carrying hemoglobin in
the red blood cells is the physiologic rheostat determining the amounts of circulating
Epo. Anemia causes tissue hypoxia, resulting in an increase of serum Epo levels.

11.2 Vitamin D Receptors in Blood Cells

The genomic actions of 1,25(OH) D are mediated by the intracellular vitamin
2
3
D receptor (VDR), which belongs to a large family of nuclear receptors [1]. VDR
forms a heterodimer with the retinoid X receptor (RXR); this complex regulates
expression of target genes by binding to vitamin D responsive elements (VDREs) in
the promoter regions of their target genes [2]. Patients with hereditary vitamin
D-resistant rickets type II (HVDRR) have various mutations of the VDR resulting in
prominent skeletal abnormalities and hematopoietic abnormalities [3, 4]. Expression
of VDR has been detected in bone marrow-derived stromal cells, as well as various
normal and leukemic hematopoietic cells [5, 6].

11.2.1 Vitamin D Receptors in Myeloid Cells

VDR is expressed constitutively in monocytes, neutrophils and antigen-presenting
cells such as macrophages and dendritic cells [5, 7–9]. Circulating monocytes have