Page 114 - Vitamin D and Cancer

5 Vitamin D and Angiogenesis 101

In this process, the capillary wall protrudes into the lumen to split a single vessel in
two [8]. It is a fast and energy-efficient process since the proliferation of endothelial
cells is not required. Endothelial cells are rearranged and remodeled instead. Both
intussusceptive and sprouting angiogenesis occur in the leading edge of the tumor,
while in the stabilized tumor regions, intussusception mostly leads to network
remodeling and occlusion of vascular segments [9]. New vessels can also grow by
the recruitment of circulating endothelial progenitor cells. The contribution of
endothelial progenitor cells to tumor angiogenesis is controversial. Some studies
support that the recruitment of endothelial progenitor cells is sufficient for tumor
angiogenesis [10–12], while others show minimal involvement of endothelial pro-
genitor cells [13, 14]. Transplantation of wild-type bone marrow or vascular
endothelial growth factor (VEGF)-mobilized stem cells is able to restore tumor
angiogenesis in the angiogenic-defective, tumor-resistant Id-mutant mice [10]. Low
levels (4.9%) of endothelial progenitor cells are found in tumor endothelium in
patients who developed tumors after receiving bone marrow transplantation [12]. A
study using genetically tagged endothelial cells fails to detect bone-marrow-derived
cells in newly formed tumor endothelium [14]. Vasculogenic mimicry is a phenom-
enon when highly aggressive tumor cells, such as melanoma, form patterned vas-
cular channels in the absence of endothelial cells, which provides tumors with a
secondary circulation mechanism [15].
Lymph angiogenesis, the formation of new sprouts on existing lymphatic ves-
sels, is another mechanism for tumor cells to receive better circulation. Tumor cells
and inflammatory cells produce a variety of lymph angiogenic factors, such as
VEGF-C, PDGF-BB, and Angiopoietin-2, to stimulate the formation of new lym-
phatic vessels [16].

5.1.2 Endogenous Activators and Inhibitors

Angiogenesis is regulated by a delicate balance of activators and inhibitors. This
balance is disrupted in favor of angiogenic events during tumor development,
which is described as the angiogenic switch is turned on. The endogenous angio-
genic factors are released by the tumor cells and degraded extracellular matrix in
the tumor microenvironment. Angiogenic activators include hypoxia which acti-
vates hypoxia inducible factor a (HIFa) [17], growth factors such as A VEGFA
(also known as vascular permeability factor, VPF), basic fibroblast growth factor
(bFGF) [18], PDGF [19], pleiotrophin (PTN) [20], granulocyte colony-stimulating
factor (G-CSF) [21], hepatocyte growth factor (HGF)/scatter factor (SF) [22], pla-
cental growth factor [23], transforming growth factor-a (TGF-a) [24], and TGF-b
[25]. VEGFA is the most important molecule that stimulates angiogenesis [26]. It
not only promotes endothelial cell proliferation and mobility, but also induces vaso-
dilatation of the existing blood vessels and enhances vessel wall permeability. VEGF
facilitates the degradation of ECM by upregulating the expression of MMPs and
plasminogen activators. In addition to growth factors, other molecules also stimulate