Page 113 - Vitamin D and Cancer

100 Y. Ma et al.

5.1 Overview of Angiogenesis

5.1.1 Angiogenesis Process

Angiogenesis generally refers to the formation of new capillaries from existing ves-
sels [1]. Angiogenesis is an essential and complex process involved in develop-
ment, reproduction, and wound healing. Pathological angiogenesis can be found in
many disorders such as cancer, atherosclerosis, autoimmune diseases, and age-
related macular degeneration [1]. Although quiescent in adulthood, endothelial
cells proliferate rapidly in response to a stimulus such as hypoxia [2]. Folkman first
proposed the hypothesis that tumor growth is dependent on angiogenesis in 1971
[3]. This is based on the observation that solid tumors cannot grow beyond a size
of approximately 2 mm diameter without having their own blood supply to provide
oxygen and nutrients. In addition to the growth of primary tumor, angiogenesis is
also essential for local tumor invasion and metastasis.
Angiogenesis occurs in several differentiated steps, including initiation, endothe-
lial cell proliferation and migration, lumen formation, maturation, and remodeling
[4]. The angiogenesis process begins with vasodilation and increased vascular per-
meability of existing vasculature, which subsequently leads to the extravasation of
plasma proteins that form scaffold to support the migrating endothelial cells.
Angiopoietin-2, which inhibits Tie2 signaling, promotes the loosening of the sup-
port cells [5]. It is followed by the degradation of the basement membrane and
extracellular matrix (ECM) by proteases including matrix metalloproteinase
(MMP), plasminogen activator, chymase, and heparinase secreted by activated
endothelial cells [4]. Once the path is cleared, endothelial cells migrate through the
degraded ECM. A variety of growth factors are released from the ECM and stimu-
late the proliferation of endothelial cells, which results in the formation of solid
endothelial cell sprouts into the stromal space of previously avascular tissue. Adhesion
molecules involved in cell–cell and cell–matrix interactions, such as integrin avb3,
vascular endothelial cadherin, intercellular adhesion molecule-1 (ICAM-1), vascular
adhesion molecule-1 (VCAM-1), P-selectin, and E-selectin, also contribute to the
processes of endothelial cell migration, spreading, invasion, and proliferation [6].
Adhesion molecules also determine the polarity of the endothelial cells, a necessary
step for lumen formation in the solid sprouts [6]. Then, capillary loops are formed
and tubes developed with the formation of tight junctions and deposition of new
basement membrane. The newly formed capillaries are stabilized by the recruit-
ment of pericytes and smooth muscle cells, which is regulated by platelet-derived
growth factor (PDGF). Finally, vessel maturation involves remodeling by which the
initial capillary network is modified by pruning and vessel enlargement.
Besides this sprouting angiogenesis, several other mechanisms for neovascular-
ization in tumors have been discovered, including intussusceptive angiogenesis,
endothelial progenitor cells recruitment, vasculogenic mimicry, and lymph angio-
genesis [7]. Intussusceptive angiogenesis, also known as splitting angiogenesis, is
a non-sprouting vessel formation which results in the expansion of capillary plexus.