Angiogenesis is a physiological process associated with development and
repair of tissues. In embryonic stage, vasculogenesis occurs by de novo synthesis of a
network of primitive blood vessels from precursors of endothelial cells called
angioblasts which proliferate and coalesce to form the primary capillary plexus. The
primary capillary plexus serves as a scaffold for further angiogenesis. It involves
remodeling by sprouting and branching of preexisting vessels. In adults, angiogenesis
occurs during ovarian cycles and in physiological processes like wound healing and
tissue repair. Tumor induced angiogenesis is a pathological condition wherein
angiogenesis is up regulated due to aberrant deployment of normal angiogenic
machinery. In small tumors, the cells receive nutrition initially by passive diffusion.
However, as the tumor grows in size, within the confinement of tumor the availability
of nutrients is limited due to increasing competition between rapidly proliferating cells
and the diffusion of nutrients is impeded by high interstitial pressure. In order to
overcome this nutrient deprivation and for growth, invasion and subsequent metastasis,
the tumor cells induce formation of new blood vessels from preexisting ones. This
enables the survival of the tumor cells in a hostile microenvironment. Neo-angiogenesis
is a complex process involving an extensive interplay between cells, soluble factors and
extracellular matrix components. A critical equilibrium is regulated by anti and proangiogenic
factors and the balance is shifted in favor of angiogenesis by hypoxia or
inflammation. In tumor associated angiogenesis, the cancerous cells secrete or stimulate
the secretion of various pro-angiogenic factors including Angiogenin, Vascular
endothelial growth factor (VEGF), Fibroblast growth factor (FGF) and Transforming
growth factor-β (TGF-β). The stimulation for neo-angiogenesis is called an angiogenic
switch. The principal stimulation is thought to be oxygen deprivation possibly assisted
by inflammation, oncogenic mutation, mechanical stress etc. VEGF is the most specific
angiogenic factor for endothelial cells. VEGF binds to its receptors inducing signaling
pathways that in turn bring about endothelial cell proliferation, differentiation, migration, increased vascular permeability and release of endothelial cell precursors
from the bone marrow. Sequentially, angiogenesis involves the degradation of basement
by proteases, migration of endothelial cells (EC) into interstitial spaces and sprouting,
ECs proliferation at the migrating tip and lumen formation, generation of new basement
membrane with the recruitment of pericytes, formation of anastomoses and finally
blood flow. Targeting angiogenesis for treatment of cancer has been an appealing
concept among researchers for over three decades and recently many angiogenic
inhibitors have moved from preclinical to clinical trials. Most of angiogenesis inhibitors
have been found to be cytostatic rather than cytocidal. Hence, anti-angiogenic therapy is
useful when administered in combination with conventional chemotherapeutic agents.
Today there are more than 30 anti-angiogenic drugs in use showing considerable
disease response. The development of anti-angiogenic drugs involves identification of
new targets in the angiogenic pathway as well as identification and management of a
new range of toxicities.
Keywords: Angiogenesis, angiogenesis inhibitors, endothelial cells, growth
factors, hypoxia, intussusception, sprouting, tumor, vasculogenesis, VEGF.
