Angiogenesis in cancer
angiogenesis complicates cancer
performs a critical role in the development
of cancer. Solid tumors smaller than 1 to 2
cubic millimeters are not vascularized. To spread,
they need to be supplied by blood vessels that
bring oxygen and nutrients and remove metabolic
Beyond the critical volume of 2 cubic millimeters,
oxygen and nutrients have difficulty diffusing
to the cells in the center of the tumor, causing
a state of cellular hypoxia that marks the onset
of tumoral angiogenesis.
New blood vessel development is an important
process in tumor progression. It favors the
transition from hyperplasia to neoplasia i.e.
the passage from a state of cellular multiplication
to a state of uncontrolled proliferation characteristic
of tumor cells.
Neovascularization also influences the dissemination
of cancer cells throughout the entire body eventually
leading to metastasis formation.The vascularization
level of a solid tumor is thought to be an excellent
indicator of its metastatic potential.
The molecular factors involved in the stimulation
of blood vessel growth are described in detail
in The process of
of standard therapies
therapies to combat cancer are usually aimed at
interfering with the cellular replication process
which is accelerated in tumors. Despite the efforts
made since 1971 to fight cancer -- the year the
United States declared war on the disease -- new
cases of most cancers have increased significantly.
Ninety percent of all cancers are solid tumors
and thus depend on angiogenesis to support their
Resistance to treatment is a major issue in oncology.
In hormone-dependent cancer for instance, after
standard anti-hormonal therapy, it is common to
see a recurrence of cancer. This occurs when a
malignant cell is transformed a second time, thus
making its replication independent of hormones.
The same phenomenon takes place with cancers treated
with chemotherapy. Often a transformed cell exposed
to a powerful chemical agent goes through a mutation,
giving it a selective advantage for growth, such
as the production of a growth factor or resistance
to chemotherapeutic agents.
It has also been shown that the resection of a
primary tumor is often accompanied by metastases
caused by a systemic disturbance of the angiogenic
balance of the body. All these standard therapies
could profit from a concomitant treatment that
would restrict latent tumors in a prevascular
as a strategy against cancer
early as the 1970s, Dr. Judah Folkman of the Harvard
Medical School suggested inhibiting new blood
vessel formation as a way to fight cancer.
The malignant tissue would be deprived of its
oxygen and nutrient supply, as well as be unable
to eliminate metabolic wastes. This in turn would
inhibit tumor progression and metastatic progression
that accompanies most advanced cancers. These
are the main steps of the angiogenic process that
can be interrupted:
- Inhibiting endogenous angiogenic factors,
such as bFGF (basic Fibroblast Growth Factor)
and VEGF (Vascular Endothelial Growth Factor)
- Inhibiting degradative enzymes (Matrix Metalloproteinases)
responsible for the degradation of the basement
membrane of blood vessels
- Inhibiting endothelial cell proliferation
- Inhibiting endothelial cell migration
- Inhibiting the activation and differentiation
of endothelial cells
the challenge is to develop an antiangiogenic
factor that does not affect the existing vasculature.
is an inhibitor of angiogenesis
number of studies have shown Neovastat to have
antiangiogenic properties. The mechanisms of action
- Inhibiting degradative Matrix Metalloproteinases,
- Blocking receptor sites for the angiogenic
growth factor VEGF, which prevents endothelial
cells from proliferating, migrating, and organizing
to form new blood vessels in vitro.
As well, clinical and pre-clinical studies
show Neovastat can be used alone or in combination
with other therapies. Clinical experience with
540 patients, some of whom have been administered
the drug for almost four years, have confirmed
Neovastatís excellent safety and tolerability
profile in monotherapy and in concomitant chemotherapy