ARTICLE
Auteur(s) : Marco
Presta1, Domenico
Ribatti2
1Department of Biomedical Sciences
and Biotechnology, University of Brescia, Italy
2Department of Human Anatomy and Histology,
University of Bari, Italy
Angiogenesis is an important event in both physiological and
pathological conditions. Under physiological conditions,
angiogenesis is tightly controlled, however, increased production
of angiogenic stimuli and/or reduced production of angiogenic
inhibitors leads to abnormal neovascularization, such as occurs in
cancer, chronic inflammatory disease, diabetic retinopathy, macular
degeneration and cardiovascular disorders.
Starting with Judah Folkman’s hypothesis that tumor growth is
angiogenesis-dependent, this area of research now has a solid
scientific foundation. Several clinical studies have shown a
positive correlation between the number of vessels in many solid
and hematologic tumors and metastasis formation and/or disease
prognosis. During tumor angiogenesis, in addition to the formation
of new blood vessels from pre-existing ones, it has been proposed
that endothelial progenitor cells (EPCs), residing in the adult
bone marrow, are recruited by tumor-secreted factors to sites of
neovascularization where they are incorporated into growing
vessels. However, the actual contribution of EPCs to tumor
angiogenesis remains controversial.
Whereas conventional chemotherapy, radiotherapy, and
immunotherapy are directed against tumor cells, antiangiogenic
therapy is aimed at the vasculature of a tumor, in the hope of
either causing tumor regression or keeping tumors in a state of
dormancy. For these reasons, antiangiogenic tumor therapy has
generated much interest in preclinical and clinical assessment.
Nevertheless, even though numerous compounds inhibit angiogenesis,
few of them have proved effective in vivo, and only a couple of
agents have been able to induce tumor regression.
It has been estimated that over 10,000 cancer patients
worldwide have received experimental forms of antiangiogenic
therapy. However, the results from these clinical trials have not
shown the dramatic antitumor effects that were expected following
preclinical studies. This discrepancy is likely to be due, in part,
to preclinical models where agents were administered to small, fast
growing, highly angiogenic tumors, whereas their efficacy in
clinical trials has almost exclusively been tested in late stage,
well established cancers, which were well vascularized and less
likely to be dependent upon new vessel formation. Additionally,
preclinical and clinical data have shown the possibility that
tumors may acquire resistance to antiangiogenic drugs or may escape
antiangiogenic therapy via compensatory mechanisms. From the
results obtained so far in clinical trials, it can be concluded
that the future clinical success of angiogenesis inhibitors will be
related to their use in combination with chemotherapy or
radiotherapy.
Use of neutralizing antibodies and other inhibitors has
demonstrated that blockade of vascular endothelial growth factor
(VEGF) alone can substantially suppress tumor growth and
angiogenesis in several experimental models. This has led to the
development of the neutralizing anti-VEGF antibody bevacizumab, the
first FDA-approved antiangiogenic molecule. Currently, most of the
FDA-approved drugs, as well as those in phase III clinical trials,
target a single proangiogenic protein. However, multiple angiogenic
molecules may be produced by tumors, and tumors at different stages
of development may depend on different angiogenic factors for their
blood supply. Therefore, blocking a single angiogenic molecule
might have little or no impact on tumor growth. Multi-targeted
tyrosine kinase inhibitors, such as sorafenib and sunitinib, which
block several tyrosine kinase receptor-mediated pathways, represent
a novel approach to angiosuppression. Also, the discovery of the
importance of inflammatory cells infiltrating the tumor stroma in
promoting angiogenesis raises the possibility of therapeutically
targeting these cells instead of the proangiogenic factors they
secrete.
The clinical challenges facing the development of
antiangiogenesis treatments include finding biological markers that
would help to identify subsets of patients more likely to respond
to a given antiangiogenic therapy, determining optimal dosing,
detecting early clinical benefit or emerging resistances, and
deciding whether to change therapy in second-line treatments.
An ideal angiogenesis inhibitor should be orally bioavailable
with acceptable short- and long-term toxicity, and have a
clinically useful antitumor effect. Moreover, carefully constructed
clinical trials with valid endpoints need to be undertaken.
Finally, cancer genomics and proteomics are likely to identify
novel, tumor-specific endothelial targets, and accelerate drug
discovery. With the advent of specific and potent new agents,
oncologists have a variety of direct and indirect antiangiogenic
agents to choose from when designing therapy protocols.
This special issue of European Cytokine Network was prepared in
order to highlight some aspects of the process of angiogenesis and
the molecular mechanisms involved, and to discuss some agents that
have been shown to inhibit angiogenesis. We express our gratitude
to all our colleagues who have contributed to this issue.
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