Angiogenesis and cancer: A cross-talk between basic science and clinical trials (the “do ut des” paradigm)
Introduction
During the process of carcinogenesis, there is a progressive accumulation of changes in different genes leading to the insurgence of subpopulations of cells with specific biologic characteristics. This genetic instability is responsible for the activation of proto-oncogenes, the suppression (or decrease) in the activity of tumor-suppressor genes, unlimited cell growth and the loss of cells’ ability to undergo apoptosis, among others changes [1]. The metastatic process is the result of the systemic dissemination of cellular clones that have a pronounced tendency towards invading surrounding tissues.
Metastasis is one of the hallmarks of cancer. In cancer patients, metastatic lesions are often the source of their symptoms and their primary cause of death. In this context, angiogenesis plays a crucial role in facilitating the growth of the primary tumor and in generating metastasis. Moreover, angiogenesis also occurs physiologically, for instance, during the reproductive cycle and wound healing, and in pathological processes characterized by the presence of chronic inflammation, including psoriasis and arthritis.
The growth of a malignant tumor is heavily conditioned by adequate vasculature. Cancer cell survival is strictly dependent on optimal supplies of oxygen and nutrients, and also on the ability to eliminate toxic molecules. Oxygen, in fact, diffuses from capillaries to a distance of only 150–200 μm. As a consequence, to become clinically relevant, a tumor requires its own new and dedicated vasculature, which is mainly created by remodeling a pre-existing primitive network of blood vessels [2], [3], [4].
Section snippets
Regulation of angiogenesis
The regulation of angiogenesis both in physiologic and pathologic conditions is a complex, multistep process resulting from a dynamic balance between pro-angiogenic and antiangiogenic factors [5]. The mechanisms by which cancer cells stimulate pathological angiogenesis mimic those used by normal cells to foster physiological angiogenesis [6]. However, the tumor microvasculature is structurally, functionally and even genetically altered in comparison to that we observe in physiologic conditions
Angiogenesis as a therapeutic target in human tumors
Several attempts have been made to classify the therapeutic agents that interfere with the process of angiogenesis. This task, however, has revealed itself to be particularly arduous because of the large number of complex and mainly unpredictable mechanisms involved in the angiogenic cascade. Because of the variability in experimental models designed to assess angiogenesis, and suboptimal reproducibility between pre-clinical and clinical effects, a classification system based on the efficacy of
Integration of antiangiogenic drugs into the anticancer armamentarium
A review of phase 1 clinical trials in oncology sponsored by the Cancer Therapy Evaluation Program at the National Cancer Institute, USA between 1991 and 2002 was recently published [42]. This analysis revealed a very low rate of response in 15 trials (the overall response rate was 3.9%, and the complete response rate was 0.6%) when antiangiogenic drugs were used as single agents. In contrast, the rate of stable disease and less-than-partial response was found to be 31%. Interestingly, the
Metronomic chemotherapy
Among the various potential approaches to inhibiting angiogenesis, metronomic therapy merits particular mention. Metronomic chemotherapy (metroCT) refers to the frequent, even daily, administration of CT in doses below the MTD (maximum tolerated dose), for long periods of time, with no prolonged drug-free breaks [72]. In some pre-clinical models, metroCT was effective in treating tumors previously resistant to the same CT agents used in a non-metronomic way [73], [74]. It was also shown that
Toxicity issues
Antiangiogenic therapy is generally well tolerated. The previously described analysis of phase 1 trials did not report toxic death for any of the 402 patients assessed for toxicity when antiangiogenic agents where used as monotherapy [42]. Mature data on safety profiles are available for bevacizumab, following the results of recently reported phase II and phase III trials. Hypertension is a common but manageable side effect. The pathogenic mechanism still remains to be elucidated. In
Perspectives
The previous belief that endothelial cells within tumor vessels are genetically stable has been recently been cast into doubt, with studies reporting significant variability of the vascular characteristics, which are often tissue- and tumor-specific. In fact, several microenvironmental factors that are strictly dependent on the tumor may influence the genotype of the cells forming the tumor vasculature. The exact mechanisms of these genetic changes are not known, although different hypotheses
Reviewers
Jerome Fayette, M.D., Ph.D., Hopital Edouard Herriot, Medical Oncology Department, Pavilion E, 5, place d’Arsonval, FR-69003 Lyon, France.
Jean-Pierre Armand, M.D., Medical Oncology Department, Institut Gustave Roussy, 39, rue Camille Desmoulins, FR-94805 Villejuif, Cedex, France.
Prof. Alberto F. Sobrero, Medical Oncology, Ospedale S. Martino, Largo Benzi 10, IT-16132 Genova, Italy.
Prof. Gilberto Schwartsmann, Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande so Sul,
Acknowledgments
The authors are indebted to Mrs. C. Straehle for her editorial assistance, and also to the Fonds National de la Recherche Scientifique (FNRS) and to the Associazione Italiana di Oncologia Medica (AIOM) for their grants to Gilberto de Castro Junior and to Fabio Puglisi, respectively. They are both visiting Research Fellows at the Medical Oncology Clinic, Institut Jules Bordet, in Brussels, Belgium.
Ahmad Awada M.D., Ph.D., was born in Lebanon and received his medical training at the Medical School of the Free University in Brussels, Belgium. At the Jules Bordet Institute in Brussels, he specialized in Internal Medicine and Medical Oncology. His clinical activities focus on the treatment of solid tumors and the development of new therapies and anticancer drugs in phases I and II clinical trials using both cytotoxic and molecular-targeted agents, some of them widely used in daily clinical
References (94)
- et al.
The hallmarks of cancer
Cell
(2000) - et al.
VEGF-receptor signal transduction
Trends Biochem Sci
(2003) - et al.
Vascular permeability factor (VPF)/vascular endothelial growth factor (VEGF) receptor-1 down-modulates VPF/VEGF receptor-2-mediated endothelial cell proliferation, but not migration, through phosphatidylinositol 3-kinase-dependent pathways
J Biol Chem
(2001) - et al.
Role of lymphangiogenic factors in tumor metastasis
Biochim Biophys Acta
(2004) - et al.
Angiostat a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung F carcinoma
Cell
(1994) - et al.
Endostatin: an endogenous inhibitor of angiogenesis and tumor growth
Cell
(1997) - et al.
Transgenic mouse models of tumour angiogenesis: the angiogenic switch, its molecular controls, and prospects for pre-clinical therapeutic models
Eur J Cancer
(1996) - et al.
Will the dark sky over advanced renal cell carcinoma soon become brighter?
Eur J Cancer
(2005) - et al.
Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels
Ann Oncol
(2002) - et al.
Vascular endothelial growth factor: its prognostic, predictive, and therapeutic implications
Lancet Oncol
(2001)
Clinical significance of determination of surrogate markers of angiogenesis in breast cancer
Crit Rev Oncol Hematol
What is the evidence that tumors are angiogenesis dependent?
J Natl Cancer Inst
Clinical translation of angiogenesis inhibitors
Nat Rev Cancer
Neoplastic angiogenesis—not all blood vessels are created equal
NEJM
Molecular regulation of vessel maturation
Nat Med
Mechanisms of normal and tumor-derived angiogenesis
Am J Physiol Cell Physiol
Lymphoma-specific genetic aberrations in microvascular endothelial cells in B-cell lymphomas
N Engl J Med
Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis
J Clin Oncol
Molecular and biological properties of vascular endothelial growth factor
J Mol Med
Vascular permeability factor: a unique regulator of blood vessel function
J Cell Biochem
Molecular and biological properties of the vascular endothelial growth factor family of proteins
Endocr Rev
Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy
J Clin Oncol
The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor
Science
Vascular endothelial growth factor (VEGF) and its receptors
FASEB J
VEGF and the quest for tumour angiogenesis factors
Nat Rev Cancer
Lymphangiogenesis new mechanisms
Ann NY Acad Sci
Negative regulation of hypoxia-inducible genes by the von Hippel–Lindau protein
Proc Natl Acad Sci USA
Reversion of deregulated expression of vascular endothelial growth factor in human renal carcinoma cells by von Hippel–Lindau tumor suppressor protein
Cancer Res
Post-transcriptional regulation of vascular endothelial growth factor mRNA by the product of the VHL tumor suppressor gene
Proc Natl Acad Sci USA
The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis
Nature
Cancer genes and the pathways they control
Nat Med
Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1
Science
Thrombospondin-2: a potent endogenous inhibitor of tumor growth and angiogenesis
Proc Natl Acad Sci USA
Inhibition of angiogenesis by recombinant human platelet factor-4 and related peptides
Science
Interferons alpha and beta down-regulate the expression of basic fibroblast growth factor in human carcinomas
Proc Natl Acad Sci USA
Antiangiogenic activity of the cleaved conformation of the serpin antithrombin
Science
Tumor angiogenesis
Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF
Science
The chick embryo chorioallantoic membrane as a model system for the study of tumor angiogenesis, invasion and development of antiangiogenic agents
Curr Cancer Drug Targets
Effects of angiogenesis inhibitors on multistage carcinogenesis in mice
Science
Angiogenesis research: guidelines for translation to clinical application
Thromb Haemost
Antiangiogenic concentrations of paclitaxel induce an increase in microtubule dynamics in endothelial cells but not in cancer cells
Cancer Res
Inhibition of endothelial cell function in vitro and angiogenesis in vivo by docetaxel: association with impaired repositioning of the microtubule organizing center
Mol Cancer Ther
Antiangiogenic potential of camptothecin and topotecan
Cancer Chemother Pharmacol
Combination of antiangiogenic therapy with other anticancer therapies: results, challenges, and open questions
J Clin Oncol
Risks and benefits of phase 1 oncology trials, 1991 through 2002
N Engl J Med
A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer
N Engl J Med
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Ahmad Awada M.D., Ph.D., was born in Lebanon and received his medical training at the Medical School of the Free University in Brussels, Belgium. At the Jules Bordet Institute in Brussels, he specialized in Internal Medicine and Medical Oncology. His clinical activities focus on the treatment of solid tumors and the development of new therapies and anticancer drugs in phases I and II clinical trials using both cytotoxic and molecular-targeted agents, some of them widely used in daily clinical practice. Currently, he is the Head of the Medical Oncology Clinic of the Jules Bordet Institute, Brussels, and he also participates in several European Organisation for Research and Treatment of Cancer (EORTC) research groups. He is the author of over 70 peer-reviewed papers in high impact medical journals, as well as more than 20 book chapters. He is also the recipient of an award from the Belgian Royal Academy of Medicine.
Nagi S. El Saghir, M.D., F.A.C.P., graduated from the Free University of Brussels, Belgium. He completed his residency at The Brooklyn Hospital of SUNY-Downstate in Brooklyn, and his Fellowship at St. Luke's, Roosevelt Hospital Center of Columbia University in New York. He was Clinical Instructor of Medicine at Long Island College Hospital and State University of New York, then Assistant Professor at King Saud University in Rihadh, Saudi Arabia, and later Clinical Assistant Professor at Oakwood Hospital and Wayne State University in Detroit, Michigan. He now is Clinical Associate Professor of Medicine and Hematology–Oncology at the American University of Beirut, Beirut, Lebanon, and also a member of the EORTC Breast Cancer Group.
Gilberto de Castro Junior, M.D., M.Sc., received his M.D. degree at the University of São Paulo Medical School, São Paulo, Brazil and completed his residency and specialization in both Internal Medicine and Medical Oncology at the Hospital das Clínicas da Faculdade de Medicina da USP, São Paulo, Brazil. He received his M.Sc. degree in 2005 at the same University working on concurrent chemoradiation in patients with unresectable locally advanced head and neck cancer. He was a Fellow of the Clinique d’Oncologie Médicale, Institut Jules Bordet, Brussels, Belgium, between 2004 and 2005, sponsored by Fonds National de la Recherche Scientifique – Belgium. Nowadays, he works as an Attending Physician at the Hospital das Clínicas da Faculdade de Medicina da USP, São Paulo, Brazil, in cancer patient daily clinical care, clinical and translational research, and cancer education. His main areas of interest include head and neck cancer and new drug development.
Evandro de Azambuja, M.D., MSc, was born in Brazil and received his medical training at the Medical School of the Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil. At the Hospital de Clínicas, Porto Alegre, Brazil, he did his specialization in Internal Medicine and Medical Oncology. He received his master degree in December 2002. He is the recipient of an Award from the Belgium Society of Medical Oncology, in Belgium. Nowadays, he is a fellow at Institut Jules Bordet, Brussels, Belgium and a current PhD student at the Federal University of Rio Grande do Sul, Porto Alegre, Brazil. He is the author of nine peer-reviewed papers in medical journals.