BBA - Reviews on Cancer (v.1654, #1)

Role of lymphangiogenic factors in tumor metastasis by Yulong He; Terhi Karpanen; Kari Alitalo (3-12).
Nearly four centuries after the discovery of lymphatic vessels, the molecular mechanisms underlying their development are beginning to be elucidated. Vascular endothelial growth factor C (VEGF-C) and VEGF-D, via signaling through VEGFR-3, appear to be essential for lymphatic vessel growth. Observations from clinicopathological studies have suggested that lymphatic vessels serve as the primary route for the metastatic spread of tumor cells to regional lymph nodes. Recent studies in animal models have provided convincing evidence that tumor lymphangiogenesis facilitates lymphatic metastasis. However, it is not clear how tumor-associated lymphangiogenesis is regulated, and little is known about how tumor cells escape from the primary tumor and gain entry into the lymphatics. This review examines some of these issues and provides a brief summary of the recent developments in this field of research.
Keywords: VEGFR-3; Lymphangiogenesis; Tumor metastasis;

During angiogenesis, endothelial cell growth, migration, and tube formation are regulated by pro- and anti-angiogenic factors, matrix-degrading proteases, and cell–extracellular matrix interactions. Temporal and spatial regulation of extracellular matrix remodeling events allows for local changes in net matrix deposition or degradation, which in turn contributes to control of cell growth, migration, and differentiation during different stages of angiogenesis. Remodeling of the extracellular matrix can have either pro- or anti-angiogenic effects. Extracellular matrix remodeling by proteases promotes cell migration, a critical event in the formation of new vessels. Matrix-bound growth factors released by proteases and/or by angiogenic factors promote angiogenesis by enhancing endothelial migration and growth. Extracellular matrix molecules, such as thrombospondin-1 and -2, and proteolytic fragments of matrix molecules, such as endostatin, can exert anti-angiogenic effects by inhibiting endothelial cell proliferation, migration and tube formation. In contrast, other matrix molecules promote endothelial cell growth and morphogenesis, and/or stabilize nascent blood vessels. Hence, extracellular matrix molecules and extracellular matrix remodelling events play a key role in regulating angiogenesis.
Keywords: Angiogenesis; Extracellular matrix; Fibronectin; Collagen; Thrombospondin; Endothelial cell;

Stimulation of angiogenesis by Ras proteins by Onno Kranenburg; Martijn F.B.G. Gebbink; Emile E. Voest (23-37).
Cells that have acquired a proliferative advantage form islets of hyperplasia during the initial stages of tumor development. Like normal cells, they require oxygen and nutrients to survive and proliferate. The centre of the islets is characterized by low oxygen pressure and low pH, conditions that stimulate the sprouting of new capillaries from nearby vascular beds. It is now well established that neovascularisation (angiogenesis) of the hyperplasias is essential for further development of the tumor. The family of ras oncogenes promotes the initiation of tumor growth by stimulating tumor cell proliferation, but also ensures tumor progression by stimulating tumor-associated angiogenesis. Oncogenic Ras proteins stimulate a number of effector pathways that culminate in the transcriptional activation of genes that control angiogenesis. Moreover, Ras signaling leads to stabilization of the produced mRNAs and, possibly, to enhanced initiation of their translation. In this review we describe the mechanisms that underlie Ras regulation of vascular endothelial growth factor (VEGF), cyclooxygenases (COX-1/-2), thrombospondins (TSP-1/-2), urokinase plasminogen activator (uPA) and matrix metalloproteases-2 and -9 (MMP-2/-9). As a result of these Ras-regulated changes in gene expression, the tumor cells cause stimulation of endothelial cells in nearby vascular beds (directly via VEGF, and indirectly via COX-produced prostaglandins) and promote remodeling of the extracellular matrix (by lowering TSP and increasing uPA/MMPs). The latter effect makes growth factors available for endothelial cell activation and migration. In addition, tumor cell-activated stromal cells also contribute to the stimulation of angiogenesis by further enhancing the production and secretion of pro-angiogenic factors into the tumor stroma.
Keywords: Ras; Angiogenesis; VEGF; Cyclooxygenase; Thrombospondin; Metalloprotease; Urokinase;

Molecular targeting of angiogenesis by Patrizia Alessi; Christina Ebbinghaus; Dario Neri (39-49).
The majority of pharmacological approaches for the treatment of solid tumors suffer from poor selectivity, thus limiting dose escalation (i.e., the doses of drug which are required to kill tumor cells cause unacceptable toxicities to normal tissues). The situation is made more dramatic by the fact that the majority of anticancer drugs accumulate preferentially in normal tissues rather than in neoplastic sites, due to the irregular vasculature and to the high interstitial pressure of solid tumors.One avenue towards the development of more efficacious and better tolerated anti-cancer drugs relies on the targeted delivery of therapeutic agents to the tumor environment, thus sparing normal tissues. Molecular markers which are selectively expressed in the stroma and in neo-vascular sites of aggressive solid tumors appear to be particularly suited for ligand-based tumor targeting strategies. Tumor blood vessels are accessible to agents coming from the bloodstream, and their occlusion may result in an avalanche of tumor cell death. Furthermore, endothelial cells and stromal cells are genetically more stable than tumor cells and can produce abundant markers, which are ideally suited for tumor targeting strategies.This review focuses on recent advances in the development of ligands for the selective targeting of tumor blood vessels and new blood vessels in other angiogenesis-related diseases.
Keywords: Angiogenesis; Neo-vasculature; Tumor targeting; EDB domain of fibronectin; Recombinant antibody;

Endothelial cell integrins and COX-2: mediators and therapeutic targets of tumor angiogenesis by Curzio Rüegg; Olivier Dormond; Agnese Mariotti (51-67).
Vascular integrins are essential regulators and mediators of physiological and pathological angiogenesis, including tumor angiogenesis. Integrins provide the physical interaction with the extracellular matrix (ECM) necessary for cell adhesion, migration and positioning, and induce signaling events essential for cell survival, proliferation and differentiation. Integrins preferentially expressed on neovascular endothelial cells, such as αVβ3 and α5β1, are considered as relevant targets for anti-angiogenic therapies. Anti-integrin antibodies and small molecular integrin inhibitors suppress angiogenesis and tumor progression in many animal models, and are currently tested in clinical trials as anti-angiogenic agents. Cyclooxygense-2 (COX-2), a key enzyme in the synthesis of prostaglandins and thromboxans, is highly up-regulated in tumor cells, stromal cells and angiogenic endothelial cells during tumor progression. Recent experiments have demonstrated that COX-2 promotes tumor angiogenesis. Chronic intake of nonsteroidal anti-inflammatory drugs and COX-2 inhibitors significantly reduces the risk of cancer development, and this effect may be due, at least in part, to the inhibition of tumor angiogenesis. Endothelial cell COX-2 promotes integrin αVβ3-mediated endothelial cell adhesion, spreading, migration and angiogenesis through the prostaglandin-cAMP-PKA-dependent activation of the small GTPase Rac.In this article, we review the role of integrins and COX-2 in angiogenesis, their cross talk, and discuss implications relevant to their targeting to suppress tumor angiogenesis.
Keywords: Integrin; Cell adhesion; Signaling; Angiogenesis; Cancer; Therapy;

EG-VEGF and Bv8: a novel family of tissue-restricted angiogenic factors by Napoleone Ferrara; Jennifer LeCouter; Rui Lin; Franklin Peale (69-78).
A novel family of angiogenic mitogens have been recently characterized. Endocrine gland-derived vascular endothelial growth factor (EG-VEGF), and the mammalian homologue of Bombina variegata peptide 8 (Bv8), are two highly related endothelial cell mitogens and chemotactic factors with restricted expression profiles and selective endothelial cell activity. These peptides share two cognate G-protein coupled receptors. The expression of human EG-VEGF occurs predominantly in steroidogenic glands. Consistent with such an expression pattern, the human EG-VEGF gene promoter has a potential binding site for steroidogenic factor (SF)-1, a pivotal element for steroidogenic-specific transcription. In the human ovary, the expression of EG-VEGF is temporally and spatially complementary to the expression of VEGF-A, both in the follicular and in the luteal phase, suggesting complementary and coordinated roles of these molecules in ovarian angiogenesis. Also, EG-VEGF expression correlates with vascularity in the polycystic ovary syndrome, a leading cause of infertility. Bv8 expression is mainly restricted to the testis. The identification of these tissue-selective angiogenic factors raises the possibility that other secreted molecules with selectivity for the endothelium of other organs exist.
Keywords: EG-VEGF; VEGF-A; Ovary; GPCR; Endothelium; Angiogenesis;

Genetic dissection of tumor angiogenesis: are PlGF and VEGFR-1 novel anti-cancer targets? by Aernout Luttun; Monica Autiero; Marc Tjwa; Peter Carmeliet (79-94).
Many proliferative diseases, most typically cancer, are driven by uncontrolled blood vessel growth. Genetic studies have been very helpful in unraveling the cellular and molecular players in pathological blood vessel formation and have provided opportunities to reduce tumor growth and metastasis. The fact that tumor vessels and normal blood vessels have distinct properties may help in designing more specific—and therefore safer—anti-angiogenic strategies. Such strategies may interfere with angiogenesis at the cellular or molecular level. Possible molecular targets include angiogenic growth factors and their receptors, proteinases, coagulation factors, junctional/adhesion molecules and extracellular matrix (ECM) components. Some anti-angiogenic drugs, i.e., vascular endothelial growth factor (VEGF) antibodies and VEGF receptor-2 (VEGFR-2) inhibitors, have progressed into clinical cancer trials. While the results of these trials support the potential of anti-angiogenic therapy to treat cancer, they also demonstrate the need for more effective and safer alternatives. Targeting placental growth factor (PlGF) or VEGFR-1 may constitute such an alternative since animal studies have proven their pleiotropic working mechanism and attractive safety profile. Together, these insights may bring anti-angiogenic drugs closer from bench to bedside.
Keywords: Angiogenesis; Tumor; Metastasis; VEGF; PlGF; VEGF receptor; Anti-angiogenesis;

Surgery and angiogenesis by Jarmila D.W. van der Bilt; Inne H.M. Borel Rinkes (95-104).
Surgery may be regarded as an angiogenesis-inducing condition since it evokes the release of many angiogenic factors. Regarding the mechanistic overlap between tumor-associated neovascularisation and (physiological) angiogenesis in response to injury and hypoxia, surgery may promote the uncontrolled growth of residual dormant tumor cells. With the advent of anti-angiogenic agents, surgeons will be faced with more patients undergoing surgery for primary and secondary tumors under anti-angiogenic treatment. This could present problems with regard to angiogenesis-dependent phenomena such as wound repair, healing of intestinal anastomoses and liver regeneration. In this review we will discuss these matters from a biomedical and clinical point of view.
Keywords: Angiogenesis; Micrometastasis; Anti-angiogenic therapy; Wound healing; Liver regeneration; Hypoxia;