Tumor angiogenesis: past, present and the near future

Abstract

The concept of treating solid tumors by inhibiting tumor angiogenesis was first articulated almost 30 years ago. For the next 10 years it attracted little scientific interest. This situation changed, relatively slowly, over the succeeding decade with the discovery of the first pro-angiogenic molecules such as basic fibroblast growth factor and vascular endothelial growth factor (VEGF), and the development of methods of successfully growing vascular endothelial cells in culture as well as in vivo assays of angiogenesis. However, the 1990s have witnessed a striking change in both attitude and interest in tumor angiogenesis and anti-angiogenic drug development, to the point where a remarkably diverse group of over 24 such drugs is currently undergoing evaluation in phase I, II or III clinical trials. In this review I will discuss the many reasons for this. These features, together with other recent discoveries have created intense interest in initiating and expanding anti-angiogenic drug discovery programs in both academia and industry, and the testing of such newly developed drugs, either alone, or in various combinations with conventional cytotoxic therapeutics. However, significant problems remain in the clinical application of angiogenesis inhibitors such as the need for surrogate markers to monitor the effects of such drugs when they do not cause tumor regressions, and the design of clinical trials. Also of concern is that the expected need to use anti-angiogenic drugs chronically will lead to delayed toxic side effects in humans, which do not appear in rodents, especially in short-term studies.

Ablation of microvessels in vivo upon dimerization of iCaspase-9

“…26,27 In the case of cancer, it is thought that these strategies can potentially overcome acquired Gene Therapy drug resistance since the cellular targets of such therapies are normal, genetically stable microvascular endothelial cells. 15 However, because such approaches target specific signaling pathways, resistance to anti-angiogenic therapy may arise if tumor cells secrete multiple survival factors to maintain their own capillary network. These 'alternative' angiogenic factors may either override apoptotic signals mediated by 'direct-acting' anti-angiogenic drugs, or prevent endothelial cell apoptosis when survival pathways are blocked with inhibitors of survival signaling pathways.…”

“…Endogenous inhibitors of angiogenesis such as endostatin and interferon-␣, as well as drugs and antibodies that inhibit pro-angiogenic signaling pathways are presently in clinical trials for the treatment of solid tumors. 15 Most of these strategies are based on the blockade of upstream signaling events that are triggered at the level of the endothelial cell membrane. These anti-angiogenic approaches have shown efficacy by themselves or in combination with other therapeutic modalities for the inhibition of tumor growth in animal models.…”

“…These anti-angiogenic approaches have shown efficacy by themselves or in combination with other therapeutic modalities for the inhibition of tumor growth in animal models. [15][16][17] The anti-angiogenic effect is mediated at least in part by the suppression of intracellular pro-survival molecules that act to repress the activation of apical caspases and apoptosis in endothelial cells. However, the engagement of parallel endothelial cell survival pathways may be sufficient to re-establish tissue vascularization and resistance to anti-angiogenic therapies.…”

EP2, a receptor for PGE2, regulates tumor angiogenesis through direct effects on endothelial cell motility and survival

“…A variety of mediators regulate angiogenesis, including growth factors and their cell surface receptors, matrix-degrading enzymes (e.g. matrix metalloproteinases) and adhesion receptors of the integrin family (Klagsbrun and Moses, 1999;Kerbel, 2000;Yancopoulos et al, 2000).…”

Dual blockade of EGFR and ERK1/2 phosphorylation potentiates growth inhibition of breast cancer cells

“…Many of these are now in clinical trials (Kerbel, 2000;Mendelsohn and Baselga, 2000;Posey et al, 2001). Epidermal growth factor receptor (EGFR) (also known as erbB1) and HER2 (or erbB2) are two widely studied molecules that are prototypic members of the erbB family of tyrosine kinase receptors (Olayioye et al, 2000).…”