Approaching Angiogenesis

Anticancer drug targets: approaching angiogenesis Eli Keshet, Shmuel A. Ben-Sasson J Clin Invest. 1999;104(11):1497-1501. https://doi.org/10.1172/JCI8849. Perspective For more than 50 years, a direct strategy dominated the field of cancer therapy. The selected target was the tumor cell itself; any cytotoxic drug that could kill tumor cells in vitro was by definition a candidate for in vivo chemotherapy. It soon became apparent, however, that normal cells could also be susceptible to the same spectrum of drugs. Moreover, because of the inherent genetic instability of neoplastic cells, exposure to chemotherapy eventually results in the selection of drug-resistant clones. The indirect strategy of antiangiogenic therapy provides an alternative that uses the evolving vasculature, which nourishes the growing tumor, as the prime target. With this approach, oncologists no longer need to restrict their attention to the individual cancer cell but may focus on its tissue context in general, and on angiogenesis, the process of blood-vessel formation, in particular. This conceptual framework, which has guided the search for new methods to identify novel anticancer drugs, is the subject of this Perspective. Strategic considerations The concept of cancer antiangiogenic therapy stems from Folkman’s initial proposition that the expansion of the tumor mass beyond a size of a few cubic millimeters totally depends on de novo formation of a vascular network that provides the growing tumor with oxygen and essential nutrients (1). This thesis, now confirmed by a large body of experimental evidence, […] Find the latest version: https://jci.me/8849/pdf Anticancer drug targets: Perspective approaching angiogenesis SERIES on targets for cancer therapy Eli Keshet1 and Shmuel A. Ben-Sasson2 William G. Kaelin, Jr., Editor 1Department of Molecular Biology, and 2Department of Experimental Medicine and Cancer Research, The Hebrew University–Hadassah Medical School, Jerusalem 91120, Israel Address correspondence to: Eli Keshet, Department of Molecular Biology, The Hebrew University–Hadassah Medical School, Jerusalem 91120, Israel. E-mail: [email protected]. For more than 50 years, a direct strategy dominated the tumors (and probably many leukemias [5]) are angio- field of cancer therapy. The selected target was the tumor gensis-dependant, this approach circumvents the need cell itself; any cytotoxic drug that could kill tumor cells to tailor therapy to the unique genetic makeup of an in vitro was by definition a candidate for in vivo individual tumor. Second, the targeted vascular endothe- chemotherapy. It soon became apparent, however, that lial cells are normal, genetically stable cells, and therefore normal cells could also be susceptible to the same spec- are less likely than are tumor cells to become drug-resist- trum of drugs. Moreover, because of the inherent genet- ant. Thus, once a genuine antiangiogenic therapy is ic instability of neoplastic cells, exposure to chemother- proven effective in a clinical trial, it could become the apy eventually results in the selection of drug-resistant major or even the sole anticancer therapy. clones. The indirect strategy of antiangiogenic therapy How realistic are the prospects of antiangiogenic ther- provides an alternative that uses the evolving vascula- apy? The answer to this question depends on the ability ture, which nourishes the growing tumor, as the prime to inhibit angiogenesis specifically, without damaging target. With this approach, oncologists no longer need any other tissue. Thus, antiangiogenic therapy must be to restrict their attention to the individual cancer cell but endothelial cell–specific and must distinguish between may focus on its tissue context in general, and on angio- tumor and normal vasculatures. Another issue concerns genesis, the process of blood-vessel formation, in partic- the overall course of antiangiogenic therapy: will it nec- ular. This conceptual framework, which has guided the essarily be chronic in nature, only keeping the tumor search for new methods to identify novel anticancer from growing bigger, or is it possible that antiangiogenic drugs, is the subject of this Perspective. therapy will also induce tumor regression? Because of our limited understanding of angiogenesis in general Strategic considerations and tumor angiogenesis in particular, we are still far The concept of cancer antiangiogenic therapy stems from being able to provide a comprehensive answer. from Folkman’s initial proposition that the expansion Hopes for inhibiting ongoing tumor neovasculariza- of the tumor mass beyond a size of a few cubic millime- tion without inducing adverse effects on the host circu- ters totally depends on de novo formation of a vascular latory system rest in part on the observation that the vas- network that provides the growing tumor with oxygen culature in normal adults is generally quiescent, with and essential nutrients (1). This thesis, now confirmed only 0.01% of endothelial cells undergoing cell division at by a large body of experimental evidence, implies that any given time. In tumors, the fraction of cycling tumors can potentially be starved to death by inhibiting endothelial cells might be 2–3 orders of magnitude high- their neovascularization. Viewing the tumor as an er. Therefore, antagonizing endothelial cell proliferation ecosystem involving reciprocal paracrine interactions is likely to have a minimal effect on the normal vascula- between tumor cells and endothelial cells further under- ture. Anticipated exceptions are the impairment of repro- scores the importance of a persistent vascular supply for ductive cycles in premenopausal women (due to the fact optimal tumor growth (2). that hormone-driven angiogenesis naturally takes place Tumor angiogenesis is generally viewed as a conse- in the ovary and endometrium) and a compromised quence of the activation of an angiogenic switch — a dis- capacity for angiogenesis associated with wound healing. crete genetic event in the succession of genetic alter- These foreseen complications, however, are considered ations underlying tumor progression that endows the acceptable in face of the risk of tumor progression. tumor with the ability to recruit blood vessels from the Another distinguishing characteristic of tumor vessels neighboring tissue. In several animal models, a discrete that might be exploited in selectively targeting them is angiogenic switch has been demonstrated during early their relative state of immaturity. Ongoing neovascular- stages of tumor development that preceded the appear- ization and constant remodeling of tumor vessels (evi- ance of large malignant tumors (3). denced by regressive changes taking place concomitant- In principle, targeting the tumor vasculature rather ly with vessel proliferation) account for the fact that, at than targeting tumor cells (an approach that is consid- any given time during the course of tumor growth, a sig- ered by Ohh and colleagues [4] in this issue of the JCI, as nificant fraction of tumor vessels is poorly structured and well as by the other authors in this Perspectives series) immature. One hallmark of the immature vessels present has 2 remarkable advantages. First, because all solid in tumors is incomplete coating with periendothelial The Journal of Clinical Investigation | December 1999 | Volume 104 | Number 11 1497 cells, resulting from the fact that the recruitment of these passed an in vivo test of tumor growth inhibition in a smooth muscle–like cells lags behind the initial forma- conventional animal model. Thrombospondin-1 was the tion of the endothelial plexus. A greater vulnerability of first bona fide antiangiogenic factor to be discovered (6). immature vessels, or the differential dependence of In a series of publications, Bouck and colleagues showed immature vessels on specific survival factors might in that the level of production of this naturally occurring theory be exploited to enforce vessel regression. glycoprotein is inversely correlated with the level of tissue At the molecular level, qualitative differences between angiogenesis and tumorigenesis in vivo. Thrombos- tumor vessels and established normal vessels might be pondin-1 and -2 remain the most outstanding examples reflected in the preferential representation of certain for the mechanism of fine-tuning of angiogenesis by cell-surface proteins on angiogenic tumor vessels. For extracellular proteins. Further attempts were made to dis- example, VEGF receptors and αvβ3 and αvβ5 integrins sect the molecular structure of this large protein and are relatively weakly expressed in normal endothelia, derive from it peptides with antiangiogenic activity. and might provide useful targets for inhibition of Overall, many of the signals controlling the process of tumor vessel angiogenesis. angiogenesis are mediated by specific interactions between proteins, including ligand-receptor, cell–extra- Tipping the balance cellular matrix (ECM), and antiangiogenic factor inter- In general, angiogenesis is controlled by a balance actions. Thus, the ability to identify peptide domains between proangiogenic and antiangiogenic factors. that are specifically involved in tumor angiogenesis These can be circulatory factors or can act locally as holds great promise. A recently described and powerful paracrine factors. Obviously, if we know the molecular methodology — isolation of peptides from phage display nature of the proangiogenic signals, we can try to antag- libraries that bind to proteins that are

Load more