Abstract
Excessive abnormal angiogenesis plays a pivotal role in tumor progression and is a hallmark of solid tumors. This process is driven by an imbalance between pro- and anti-angiogenic factors dominated by the tissue hypoxia-triggered overproduction of vascular endothelial growth factor (VEGF). VEGF-mediated signaling has quickly become one of the most promising anti-angiogenic therapeutic targets in oncology. Nevertheless, the clinical efficacy of this approach is severely limited in certain tumor types or shows only transient efficacy in patients. Acquired or intrinsic therapy resistance associated with anti-VEGF monotherapeutic approaches indicates the necessity of a paradigm change when targeting neoangiogenesis in solid tumors. In this context, the elaboration of the conceptual framework of “vessel normalization” might be a promising approach to increase the efficacy of anti-angiogenic therapies and the survival rates of patients. Indeed, the promotion of vessel maturation instead of regressing tumors by vaso-obliteration could result in reduced tumor hypoxia and improved drug delivery. The implementation of such anti-angiogenic strategies, however, faces several pitfalls due to the potential involvement of multiple pro-angiogenic factors and modulatory effects of the innate and adaptive immune system. Thus, effective treatments bypassing relapses associated with anti-VEGF monotherapies or breaking the intrinsic therapy resistance of solid tumors might use combination therapies or agents with a multimodal mode of action. This review enumerates some of the current approaches and possible future directions of treating solid tumors by targeting neovascularization.
Highlights
Tumorigenesis is a multistep process in which genetic and epigenetic mechanisms lead to the dysregulation of proto-oncogenes and tumor suppressor genes initiating the malignant transformation of cells [1]
Milestone discoveries were made concerning the identification of angiogenic factors, the regulation of neoangiogenesis and the development of anti-angiogenic therapeutic modalities that could interfere with pathological angiogenesis
Information from over 3000 registered clinical trials can be retrieved with the key words “tumor anti-angiogenic” from the ClinicalTrials.gov database run at the National Institutes of Health, and about 2000 hits are found with the key word combination “anti-vascular endothelial growth factor (VEGF) tumor”
Summary
Tumorigenesis is a multistep process in which genetic and epigenetic mechanisms lead to the dysregulation of proto-oncogenes and tumor suppressor genes initiating the malignant transformation of cells [1]. Folkman concerning tumor angiogenesis as a potential therapeutic target shifted the emphasis from traditional tumor cell-centered therapeutic strategies towards anti-angiogenic approaches, establishing a new field in oncology [2,7,8,9,10,11]. Due to the high proportion of non-responder patients with solid tumors with intrinsic or acquired resistance in conjunction with anti-VEGF treatments, there is an unmet need for novel strategies to compensate for the shortcomings of current therapeutic modalities [15]. The present review addresses topics of neovascularization, relevant factors of pathological angiogenesis, and possible cellular/molecular confounder factors underlying the limited efficacy of current anti-angiogenic approaches and discusses some novel avenues to overcome resistance
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