Angiogenesis research in the past two decades has contributed significantly towards understanding the molecular pathophysiology of cancer progression and inspired target-oriented research and pharma industry for the development of novel anti-angiogenic agents. Currently, over eleven drugs targeting angiogenesis have been approved by the FDA for the treatment of various malignancies. Of the registered anti-angiogenic clinical trials until the end of 2017 (ClinicalTrials.gov), over 47% were completed, 10% were terminated, 3% withdrawn, over 0.5% were suspended and only 4 trials have culminated in FDA approval for marketing. On the one hand, the clinical benefits of anti-angiogenic drugs prompted the development of novel anti-angiogenic agents. On the other hand, however, a plethora of recent studies demonstrated the emergence of tumor drug resistance towards currently used anti-angiogenic therapeutics. Series of preclinical and clinical studies have highlighted the enigma of drug resistance with functional bypass pathways, and identified compensatory or alternative angiogenic mechanisms assuring tumor growth in the midst of an antiangiogenic stress environment. In the present review the classical literature of such redundant angiogenic pathways in concert with the key angiogenic factors and specialized cells involved in anti-angiogenic escape mechanisms is described. A strategic discourse regarding increasing tumor drug resistance and future modalities for anti-angiogenic therapy is also discussed in view of recent advances.

Introduction 

Vasculogenesis is the fundamental de novo process required for the development of blood vessels during embryonic development, wherein the angioblasts (endothelial progenitor cells) differentiate into endothelial cells in response to local cues and finally assemble to form the initial vascular plexus. Angiogenesis is the extension of vasculogenesis, which involves the development of new capillaries on pre-existing vessels. A vast body of literature has accumulated which describes the dynamics and complexities of new vessel formation (Chappell et al., 2016). From a physiological perspective, angiogenesis appears to be indispensable for tissue homeostasis, as the growth and development of an organism requires a well-developed network of blood vessels to ensure a continuous supply of oxygen and nutrients. Nevertheless, important physiological processes such as embryogenesis, organogenesis, wound healing, tissue repair, etc., cannot be achieved, unless there is a well-developed, mature orchestration of vascular network. Dissolution of vascular basal membrane, degradation of extracellular matrix (ECM), increase in vascular permeability, migration, invasion and proliferation of endothelial cells (ECs) and tube formation are the hallmarks of the angiogenic process. In brief, the process of neovascularization relies on a complex network and cross talks of proangiogenic factors, stromal cell interactions and remodeling of ECM (Gacche and Meshram, 2014). Under normal physiological conditions, the process of angiogenesis is regulated by maintaining a balance between activators and inhibitors of angiogenesis. The vessels developed through physiological angiogenesis are normal, stable and rarely proliferate under physiological conditions. However, in pathological conditions like cancer, the balance is more in favor of proangiogenic factors; as a result, there is excessive remodeling of vasculature. In contrast, the complex, abnormal, leaky and torturous vessels of tumors is the hallmark of pathological angiogenesis (Goel et al., 2011).