From Vessel Normalization to Vascular Destruction: Therapeutic Paradoxes in Antiangiogenesis

Zidane Aleyasin^*
*Correspondence: Zidane Aleyasin, Department of Oncology, Arab American University, 13 Zababdeh, Jenin P.O. Box 240, Palestine, Email:

Introduction

Tumor angiogenesis-the process by which cancerous tissues stimulate the formation of new blood vessels-has long been recognized as a hallmark of cancer. Pioneering work by Judah Folkman in the 1970s laid the foundation for a new era in cancer therapeutics, one centered on antiangiogenic therapy. The rationale was seemingly straightforward: by blocking the blood supply to tumors, one could "starve" them of oxygen and nutrients, halting growth and metastasis. This concept rapidly evolved into the development of agents targeting key angiogenic molecules such as Vascular Endothelial Growth Factor (VEGF) and its receptors.

However, clinical experience has revealed that the effects of antiangiogenic therapy are far from straightforward. In some contexts, vascular targeting enhances drug delivery and improves therapeutic outcomes; in others, it paradoxically accelerates tumor progression, metastasis, or resistance. These contradictory observations have led to the recognition of a therapeutic paradox: antiangiogenic therapy can both normalize and destroy tumor vasculature, with drastically different biological and clinical consequences [1,2].

Description

Angiogenesis is orchestrated through a complex interplay of pro- and anti-angiogenic signals, which maintain vascular homeostasis under normal physiological conditions. Tumors exploit this balance, primarily by inducing hypoxia, which in turn stimulates the production of proangiogenic factors such as VEGF, Fibroblast Growth Factors (FGFs), angiopoietins, and platelet-derived growth factor (PDGF). These factors promote endothelial cell proliferation, migration, and tube formation, leading to a dense but dysfunctional vascular network. Tumor vessels tend to be tortuous, hyperpermeable, and lack proper pericyte coverage. This chaotic vascular architecture contributes to uneven perfusion, hypoxia, acidosis, and elevated interstitial pressure, which impair drug delivery and facilitate tumor progression [3].

The vessel normalization hypothesis, introduced by Rakesh Jain, challenged the idea that all tumor blood vessels should be eradicated. Instead, Jain proposed that judicious use of antiangiogenic agents-particularly at low to moderate doses-could transiently restore the structural and functional integrity of tumor vasculature. This process includes improved pericyte attachment, reduced vascular leakiness, normalized basement membrane structure, and enhanced perfusion. The outcome is a temporary window wherein oxygenation is improved, interstitial pressure is reduced, and the tumor becomes more amenable to other therapies such as chemotherapy, radiotherapy, and immunotherapy. Molecularly, vessel normalization is characterized by downregulation of VEGF and Angiopoietin-2, restoration of endothelial junction proteins like VE-cadherin, and stabilization through TIE2 activation. Nitric oxide signaling also plays a role in restoring vascular tone and responsiveness. In both preclinical models and human studies, such as those involving glioblastoma and colorectal cancer, low-dose anti-VEGF therapy has led to improved delivery and efficacy of co-administered therapies. Imaging studies and biomarker analyses during these windows have demonstrated reductions in tumor hypoxia and improved drug penetration [4].

The duality between normalization and destruction presents a significant challenge in optimizing antiangiogenic therapy. In glioblastoma, for example, bevacizumab has been shown to improve radiographic appearance and reduce cerebral edema, yet it has not significantly extended overall survival. This may be due to the short-lived nature of the normalization window and the eventual development of infiltrative, hypoxia-driven tumor phenotypes. In colorectal cancer, bevacizumab combined with chemotherapy has improved progression-free survival, suggesting that timing and dosing to exploit normalization are critical. Conversely, in pancreatic cancer-a tumor marked by dense stroma and limited vascularity-antiangiogenic strategies have largely failed, highlighting tumor-specific context as a determining factor [5].

Conclusion

The paradox of antiangiogenic therapy-its ability to both normalize and destroy tumor vasculature-reflects the complexity of the tumor microenvironment and the need for nuanced treatment strategies. Vessel normalization presents a therapeutic window of opportunity, enhancing perfusion, oxygenation, and the efficacy of combined treatments. In contrast, excessive or poorly timed antiangiogenic therapy can induce severe hypoxia, drive resistance, and foster metastasis. Optimizing dose, timing, sequencing, and patient selection is essential to reconcile these opposing outcomes. A deeper understanding of vascular biology, coupled with real-time monitoring and integrative technologies, will be crucial in advancing the use of antiangiogenic therapy. Rather than aiming to obliterate the tumor vasculature, the future lies in manipulating and managing it-transforming a hostile microenvironment into one that supports effective and durable cancer control.

Acknowledgement

None.

Conflict of Interest

None.

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