Stabilization versus Ablation of Tumor Vasculature: Implications in Radio and Chemo-Sensitization

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It is well established that tumors are unable to grow beyond certain size (1-2 mm) unless they acquire their own blood supply via. angiogenesis. In addition, angiogenesis helps tumors to invade adjacent tissues and metastasize to distant sites. Therefore, it has been postulated that interfering with the blood supply using antiangiogenic therapies will destroy the tumor. However, there is an emerging alternative concept that depriving the tumor of its blood supply interferes with the delivery of chemotherapeutic agents to the tumor and creates unfavorable hypoxic environment that compromises the action of radiotherapy. This concept was supported by the modest responses to anti-angiogenic therapies in clinical trials and the lack of any impact on patient’s survival when antiangiogenic drugs are administered as single agents. Although, Hurwitz, et al have shown that combining the antiangiogenic drug, Bevacizumab with chemotherapy significantly improved survival among metastatic colorectal cancer patients. Still, other studies demonstrated reductions in tumor concentrations of chemotherapy or effectiveness of radiotherapy when antiangiogenic drugs were co-administered. Even when antiangiogenic drugs yielded significant effects on the growth of some tumors such as renal cell carcinoma, cervical cancer and ovarian cancer, they failed to demonstrate significant improvements in patients’ survival. Furthermore, complete resistance to antiangiogenic therapies have been reported for prostate and pancreatic adenocarcinoma and melanoma. In order to explain this inconsistency, further research is needed for better understanding of the underlying cellular and molecular mechanisms of tumor vascularization and its interaction with cancer therapies in different tumor beds.

Tumors’ blood vessels are often larger and more conspicuous than those of normal tissues. However, tumors tend to actually have less blood supply than normal tissues because tumor blood vessels are fragile, leaky, morphologically abnormal and malfunctioning. While the normal vasculature consists of evenly spaced, well-differentiated arteries, arterioles, capillaries, venules and veins, the tumor vasculature is heterogeneous, unevenly distributed and chaotic with a tortious irregular course that leads to zones of hypoxia and acidosis. Tumors initiate a vascular supply through secreting angiogenic factors, mainly Vascular Endothelial Growth Factor (VEGF). Despite being of critical value in controlling the physiological processes of angiogenesis and vascular permeability, when continuously over-expressed in tumor tissues, VEGF induces accelerated and defective angiogenesis wherein vessels are immature, leaky, tortious and characterized by defective anatomy and physiology. These structural abnormalities contribute to spatial and temporal heterogeneity in tumor blood function, resulting in poorly perfused and subsequently hypoxic tumor microenvironment. Targeting tumor vessels via. Anti-VEGF/VEGFR drugs have not been effective as a cure since impeding tumor blood supply deprives the tumor of oxygen, leading to hypoxia and acidosis that, in turn, can promote tumor growth, abnormal angiogenesis, and metastasis and also compromise the cytotoxic functions of immune cells that infiltrate tumors. In addition, reduced tumor vascularity is a main contributor to therapeutic resistance in cancer since it interferes with the delivery of anti-cancer agents to the tumor targeted by chemotherapy or minimizes the production of Reactive Oxygen Species (ROS) in the tumor area, which is essential for radiation therapy induced cell killing [18,19]. Radiation-induced effects on cancer are brought about by inducing ROS production, DNA damage and apoptosis. However, poor vascularization and hypoxia that characterize solid tumors induce resistance to radiotherapy and are positively correlated with more invasion and metastasis. 

This is achieved by two mechanisms: first, through the lack of O2 and hence the interference with radiation-induced ROS production. Second, via. the hypoxia inducible factor-1a (HIF-1a) that provokes adaptive intracellular responses that, in turn, facilitate cell proliferation, interfere with apoptosis, provide protection from cell demise and ultimately rendering tumors radioresistant. As a result, increasing the chemotherapeutic doses or strategies to intensify radiotherapy have been employed to increase the treatment efficacy. However, these procedures can potentially lead to a higher risk of serious side effects. To raise the therapeutic ratio (the ratio between the desirable cytotoxic effects and normal tissue complications), new strategies to enhance chemo and radiosensitivity of cancer are needed. To this end, we need to develop methods to improve tumor blood perfusion and normalize vascular development in order to increase tumor vulnerability to anti-cancer therapy as a better alternative to starving a tumor of its blood supply, which is not curative. Furthermore, one needs to emphasize that antiangiogenic drugs are not without side effects. Indeed, they have been reported to induce a myriad of toxic effects such as hypertension, hemorrhage, thromboembolism, proteinuria, malaise, fatigue, biochemical hypothyroidism, and cardiac failure, all are related to the non-specific action of antiangiogenic drugs that affects both normal and cancer tissues.