Abstract
Angiogenesis, the growth of new vessels from pre-existing ones, is an important feature of tumor growth that has been exploited as a therapeutic target in oncology. Given its key role in facilitating blood vessel sprouting, VEGF has been a major focus of anti-angiogenic strategies, but the observation of resistance in some clinical trials utilizing such agents has led to a search for new or complementary targets in angiogenesis process. The Angiopoietin/Tie2 pathway and in particular the Angiopoietin-2 (Ang-2) ligand which is critically involved in the destabilization of normal vasculature, has been identified as one such target. The current study investigated the potential benefits of combining an Ang-2 targeted therapy with small molecule VEGF targeted agents (Sunitinib, Cediranib) in a human renal cell carcinoma model. The results showed that while both Ang-2 and VEGF interference on their own impaired tumor growth and new blood vessel formation, the combination of agents that targeted both pathways resulted in significantly superior anti-tumor and anti-angiogenic effects.
Highlights
Angiogenesis, the formation of new blood vessels from pre-existing ones, is an important process in normal vascular development and physiological conditions such as wound healing, reproduction and the menstrual cycle [1]
Angiogenesis is an important feature of tumor growth that has been considered to be a potential target for cancer therapy for decades
The Angiopoietin/Tie2 axis is responsible for the first step in angiogenesis or the vessel destabilization while pro-angiogenic factors such as Vascular Endothelial Growth Factor (VEGF) activate the endothelial cells
Summary
Angiogenesis, the formation of new blood vessels from pre-existing ones, is an important process in normal vascular development and physiological conditions such as wound healing, reproduction and the menstrual cycle [1]. Many agents targeting Vascular Endothelial Growth Factor (VEGF) are commonly used in the clinic; in diseases such as kidney cancer [9,10]. Resistance to such therapies may occur [11,12,13], likely due to the redundancy of signaling pathways involved in the activation of sprouting angiogenesis [14]. The search for new or complementary targets in the angiogenic process to circumvent resistance and such therapies is being actively pursued [7,11,12]
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