Abstract
Chemotherapy is often hindered by abnormal tumor vascularity, which causes impaired delivery of drugs into the tumor. Angiopoietin-1 has potent roles in angiogenesis and vessel maturation. We report here that an angiopoietin-1 variant, COMP-Ang1, promotes vascular remodeling and pericyte coverage and thereby promotes the efficient delivery of a chemotherapeutic drug into tumors of murine Lewis lung carcinoma. The combination of COMP-Ang1 with the cytotoxic drug 5-fluorouracil potentiated the effect of 5-fluorouracil on tumor growth without increasing animal toxicity. Moreover, COMP-Ang1 increased perfusion into the tumor. Although COMP-Ang1 increased the functional vasculature in the tumor, COMP-Ang1 alone did not promote tumor growth, possibly due to its promotion of increased pericyte coverage. This study suggests that COMP-Ang1 may improve the microcirculation within a tumor by increasing functional vasculature and tissue perfusion and that the combination of chemotherapy together with COMP-Ang1 might be an advantageous therapeutic approach.
Highlights
Current treatments for solid tumors are often compromised by the impaired delivery of the therapeutic agents and the low drug sensitivity of the tumor cells
On day 21, we examined the vascular remodeling in response to the treatment by measuring the vascular area and the coverage of pericytes (Fig. 1)
The number of blood vessel segments in each section was slightly lower in COMPAng1–treated tumors compared with control-treated tumors, but this difference was not statistically significant (Fig. 1E)
Summary
Current treatments for solid tumors are often compromised by the impaired delivery of the therapeutic agents and the low drug sensitivity of the tumor cells. Elevated interstitial fluid pressure may be one of the causes of the poor availability of circulating therapeutic agents [1]. Ang signaling via the Tie receptor expressed on endothelial cells is involved in blood vessel formation and maturation [9, 10]. By increasing the interaction between endothelial cells and pericytes, Ang is known to stabilize blood vessels [11, 12]. Overexpression of Ang produces enlarged and leakage-resistant vessels in adult mice [12]. Given the potency of Ang in stabilization and leakage-resistant remodeling in blood vessels, Ang could improve tumor circulation by promoting vascular remodeling in tumors
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