Apelin as a marker for monitoring the tumor vessel normalization window during antiangiogenic therapy

Abstract

Antiangiogenic agents transiently normalize tumor vessel structure and improve vessel function, thereby providing a window of opportunity for enhancing the efficacy of chemotherapy or radiotherapy. Currently, there are no reliable predictors or markers reflecting this vessel normalization window during antiangiogenic therapy. Apelin, the expression of which is regulated by hypoxia, and which has well‐described roles in tumor progression, is an easily measured secreted protein. Here, we show that apelin can be used as a marker for the vessel normalization window during antiangiogenic therapy. Mice bearing s.c. tumors resulting from inoculation of the colon adenocarcinoma cell line HT29 were treated with a single injection of bevacizumab, a mAb neutralizing vascular endothelial growth factor. Tumor growth, vessel density, pericyte coverage, tumor hypoxia, and small molecule delivery were determined at four different times after treatment with bevacizumab (days 1, 3, 5, and 8). Tumor growth and vessel density were significantly reduced after bevacizumab treatment, which also significantly increased tumor vessel maturity, and improved tumor hypoxia and small molecule delivery between days 3 and 5. These effects abated by day 8, suggesting that a time window for vessel normalization was opened between days 3 and 5 during bevacizumab treatment in this model. Apelin mRNA expression and plasma apelin levels decreased transiently at day 5 post‐treatment, coinciding with vessel normalization. Thus, apelin is a potential indicator of the vessel normalization window during antiangiogenic therapy.

Targeting APLN/APLNR Improves Antiangiogenic Efficiency and Blunts Proinvasive Side Effects of VEGFA/VEGFR2 Blockade in Glioblastoma

“…A clinical perspective for the coapplication of apelin-F13A together with VEGFA/VEGFR2 inhibitors is also suggested because coadministration of apelin-F13A and DC101 synergistically blunted GBM vascularization and diminished the proinvasive sideeffects associated with VEGFA/VEGFR2 inhibition. In addition, the reduced vascularization might be accompanied with vascular normalization that could be supportive for combined chemotherapy (18).…”

“…In hypoxic regions, apelin was highly coexpressed with VEGFA (15)(16)(17). In this context, it was suggested that apelin levels indicate improved tumor hypoxia due to vascular normalization upon bevacizumab treatment (18).…”

Chronic treatment with apelin, losartan and their combination reduces myocardial infarct size and improves cardiac mechanical function

“…Apelin is an endogenous peptide that belongs to the adipokines family and a ligand for the orphan G protein‐coupled receptor (APJ) . In normal conditions, APJ is expressed in the vascular smooth muscle cells, endothelium, and myocardial cells, and plays an important role in regulating blood pressure, cardiac contractility, and angiogenesis …”

Integrated Analysis of miRNA-mRNA Network Reveals Different Regulatory Patterns in the Endometrium of Meishan and Duroc Sows during Mid-Late Gestation

“…The only gene found in common in the two comparisons was APLN, encoding apelin. Apelin is an endogenous peptide that functions as the ligand of the G protein-coupled receptor APJ, which may be involved in many physiological processes including angiogenesis [56]. Apelin plays a role in regulating the hemodynamics of pregnancy [57].…”