Several reports indicate that
apelin is often over-expressed in
tumors, and therefore it has been suggested that the
apelin-
apelin receptor (APJ) system may induce
tumor progression. In contrast, our previous research revealed high expression of the
apelin-APJ system in
tumor blood vessels, suggesting its involvement in the regulation of
tumor vessel formation and normalization, resulting in the suppression of
tumor growth by promoting the infiltration of T cells. Thus, the effect of the
apelin-APJ system on
tumors remains controversial. In this report, to clarify the effect of
apelin in
tumor cells, we analyzed the function of APJ in
tumor cells using APJ knock out (KO) mice. In APJ-KO mice,
Apelin overexpression in B16/BL6 (
B16) melanoma cells induced greater
tumor growth than controls. In an APJ-KO
melanoma inoculation model, although angiogenesis is suppressed compared to wild type, no difference is evident in
tumor growth. We found that APJ deficiency promoted vascular mimicry in
tumors. In vitro, cultured APJ-KO B16 cells demonstrated a spindle-like shape. This phenotypic change was thought to be induced by epithelial-mesenchymal transition (EMT) based on evidence that APJ-KO B16 cells show persistently high levels of the mesenchymal maker, Zeb1; however, we found that EMT did not correlate with the
transforming growth factor-β/smad signaling pathway in our model. We propose that
apelin-APJ system in
cancer cells induces
tumor growth but negatively regulates EMT and
tumor malignancy.