CCL26-Mediated Modulation of Endothelial Secretome by Hypoxia-Induced Tumor-Derived Exosomes Enhances Metastatic Progression in Head and Neck Cancer.

Abstract

Tumor cells adapt to hypoxia by releasing hiTDExs enriched with bioactive molecules that modulate endothelial behavior and promote tumor progression. This study aimed to characterize how hypoxia-induced HNSCC exosomes reshape the endothelial secretome and contribute to metastatic potential. We examined whether hiTDExs reprogram endothelial cells and alter their secretome using cytokine arrays. Functional assays (migration, invasion, tube formation) showed a tumor-promoting role of CCL26 and tumor-suppressive effects of genetic inhibition of its receptor CCR3, while in silico and immunohistochemistry analyses assessed CCL26, HIF1A, and CD31 expression in relation to metastasis. Hypoxic exosomes from Detroit-562 and FaDu cells altered 25 and 52 proteins in HUVEC secretomes, with elevated CCL26 confirmed by ELISA. CCL26 significantly enhanced HNSCC cell proliferation, migration, and invasion, whereas CCL26 neutralization or genetic inhibition of its receptor CCR3 effectively abrogated these effects. High CCL26 and HIF1A correlated with metastasis, advanced stage, and poor survival. hiTDExs reprogram endothelial secretomes by elevating CCL26, promoting tumor-supportive phenotypes and driving metastatic progression in HNSCC.