Hypoxic exosomes facilitate angiogenesis and metastasis in esophageal squamous cell carcinoma through altering the phenotype and transcriptome of endothelial cells

Abstract

Background In cancer progression, hypoxia, or low oxygen tension, is a major regulator of tumor aggressiveness and metastasis. However, how cancer cells adapt to the hypoxia and communicate with other mesenchymal cells in microenvironment during tumor development remains to be elucidated. Here, we investigated the involvement of exosomes in modulating angiogenesis and enhancing metastasis in esophageal squamous cell carcinoma (ESCC). Methods Differential centrifugation, transmission electron microscopy and nanoparticle tracking analysis were used to isolate and characterize exosomes. Colony formation and transwell assay were performed to assess the proliferation, migration and invasion of human umbilical vein endothelial cells (HUVECs). The tube formation assay and matrigel plug assay were used to evaluate the vascular formation ability of HUVECs in vitro and in vivo respectively. An in vivo nude mice model was established to detect the regulatory role of exosomes in ESCC progression. Microarray analysis was performed to analyze the transcriptome profiles in HUVECs. Results Exosomes derived from ESCC cells cultured under hypoxia played a better role in promoting proliferation, migration, invasion and tube formation of HUVECs in vitro and in vivo than exosomes from ESCC cells cultured under normoxia. Moreover, hypoxic exosomes significantly enhanced the tumor growth and lung metastasis compared with normoxic exosomes in nude mice models. Interestingly, endothelial cells were programmed by hypoxic and normoxic exosomes from ESCC cells which altered the transcriptome profile of HUVECs. Conclusions Taken together, our data identified an angiogenic role of exosomes from ESCC cells which shed light on the further application of exosomes as valuable therapeutic target for ESCC. Electronic supplementary material The online version of this article (10.1186/s13046-019-1384-8) contains supplementary material, which is available to authorized users.

PTH Derivative promotes wound healing via synergistic multicellular stimulating and exosomal activities

“…Importantly, PTHrP-2-stimulated endothelial cell exosomes exhibited significant promotion effects on HaCaTs proliferation and migration, which might explain PTHrP-2's ability to cause re-epithelization. Previous studies reported that certain drugs and environments, such as hypoxia, might alter exosome contents and thereby alter the intercellular messages communicated by exosomes [39][40][41]. The exosome counts revealed that PTHrP-2 enhanced exosome secretion.…”

Inclusion Biogenesis, Methods of Isolation and Clinical Application of Human Cellular Exosomes

“…Exosomes are considered to be involved in numerous mechanisms promoting cancer development, such as pre-metastasis niche formation [113], angiogenesis [114], migration and invasion [115], immune response modulation [116], metastasis [117], and drug resistance. Moreover, increased exosome secretion is a key adaptation to hypoxia, facilitating angiogenesis and metastasis in new niche conditions [118]. Small extracellular vesicle loading systems employing exosomes and exosome mimics known as small extracellular vesicles (sEVs) are being developed as a novel delivery strategy in chemotherapy-based cancer therapies dependent on loading external cargo composed of a tumour inhibiting agent and modifying exosomal surface proteins [119].…”

<p>Esophageal Microenvironment: From Precursor Microenvironment to Premetastatic Niche</p>

“…In previous studies, ESCC cell exosomes cultured under hypoxic conditions could promote the proliferation and invasion of endothelial cells in vivo and in vitro, and show significant angiogenic effects compared with non-hypoxic conditions. 68 ESCCderived exosomes can also promote the expansion of PD-1 + TAM and the expression of CD206 to promote the progress of ESCC. 69 In addition to the study of the number and general function of exosomes, we are also committed to the study of the contents of exosomes such as miRNA, DNA, or protein molecules.…”