The hypoxic microenvironment, an important feature of solid tumors, promotes tumor cells to release exosomes and enhances tumor angiogenesis. However, the detailed functions of hypoxic exosomes and the mechanisms underlying their effects in pancreatic cancer (PC) remain mysterious. Here, we observed that hypoxic exosomes derived from PC cells promoted cell migration and tube formation of human umbilical vein endothelial cells (HUVECs). The long noncoding RNA (lncRNA) UCA1 , a key factor, was highly expressed in exosomes derived from hypoxic PC cells and could be transferred to HUVECs through the exosomes. In addition, the expression levels of UCA1 in exosomes derived from PC patients’ serum were higher than in healthy controls and were associated with poor survival of PC patients. Moreover, hypoxic exosomal UCA1 could promote angiogenesis and tumor growth both in vitro and in vivo . With respect to the functional mechanism, UCA1 acted as a sponge of microRNA (miR)-96-5p, relieving the repressive effects of miR-96-5p on the expression of its target gene AMOTL2. Collectively, these results indicate that hypoxic exosomal UCA1 could promote angiogenesis and tumor growth through the miR-96-5p/AMOTL2/ERK1/2 axis and therefore, serve as a novel target for PC treatment.

Pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive tumors all over the world, has a generally poor prognosis, and its progression is positively correlated with the density of blood vessels. Recently, tumor-associated macrophages (TAMs) were proven to be beneficial for angiogenesis, but their mechanism of action remains unclear. Our study indicated that M2 macrophages were positively correlated with the microvessel density (MVD) of PDAC tissues, and M2 macrophage-derived exosomes (MDEs) could promote the angiogenesis of mouse aortic endothelial cells (MAECs) in vitro. At the same time, the M2 MDEs could also promote the growth of subcutaneous tumors and increase the vascular density of mice. Moreover, we also found that miR-155-5p and miR-221-5p levels in the M2 MDEs were higher than those in M0 MDEs, and they could be transferred into MAECs, as demonstrated by RNA sequencing (RNA-seq) and qPCR analysis. Our data confirmed the interaction between TAMs and the angiogenesis of PDAC by exosomes. Additionally, targeting the exosomal miRNAs derived from TAMs might provide diagnostic and therapeutic strategies for PDAC.

Hyaluronan (HA) and hyaluronan synthases (HAS) have been implicated in cancer growth and progression. We previously have shown that HAS3 and HA mediate tumor growth in SW620 colon cancer cells, but the mechanism remains poorly understood. In addition, the effect of HAS3 inhibition on tumor growth with other cells lines has not been explored. We therefore hypothesized that inhibition of HAS3 in highly tumorigenic HCT116 colon cancer cells would decrease tumor growth and that the underlying mechanism would involve altering proliferation and/or apoptosis. HAS3 expression was inhibited by transfection with siRNA; a scrambled sequence served as a control. Stable transfectants were injected into the flanks of nude mice and tumor growth followed for 30 days. Proliferation and apoptosis were then assessed in the harvested tumors. Results were compared using the Students’ t-test and ANOVA where appropriate. siRNA transfection decreased HAS3 expression, protein production, and pericellular HA retention, and decreased in vivo tumor growth. Proliferation was unaffected in the HCT116 tumors, but increased slightly in the SW620 tumors. In contrast, HAS3 inhibition significantly increased apoptosis in all tumors. HAS3 inhibition decreases subcutaneous tumor growth by colon cancer cells and significantly increases apoptosis with less effect on proliferation. These data show that HAS3 and HA mediate colon cancer growth by inhibiting apoptosis.