Hypoxia alters the release and size distribution of extracellular vesicles in pancreatic cancer cells to support their adaptive survival

Abstract

Pancreatic tumors are highly desmoplastic and poorly‐vascularized, and therefore must develop adaptive mechanisms to sustain their survival under hypoxic condition. Extracellular vesicles (EV) play vital roles in pancreatic tumor pathobiology by facilitating intercellular communication. Here we studied the effect of hypoxia on the release of EVs and examined their role in adaptive survival of pancreatic cancer (PC) cells. Hypoxia promoted the release of EV in PC cell lines, MiaPaCa and AsPC1, wherein former exhibited a far greater induction. Moreover, a time‐dependent, measurable and significant increase was recorded for small EV (SEV) in both the cell lines with only minimal induction observed for medium (MEV) and large EVs (LEV). Similarly, noticeable changes in size distribution of SEV were also recorded with a shift toward smaller average size under extreme hypoxia. Thrombospondin (apoptotic bodies marker) was exclusively detected on LEVs, while Arf6 (microvesicles marker) was mostly present on MEV with some expression in LEV as well. However, CD9 and CD63 (exosome markers) were expressed in both SEV and MEVs with a decreased expression recorded under hypoxia. Among all subfractions, SEV was the most bioactive in promoting the survival of hypoxic PC cells and hypoxia‐inducible factor‐1α stabilization was involved in heightened EV release under hypoxia and for their potency to promote hypoxic cell survival. Altogether, our findings provide a novel mechanism for the adaptive hypoxic survival of PC cells and should serve as the basis for future investigations on broader functional implications of EV.

Human Cardiac Progenitor Cells Enhance Exosome Release and Promote Angiogenesis Under Physoxia

“…Our NTA analysis results showed an increased EV release under 5% O 2 condition, but not under at 1% O 2 . Other studies have observed increased secretion of EVs under hypoxia (King et al, 2012;Bian et al, 2014;Patton et al, 2019;Zhang et al, 2019), however these studies were not performed with hCPCs. Multiple studies have demonstrated enhanced functional effects of hypoxiaderived versus normoxia-derived EVs.…”

A formula constituted by arsenic trioxide and dimercaprol enhances sensitivity of pancreatic cancer xenografts to radiotherapy

“…Hypoxia occurs in most solid tumor tissues and is de ned as an essential cause of resistance of tumors to radiotherapy [27,28]. At present, most radiosensitizers consist of compounds containing nitro groups, such as misonidazole and RRx-001 [29][30][31].…”

The potential roles of exosomes in pancreatic cancer initiation and metastasis

“…Upon uptake by macrophages, miR-301a-3p can also induce HIF1α/2α-dependent M2 phenotype transformation due to the activation of PTEN/PI3K signaling cascade [ 123 ]. Hypoxia has been shown to stimulate PaCa cells to generate more of small-volume exosomes via HIF1α, which increases the survival, proliferation, and metastasis of PaCa cells [ 149 ]. Additionally, exosomal miR-1246 has been found in the serum from patients with breast and prostate cancers [ 150 , 151 ].…”