Cancer-Associated Fibroblasts Confer Gemcitabine Resistance to Pancreatic Cancer Cells through PTEN-Targeting miRNAs in Exosomes

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is currently the third leading cause of cancer-related death in the United States. Even though the poor prognosis of PDAC is often attributed to late diagnosis, patients with an early diagnosis who undergo tumor resection and adjuvant chemotherapy still show tumor recurrence, highlighting a need to develop therapies which can overcome chemoresistance. Chemoresistance has been linked to the high expression of microRNAs (miRs), such as miR-21, within tumor cells. Tumor cells can collect miRs through the uptake of miR-containing lipid extracellular vesicles called exosomes. These exosomes are secreted in high numbers from cancer-associated fibroblasts (CAFs) within the tumor microenvironment during gemcitabine treatment and can contribute to cell proliferation and chemoresistance. Here, we show a novel mechanism in which CAF-derived exosomes may promote proliferation and chemoresistance, in part, through suppression of the tumor suppressor PTEN. We identified five microRNAs: miR-21, miR-181a, miR-221, miR-222, and miR-92a, that significantly increased in number within the CAF exosomes secreted during gemcitabine treatment which target PTEN. Furthermore, we found that CAF exosomes suppressed PTEN expression in vitro and that treatment with the exosome inhibitor GW4869 blocked PTEN suppression in vivo. Collectively, these findings highlight a mechanism through which the PTEN expression loss, often seen in PDAC, may be attained and lend support to investigations into the use of exosome inhibitors as potential therapeutics to improve the effectiveness of chemotherapy.

Cancer-derived small extracellular vesicles: emerging biomarkers and therapies for pancreatic ductal adenocarcinoma diagnosis/prognosis and treatment

“…RAB27B siRNA Downregulated miR-155 inhibited the release of cancer-derived sEVs and reduced the GEM resistance [142] CAF-derived sEVs GW4869 Suppression of CAF-derived sEV secretion could reduce these PTEN targeting miRNAs and restore the PTEN expression [143] Pan02-derived sEVs Short hairpin RNAs Knocking down of overexpressed genes ITGβ4 or ITGβ5 remarkably reduced the metastatic ability of cancer cells [144] PDAC-derived sEVs (Panc-1, MiaPaCa-2, etc. )…”

“…[165,166] Katherine et al discovered GEM treated CAFs could release PTEN targeting miR-NAs (miR-21, miR-181a, miR-221, miR-222, and miR-92a) and the suppression of CAF-derived sEV secretion with inhibitor GW4869 could reduce these PTEN targeting miRNAs and restore the PTEN expression. [143] However, these strategies involve the inhibition of sEVs being secreted from both healthy cells and cancer cells. Therefore, their use in cancer treatment should be carefully considered and investigated, as sEVs also play an essential role in regulating normal biological functions as well.…”

Intercellular crosstalk between cancer cells and cancer-associated fibroblasts via extracellular vesicles

“…miR-92a-3p could target PTEN expression in PDAC cells. [ 190 ] miR-1290 Prostate cancer Promote EMT and metastasis via targeting GSK3β expression in cancer cell. [ 197 ] miR-146a-5p Prostate cancer Promote cancer metastasis.…”

Hypoxia-elicited Exosomes Promote the Chemoresistance of Pancreatic Cancer Cells by Transferring LncROR via Hippo Signaling

“…Moreover, a number of studies have found that exosomes participate in the regulation of tumor migration, invasion and angiogenesis, as well as affect various biological processes (e.g., tumor immune escape and chemoresistance) in different types of tumors (e.g., breast 5 , lung 6 , prostate 7 , and colon 8 ). In PC, Richards et al found that exosomes secreted by cancer-associated fibroblasts could regulate cell proliferation and confer resistance to gemcitabine through miRNAs targeting phosphatase and tensin homolog (PTEN) 9 . Additionally, exosomes with downregulated hsa_circ_0000069 could suppress the malignant transformation of human pancreatic duct epithelial cells 10 .…”