Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells

Abstract

Cancer associated fibroblasts (CAFs) comprise the majority of the tumor bulk of pancreatic adenocarcinomas (PDACs). Current efforts to eradicate these tumors focus predominantly on targeting the proliferation of rapidly growing cancer epithelial cells. We know that this is largely ineffective with resistance arising in most tumors following exposure to chemotherapy. Despite the long-standing recognition of the prominence of CAFs in PDAC, the effect of chemotherapy on CAFs and how they may contribute to drug resistance in neighboring cancer cells is not well characterized. Here we show that CAFs exposed to chemotherapy play an active role in regulating the survival and proliferation of cancer cells. We found that CAFs are intrinsically resistant to gemcitabine, the chemotherapeutic standard of care for PDAC. Further, CAFs exposed to gemcitabine significantly increase the release of extracellular vesicles called exosomes. These exosomes increased chemoresistance-inducing factor, Snail, in recipient epithelial cells and promote proliferation and drug resistance. Finally, treatment of gemcitabine-exposed CAFs with an inhibitor of exosome release, GW4869, significantly reduces survival in co-cultured epithelial cells, signifying an important role of CAF exosomes in chemotherapeutic drug resistance. Collectively, these findings show the potential for exosome inhibitors as treatment options alongside chemotherapy for overcoming PDAC chemoresistance.

Upregulation of IGF1 by tumor-associated macrophages promotes the proliferation and migration of epithelial ovarian cancer cells

“…The TAM CM transfer was performed according to Richards et al (9). TAM medium was centrifuged at 2,500 rpm for 30 min to remove cell debris and then mixed with complete DMEM at the ratio of 1:1.…”

“…The TME, comprising mesenchymal stem cells, cancer-associated fibroblasts (CAFs), myeloid cells, mesothelial cells and factors released by these cells, contributes to tumor growth, immune escape, distant metastasis and chemoresistance of cancer (6)(7)(8). For example, CAF-derived exosomes (tiny vesicles formed during endocytosis and 30-150 nm in size) can promote the survival and proliferation of pancreatic cancer cells, thus affecting responses to the standard chemotherapeutic agent gemcitabine (9). Mesothelial cells stimulated with TGF-β can promote OC cell attachment and proliferation by activating the promoters of matrix metalloprotein-2 and matrix metalloprotein-9 (10).…”

Exosomes: Navigating a New Route in Pancreatic Cancer

“…Indeed, Richards et al demonstrated that gemcitabine-treated CAFs secrete exosomes that increase expression of the chemoresistance-inducing factor Snail in pancreatic cancer epithelial cells, leading to their increased proliferation and chemoresistance. They further showed that treatment with GW4869, an inhibitor of exosome release, reduces survival in co-cultured epithelial cells [52]. This study demonstrated an important role of CAF-derived exosomes in chemotherapeutic drug resistance.…”

“…These data suggest that PSC-derived exosomes may be the primary driver of pancreatic cancer progression. Finally, Richards et al showed that CAF-derived exosomes, exposed to gemcitabine, are critical regulators of epithelial cancer cell proliferation and survival [52]. Together, these studies facilitate our understanding of the roles of the sophisticated pancreatic cancer microenvironment, and provide a potential pool of novel targets to improve therapeutic sensitivity and prevent tumor progression.…”

Prostate cancer exosomes as modulators of the tumor microenvironment

“…Activated fibroblasts resistant to the chemotherapy drug Gemcitabine (GEM) release exosomes containing miR-146a and mRNA for its upstream transcription factor Snail [79] . Incubation of PDAC cells with exosomes from GEM treated fibroblasts results in increased levels of Snail mRNA and miR146a in the cancer cells, leading to cell proliferation and chemoresistance.…”