Pancreatic Cancer Small Extracellular Vesicles (Exosomes): A Tale of Short- and Long-Distance Communication

Abstract

Even with all recent advances in cancer therapy, pancreatic cancer still has a dismal 5-year survival rate of less than 7%. The most prevalent tumor subtype is pancreatic ductal adenocarcinoma (PDAC). PDACs display an extensive crosstalk with their tumor microenvironment (TME), e.g., pancreatic stellate cells, but also immune cells to regulate tumor growth, immune evasion, and metastasis. In addition to crosstalk in the local TME, PDACs were shown to induce the formation of pre-metastatic niches in different organs. Recent advances have attributed many of these interactions to intercellular communication by small extracellular vesicles (sEVs, exosomes). These nanovesicles are derived of endo-lysosomal structures (multivesicular bodies) with a size range of 30–150 nm. sEVs carry various bioactive cargos, such as proteins, lipids, DNA, mRNA, or miRNAs and act in an autocrine or paracrine fashion to educate recipient cells. In addition to tumor formation, progression, and metastasis, sEVs were described as potent biomarker platforms for diagnosis and prognosis of PDAC. Advances in sEV engineering have further indicated that sEVs might once be used as effective drug carriers. Thus, extensive sEV-based communication and applications as platform for biomarker analysis or vehicles for treatment suggest a major impact of sEVs in future PDAC research.

Cellular metabolism in pancreatic cancer as a tool for prognosis and treatment (Review)

“…It has also been suggested that autophagy in CAFs could be induced by ammonia produced by cancer cells during glutaminolysis and diffused into the microenvironment, which could lead to a positive feedback, with subsequent high levels of glutamine secreted into the TME by CAFs increasing the conversion of glutamine to glutamate and ammonia along with mitochondrial activity in cancer cells (166,167). A supportive role of the metabolic scavenging in PDAC is further evidenced by the confirmed existence of CAF-derived exosomes containing mRNA, miRNA, intact metabolites and TCA cycle intermediates, which promote PC cell proliferation, migration and chemoresistance in a mechanism similar to macropinocytosis under nutrient-depleted conditions (31,(168)(169)(170). Aside from acting as a direct source of metabolites, such exosomes could create a hypoxia-mimicking microenvironment stimulating the reductive carboxylation of glutamine in cancer cells, the pathway previously observed in rapidly growing malignant cells and identified to be an alternative to oxidative metabolism as the major source of citrate and precursors for macromolecular synthesis (168,171).…”

Exosomes as prognostic biomarkers in pancreatic ductal adenocarcinoma—a systematic review and meta-analysis

“…The development of isolation kits to surmount this shortcoming will increase their accessibility. Immune purification to concentrate tumor-specific exosomes could increase sensitivity and specificity of the analysis 42 . The common ground across the eligible studies was, besides analysis of biomarkers associated with tumor development and aggressiveness, as previously mentioned, a low risk of bias regarding prognostic factor measurement -with clearly described methods for sampling and isolation of biomarkers.…”

Exosomes as Crucial Players in Pathogenesis of Systemic Lupus Erythematosus

“…Exosomes are widely distributed in various body fluids [ 32 ] and contain adhesion molecules, tetrads, enzymes, scaffolds, nucleic acids, and binding proteins ( Figure 2 ) [ 33 ]. Nucleic acids, lipids, and proteins can be transferred between cells via exosomes [ 34 ], in some cases affecting recipient cells via autocrine and paracrine mechanisms [ 35 ]. There are multiple modes of action between target cells and exosomes.…”