Tumour-derived exosomes as a signature of pancreatic cancer - liquid biopsies as indicators of tumour progression

Abstract

Pancreatic cancer is the fourth most common cause of death due to cancer in the world. It is known to have a poor prognosis, mostly because early stages of the disease are generally asymptomatic. Progress in pancreatic cancer research has been slow, leaving several fundamental questions pertaining to diagnosis and treatment unanswered. Recent studies highlight the putative utility of tissue-specific vesicles (i.e. extracellular vesicles) in the diagnosis of disease onset and treatment monitoring in pancreatic cancer. Extracellular vesicles are membrane-limited structures derived from the cell membrane. They contain specific molecules including proteins, mRNA, microRNAs and non-coding RNAs that are secreted in the extracellular space. Extracellular vesicles can be classified according to their size and/or origin into microvesicles (∼150-1000 nm) and exosomes (∼40-120 nm). Microvesicles are released by budding from the plasmatic membrane, whereas exosomes are released via the endocytic pathway by fusion of multivesicular bodies with the plasmatic membrane. This endosomal origin means that exosomes contain an abundance of cell-specific biomolecules which may act as a fingerprint of the cell of origin. In this review, we discuss our current knowledge in the diagnosis and treatment of pancreatic cancer, particularly the potential role of EVs in these facets of disease management. In particular, we suggest that as exosomes contain cellular protein and RNA molecules in a cell type-specific manner, they may provide extensive information about the signature of the tumour and pancreatic cancer progression.

Targeting glypican‐4 overcomes 5‐FU resistance and attenuates stem cell–like properties via suppression of Wnt/β‐catenin pathway in pancreatic cancer cells

“…Indeed, this may also be cost-effective, as the isolation and use of exosomal biomarkers from patients would certainly be cheaper, less invasive, and potentially more sensitive and specific than many of the current clinical diagnostic tests. 46 Interestingly, the glypicans family is an attractive candidate and several previous studies reported that exosome-associated GPC1 was a highly specific and sensitive biomarker for early detection of pancreatic cancer. 47,48 Our results indicate that GPC4 might be considered as an alternative diagnostic and prognostic biomarker in pancreatic cancer.…”

Rapid Lipid-Based Approach for Normalization of Quantum-Dot-Detected Biomarker Expression on Extracellular Vesicles in Complex Biological Samples

“…However, their invasiveness, along with tumor sampling brings about challenges with studying tumor heterogeneity and evolution, making it an unlikely process for regular monitoring (Vaidyanathan, Soon et al 2019). vesicles / mL in blood, (Keller, Ridinger et al 2011, Lee, Fraser et al 2018, making EVs highly abundant and easily available biomarkers (Nuzhat, Kinhal et al 2017, Rajagopal and Harikumar 2018, Rodrigues, Fan et al 2018, van Niel, D'Angelo et al 2018. Critical information is stored in the molecular profile of the exosomal cargo and surface expression due to their endocytotic biogenesis from parent tumor cells making them favorable for studying tumor microenvironment (Kalluri 2016).…”

“…Currently, there are no reliable markers that can accurately diagnose, classify and predict the biological behavior of pancreatic tumors. Therefore, it is imperative to focus on identifying and developing biomarkers, with high specificity and sensitivity that can help detect initial lesions in the early stages of pancreatic cancer (Herreros-Villanueva and Bujanda 2016, Nuzhat, Kinhal et al 2017) There are potential serum biomarkers for diagnosis, disease progression and monitoring of therapy (Hidalgo 2010). Carbohydrate antigen, CA19-9 is currently the most extensively studied biomarker and the only one approved by the FDA with demonstrated clinical usefulness (Goonetilleke and Siriwardena 2007).…”

“…EpCAM is a primary tumor marker, showing evidence of downregulation in circulating tumor cells during epithelial-to-mesenchymal transition , Visvader and Lindeman 2009. Studies have shown that pancreatic cancer EVs exhibit certain markers related to the cancer initiating cells, which include Tspan8, MET and EpCAM (Nuzhat, Kinhal et al 2017). Several other studies unfolded higher expression levels of EpCAM that corresponded to poor prognosis in ovarian, breast and pancreatic cancer (Schnell, Cirulli et al 2013).…”

miRNA Profiling of Magnetic Nanopore–Isolated Extracellular Vesicles for the Diagnosis of Pancreatic Cancer

“…The miRNA expression patterns have been shown to be highly tissue-specific, providing great potential as a tumorspecific biomarker. In addition, miRNA dysregulation has been reported as a feature of pancreatic cancer progression, and the transfer of EV miRNAs has been shown to cause biological changes in recipient cells (30,31). To profile the miRNA cargo in EVs at various stages of pancreatic cancer, we isolated EVs using pan-exosome markers (CD9, CD81) from 500 mL of mouse plasma using the KPCY model (n ¼ 2 healthy, n ¼ 6 PanIN, and n ¼ 5 PDAC; ref.…”