The role of exosomal microRNAs in pancreatic cancer
Review Article

The role of exosomal microRNAs in pancreatic cancer

Yifan Xu1, Xiaohui Xu1,2, Abigael Williams1, Weiqun Ding1

1Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA;2Department of General Surgery, First People’s Hospital of Taicang City, Taicang Affiliated Hospital of Soochow University, Suzhou 215400, China

Contributions: (I) Conception and design: W Ding; (II) Administrative support: None; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: None; (V) Data analysis and interpretation: None; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Dr. Weiqun Ding. Department of Pathology, University of Oklahoma Health Sciences Center, 940 Stanton L. Young Blvd., BMSB 401A, Oklahoma City, OK 73104, USA. Email:

Abstract: Pancreatic cancer is the third leading cause of cancer death in the United States. New therapeutic and diagnostic strategies are urgently needed to improve pancreatic cancer outcomes. Exosomes are endosome-derived extracellular vesicles containing cellular lipids, proteins, and microRNAs (miRNAs). Studies have shown that exosomal miRNAs are potential diagnostic biomarkers and therapeutic targets for various types of cancer. In this review, we summarize recent findings indicating the role of exosomal miRNAs in pancreatic cancer progression, therapeutic resistance, and biomarker development.

Keywords: Pancreatic cancer; exosome; microRNA (miRNA); biomarker; chemoresistance

Received: 05 January 2020; Accepted: 18 February 2020; Published: 28 February 2020.

doi: 10.21037/sci.2020.02.01

Pancreatic cancer

The pancreas is a gland organ of the digestive and endocrine system located in the left upper abdomen between the stomach and the spine. Pancreatic cancer broadly refers to tumors derived from tissues of the pancreas. Based on the tissues of origin, pancreatic cancer can be generally separated into endocrine tumors and exocrine tumors. Exocrine tissue-derived pancreatic ductal adenocarcinoma (PDAC) possesses the highest morbidity among all types of pancreatic cancer (1,2) and is the third leading cause of cancer death in the United States in 2019, as estimated by the National Cancer Institute (56,770 new cases; 45,750 death) (3). The 5-year survival rate of PDAC is 9.3% from 2009 to 2015 (4) contrasting to 67.1% for cancers in all sites during the same period (3). Based on the degree of progression, PDAC can be staged as localized cancer, cancer with regional invasion, or cancer with distal metastasis (4). Currently there are no biomarkers available for early detection of PDAC. The level of tumor marker carbohydrate antigen 19-9 (CA 19-9) is increased in the blood in 75–85% of PDAC patients, thus often serving as a biomarker for PDAC in clinical practice (5,6). However, circulating CA19-9 is not specific to PDAC, nor it is a good indicator of early stage PDAC (7). When PDAC is diagnosed at a localized stage, surgical resection, such as pancreatico-duodenectomy (Whipple’s procedure), could be an option that offers a potential cure (8,9). However, the treatment of metastatic PDAC mainly stays on symptom control, such as pain management or palliative chemotherapy (10). Therefore, development of early detection biomarkers and new therapeutics for pancreatic cancer is urgently needed. Since the tumor microenvironment is critically involved in PDAC progression (11-13), and exosomes are mediators of intercellular communication in the tumor environment (14,15), recent effort has extended to explore the role of exosomes in the progression and potential management of pancreatic cancer.


Exosomes are a group of extracellular vesicles that function in mediating intercellular communication via transferring biological materials (16). These extracellular vesicles are around 100 nm in diameter, with some variations noted by different reports (15,17,18). In the 1980s, detailed ultrastructural studies showed that vesicles are formed within multivesicular bodies (MVBs) and released to extracellular space when MVBs fused with the cell membrane during the differentiation process of immature red blood cells (19). These extracellular vesicles were coined as exosomes and were later found to be released from Epstein-Barr virus-transformed B lymphocytes and could trigger T-cell responses (20). Even later it was found that exosomes are derived from a variety of cell types, including prokaryotes and eukaryotes (15,16). It seems clear that exosomes are released from all types of cells examined thus far, and are detected in all biological fluids tested (17,18). The most commonly accepted surface markers for exosomes are tetraspanins, such as CD63, CD81 and CD9. In addition, Alix, Flotillin-1, Syntenin-1 and TSG101 are also established indicators of exosomes (16). The International Society for Extracellular Vesicles has recently stipulated the minimum requirement for exosome isolation and verification (21). In 2007, exosomes were reported to transfer genetic materials, such as mRNA and microRNAs (miRNAs) among different cell types (22), indicating a new regulatory pathway in intercellular communication. These observations, along with others, triggered a wave of research effort on cancer exosomal biology over the last decade (23-29).

The first report of PDAC exosomes was released in 2005, in which the human pancreatic cancer cell line Colo357 was used as a model to show that PDAC exosomes with heat shock protein 70 on the surface stimulate NK cells’ migratory and cytolytic activity (30). Emerging evidences since then have demonstrated the involvement of exosomes in the pathogenesis, proliferation, metastasis, and chemoresistance of pancreatic cancer (30-32). For example, Kupffer cells in the liver were shown to specifically uptake pancreatic cancer exosomes, resulting in transforming growth factor β (TGFβ) secretion, which further stimulates fibronectin production by activating hepatic stellate cells to facilitate pancreatic cancer metastasis (33). Among all the components in the exosomal cargos, exosomal miRNAs have been most frequently reported to mediate the metastasis and drug resistance in human cancers, including pancreatic cancer (34-37).

Pancreatic cancer exosomal miRNAs

miRNAs are ~22 nucleotide long small, noncoding RNAs that negatively regulate target mRNA expression by binding to the 3’ untranslated regions (38-41). It is estimated that about 70% of human mRNA transcripts are regulated by miRNAs, suggesting that miRNA regulation of gene expression is involved in almost all cellular processes, including carcinogenesis (41,42). Alterations of miRNA expression in human cancer, including pancreatic cancer, are well described (38,43-45). Pancreatic cancer cells display different miRNA profiles compared to normal pancreatic ductal cells, and circulating miRNAs have been explored to develop new biomarkers for pancreatic cancer (46-51). Expression of nearly 20 miRNAs was detected to be elevated in the circulation of pancreatic cancer patients, and the plasma miRNA signatures are potential biomarkers for detection of pancreatic cancer (52-59). These observations indicate the potential involvement of miRNAs in the pathogenesis and progression of pancreatic cancer. After miRNAs were found to be present in exosomes (22), exosomal miRNAs have been extensively profiled in various cancer model systems (60-65). Nevertheless, the first report about exosomal miRNAs in pancreatic cancer was published in 2013, describing the high expression of serum exosomal miR-17-5p and miR-21 in pancreatic cancer patients (66). Further studies have explored the involvement of exosomal miRNAs in pancreatic cancer progression and drug resistance, and the potential of exosomal miRNAs as biomarkers for pancreatic cancer.

Exosomal miRNAs as circulating biomarkers for pancreatic cancer

Even though many reports have shown the promise of circulating miRNAs as biomarkers for pancreatic cancer, there have been no miRNA-based detection available for clinical diagnosis or screening of the disease. One major challenge in the process of developing miRNAs as biomarkers for pancreatic cancer arises from the heterogeneous nature of the circulating miRNA populations. The miRNAs isolated from the circulation are presented in different forms, including protein bound or exosome associated miRNAs, and are derived from various cell types (15,67). This heterogeneity compromises the sensitivity and specificity of circulating miRNAs for detection of pancreatic cancer. Selective isolation or detection of circulating miRNAs released from pancreatic cancer cells is a critical step in the development of miRNAs as biomarkers for this malignance. One potential strategy to achieve this is to analyze circulating exosomal miRNAs, which are likely enriched in cancer-derived miRNAs, since the transfer of exosomes from primary tumors to the circulation has been demonstrated in various model systems (68,69).

In this context, multiple exosomal miRNAs have been reported as potential biomarkers for pancreatic cancer. Higher expression of serum exosomal miR-17-5p and miR-21 was first observed in patients with pancreatic cancer as compared to patients with benign pancreatic diseases and healthy controls (66). Expression of a group of serum exosomal miRNAs, including miR-1246, miR-4644, miR-3976 and miR-4306, was found to be significantly upregulated in patients with pancreatic cancer when compared to patients with benign pancreatic disorders (70). An exosomal miRNA signature with high expression of miR-10b, miR-21, miR-30c, and miR-181a and low expression of miR-let7a is a better indicator of pancreatic cancer than the exosomal glypican-1 levels (71). The level of exosomal miR-191, miR-21, and miR-451a was significantly elevated in patients with pancreatic cancer and intraductal papillary mucinous neoplasm as compared to benign controls (72). Plasma exosomal miR-451a was shown by miRNA microarray to be a minimally invasive biomarker for the prediction of recurrence and prognosis of pancreatic cancer (73). Along with others, we have recently demonstrated that miR-196a and miR-1246 are highly enriched in pancreatic cancer exosomes, and that plasma exosomal miR-1246 and miR-196a levels are significantly elevated in patients with localized pancreatic cancer (63,64). In addition to the expression of miRNAs in plasma exosomes, the exosomal miRNAs in pancreatic juice were also examined in order to develop novel biomarkers for pancreatic cancer. In this study, exosomal miR-21 and miR-155 in pancreatic juice were shown as promising biomarkers for pancreatic cancer (74). Interestingly, miR-1246 and miR-4644 in salivary exosomes were also reported to be potential indicators of pancreatobiliary tract cancer (75). Furthermore, miR-4525, miR-451a, and miR-21 in portal vein blood were found to be potential biomarkers to evaluate the risk for recurrence and poor survival in patients with resected pancreatic cancer (76).

Overall, studies have shown the promise of exosomal miRNA signatures as biomarkers for detection and prognosis of pancreatic cancer. However, there has been no consensus as to which exosomal miRNA signatures are the best indicators of pancreatic cancer, and the results often vary among different studies, raising concerns of their reproducibility. Although this is likely in part due to different methods/models used for exosome isolation or various assays applied for miRNA analysis among the reports, the heterogeneous exosome populations (15) present in the circulation may contribute to the variability. Therefore, new strategies need to be explored to selectively analyze pancreatic cancer exosomal miRNA signatures in order to establish reproducible and clinically applicable circulating exosomal miRNA signatures for pancreatic cancer.

Exosomal miRNAs in pancreatic cancer progression

Intercellular communication via exosomal miRNAs is a significant signaling event in the tumor microenvironment (15,77-79). Studies have shown that exosomal miRNA signaling contributes to tumor progression in various cancer model systems (80,81). It has been reported that miRNAs contained in exosomes are transferred to recipient cells in the tumor microenvironment or distant organs where they can regulate target gene expression to promote tumor angiogenesis, immune responses, and metastasis (77,78,82). In the context of cancer exosomal miRNA profiles, studies have demonstrated that certain miRNA species are selectively enriched in cancer exosomes compared to exosomes released by normal epithelial cells, which may contribute to cancer progression (62,64,77,83). As for pancreatic cancer, a crosstalk among pancreatic stellate cells, cancer-associated fibroblasts, and pancreatic cancer cells was found to upregulate miR-21 and miR-221 expression, which may confer aggressiveness to pancreatic cancer (84). This crosstalk among different cell types is likely attributed to exosomal miRNA transfer. In a separate study, miR-23b-3p was found to be highly enriched in pancreatic cancer cell-derived exosomes, and overexpression of miR-23b-3p enhanced proliferation, migration, and invasion of pancreatic cancer cells (85). The differential expression of exosomal miR-339-5p was also found to be involved in the invasion and migration of pancreatic cancer cells (86). Interestingly, pancreatic cancer exosomes could increase invasion and proliferation of neighboring tumor cells through transferring miR-222 (87). Hypoxic tumor cell-originated exosomal miR-301a was found to mediate M2 macrophage polarization through PTEN/PI3Kγ to assist pancreatic cancer metastasis (37). On the other hand, M2 macrophage-released exosomal miR-501-3p suppressed tumor suppressor TGFBR3 gene expression, and helped promote pancreatic cancer development by activating the TGF-β signaling pathway (88). miR-126-3p derived from bone marrow mesenchymal stem cell (BMSC) exosomes was reported to suppress pancreatic cancer development via the downregulation of ADAM9 (89). Likewise, exosomal miRNA-1231 derived from BMSCs was found to suppress the activity of pancreatic cancer (90). Furthermore, exosomes derived from human umbilical cord mesenchymal stromal cells were reported to transfer exogenous miR-145-5p to suppress pancreatic cancer progression (91). Additionally, studies have shown that exosomal miRNAs may mediate immunosuppression in pancreatic cancer. For instance, exosomes derived from pancreatic cancer cells could be delivered to dendritic cells and suppress expression of the regulatory factor X-associated protein by transferring miR-212-3p, resulting in decreased MHC II expression (92,93).

While progress has been made in our understanding of the involvement of exosomal miRNAs in pancreatic cancer proliferation, invasion, and metastasis, questions remain as to how exosomal miRNAs are transferred from cancer cells to stromal cells and vice versa, and how they act to regulate target gene expression in recipient cells to promote pancreatic cancer progression. More studies are obviously required to better define the role of exosomal miRNAs in pancreatic cancer progression.

Exosomal miRNAs in chemoresistance of pancreatic cancer

Recent studies have shown that exosomal miRNAs are involved in mediating chemoresistance of pancreatic cancer. When treated with gemcitabine, a commonly used chemo drug for pancreatic cancer treatment, cancer-associated fibroblasts released more of the transcription factor Snail, as well as miR-146a, via exosome secretion. These exosomes were transported to surrounding pancreatic cancer cells and caused gemcitabine resistance of the recipient cells (94). Evidence showed that gemcitabine treatment of pancreatic cancer cells causes high expression of miR-155 in cancer cell-derived exosomes, which is transferred to neighboring cancer cells and causes gemcitabine resistance in vitro and in vivo (34). In line with this study, a recent report demonstrated that pancreatic cancer exosomes confer gemcitabine resistance in part via exosomal miR-155-mediated suppression of a key gemcitabine metabolizing gene (DCK) in recipient cancer cells. In this case, functional suppression of miR-155 or overexpression of DCK could lead to a decrease in exosomal miR-155-mediated chemoresistance (35). Another study showed that cancer-associated fibroblasts release exosomal miR-106b, which plays a significant role in inducing gemcitabine resistance of pancreatic cancer cells by targeting TP53INP1 (95). This finding suggests a new molecular target for sensitizing pancreatic cancer cells to gemcitabine. It has also been demonstrated that exosomes released by gemcitabine- resistant pancreatic cancer stem cells mediate the horizontal transfer of drug-resistant capabilities to gemcitabine-sensitive pancreatic cancer cells via transporting miR-210 (96), adding new information to our understanding of the exosomal miRNA-mediated gemcitabine resistance of pancreatic cancer. However our knowledge in exosomal miRNA-mediated chemoresistance is still quite limited, which encourages more studies on this specific research topic, given the clinical significance of overcoming chemoresistance for pancreatic cancer patients.


Pancreatic cancer is a deadly disease primarily attributed to diagnoses at late stages and the aggressive nature of the malignance. Better understanding of the biology of pancreatic cancer is critical for the development of new diagnostic and therapeutic strategies. Recent advancement in exosomal biology has demonstrated the involvement of exosomal miRNA signaling in pancreatic cancer proliferation, invasion, metastasis, and chemoresistance, thus revealing new potential therapeutic opportunities. Circulating exosomal miRNA signatures have been frequently described as potential non-invasive biomarkers for the detection and prognosis of pancreatic cancer. These promising research findings support further studies to explore strategies targeting exosomal miRNA signaling for pancreatic cancer therapy and establish exosomal miRNA signatures for early detection and monitoring of pancreatic cancer.


Funding: National Institutes of Health (P20GM103640), National Cancer Institute (CA235208-01), Presbyterian Health Foundation, Peggy and Charles Stephenson Cancer Center.


Conflicts of Interest: The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.


  1. Cancer Net. Pancreatic Cancer: Introduction. Available online: cancer/introduction
  2. The Hirshberg Foundation for Pancreatic Cancer Research: The Pancreas. Available online: http://pancreatic. org/pancreatic-cancer/about-the-pancreas/the-pancreas/
  3. NCI. Cancer Stat Facts. Available online: 2019.
  4. NCI. Pancreatic CancerStat Facts. 2019.
  5. Ballehaninna UK, Chamberlain RS. The clinical utility of serum CA 19-9 in the diagnosis, prognosis and management of pancreatic adenocarcinoma: An evidence based appraisal. J Gastrointest Oncol 2012;3:105-19. [PubMed]
  6. Medscape: Pancreatic Cancer. Available online:
  7. Winter JM, Yeo CJ, Brody JR. Diagnostic, prognostic, and predictive biomarkers in pancreatic cancer. J Surg Oncol 2013;107:15-22. [Crossref] [PubMed]
  8. McGuigan A, Kelly P, Turkington RC, et al. Pancreatic cancer: A review of clinical diagnosis, epidemiology, treatment and outcomes. World J Gastroenterol 2018;24:4846-61. [Crossref] [PubMed]
  9. Neoptolemos JP, Kleeff J, Michl P, et al. Therapeutic developments in pancreatic cancer: current and future perspectives. Nat Rev Gastroenterol Hepatol 2018;15:333-48. [Crossref] [PubMed]
  10. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817-25. [Crossref] [PubMed]
  11. Juiz NA, Iovanna J, Dusetti N. Pancreatic Cancer Heterogeneity Can Be Explained Beyond the Genome. Front Oncol 2019;9:246. [Crossref] [PubMed]
  12. Seifert L, Werba G, Tiwari S, et al. The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression. Nature 2016;532:245-9. [Crossref] [PubMed]
  13. Li C, Cui L, Yang L, et al. Pancreatic Stellate Cells Promote Tumor Progression by Promoting an Immunosuppressive Microenvironment in Murine Models of Pancreatic Cancer. Pancreas 2020;49:120-7. [Crossref] [PubMed]
  14. Wu Q, Zhou L, Lv D, et al. Exosome-mediated communication in the tumor microenvironment contributes to hepatocellular carcinoma development and progression. J Hematol Oncol 2019;12:53. [Crossref] [PubMed]
  15. Hannafon BN, Ding WQ. Intercellular Communication by Exosome-Derived microRNAs in Cancer. Int J Mol Sci 2013;14:14240-69. [Crossref] [PubMed]
  16. Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol 2013;200:373-83. [Crossref] [PubMed]
  17. Kowal J, Tkach M, Thery C. Biogenesis and secretion of exosomes. Curr Opin Cell Biol 2014;29:116-25. [Crossref] [PubMed]
  18. EL Andaloussi S, Mager I, Breakefield XO, et al. Extracellular vesicles: biology and emerging therapeutic opportunities. Nat Rev Drug Discov 2013;12:347-57. [Crossref] [PubMed]
  19. Pan BT, Teng K, Wu C, et al. Electron microscopic evidence for externalization of the transferrin receptor in vesicular form in sheep reticulocytes. J Cell Biol 1985;101:942-8. [Crossref] [PubMed]
  20. Raposo G, Nijman HW, Stoorvogel W, et al. B lymphocytes secrete antigen-presenting vesicles. J Exp Med 1996;183:1161-72. [Crossref] [PubMed]
  21. Théry C, Witwer KW, Aikawa E, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles 2018;7:1535750. [Crossref] [PubMed]
  22. Valadi H, Ekstrom K, Bossios A, et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 2007;9:654-9. [Crossref] [PubMed]
  23. Skog J, Wurdinger T, van Rijn S, et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 2008;10:1470-6. [Crossref] [PubMed]
  24. Peinado H, Aleckovic M, Lavotshkin S, et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 2012;18:883-91. [Crossref] [PubMed]
  25. Melo SA, Luecke LB, Kahlert C, et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature 2015;523:177-82. [Crossref] [PubMed]
  26. Chen G, Huang AC, Zhang W, et al. Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature 2018;560:382-6. [Crossref] [PubMed]
  27. Ostrowski M, Carmo NB, Krumeich S, et al. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol 2010;12:19-30; sup pp 1-13.
  28. Kim MS, Haney MJ, Zhao Y, et al. Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells. Nanomedicine 2016;12:655-64. [Crossref] [PubMed]
  29. Wang T, Gilkes DM, Takano N, et al. Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis. Proc Natl Acad Sci U S A 2014;111:E3234-42. [Crossref] [PubMed]
  30. Gastpar R, Gehrmann M, Bausero MA, et al. Heat shock protein 70 surface-positive tumor exosomes stimulate migratory and cytolytic activity of natural killer cells. Cancer Res 2005;65:5238-47. [Crossref] [PubMed]
  31. Yan Y, Fu G, Ming L. Role of exosomes in pancreatic cancer. Oncol Lett 2018;15:7479-88. [PubMed]
  32. Lan B, Zeng S, Grutzmann R, et al. The Role of Exosomes in Pancreatic Cancer. Int J Mol Sci 2019. [Crossref] [PubMed]
  33. Costa-Silva B, Aiello NM, Ocean AJ, et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat Cell Biol 2015;17:816-26. [Crossref] [PubMed]
  34. Mikamori M, Yamada D, Eguchi H, et al. MicroRNA-155 Controls Exosome Synthesis and Promotes Gemcitabine Resistance in Pancreatic Ductal Adenocarcinoma. Sci Rep 2017;7:42339. [Crossref] [PubMed]
  35. Patel GK, Khan MA, Bhardwaj A, et al. Exosomes confer chemoresistance to pancreatic cancer cells by promoting ROS detoxification and miR-155-mediated suppression of key gemcitabine-metabolising enzyme, DCK. Br J Cancer 2017;116:609-19. [Crossref] [PubMed]
  36. Fong MY, Zhou W, Liu L, et al. Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis. Nat Cell Biol 2015;17:183-94. [Crossref] [PubMed]
  37. Wang X, Luo G, Zhang K, et al. Hypoxic Tumor-Derived Exosomal miR-301a Mediates M2 Macrophage Polarization via PTEN/PI3Kgamma to Promote Pancreatic Cancer Metastasis. Cancer Res 2018;78:4586-98. [Crossref] [PubMed]
  38. Lin S, Gregory RI. MicroRNA biogenesis pathways in cancer. Nat Rev Cancer 2015;15:321-33. [Crossref] [PubMed]
  39. Jonas S, Izaurralde E. Towards a molecular understanding of microRNA-mediated gene silencing. Nat Rev Genet 2015;16:421-33. [Crossref] [PubMed]
  40. Ha M, Kim VN. Regulation of microRNA biogenesis. Nat Rev Mol Cell Biol 2014;15:509-24. [Crossref] [PubMed]
  41. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell 2009;136:215-33. [Crossref] [PubMed]
  42. Chiang HR, Schoenfeld LW, Ruby JG, et al. Mammalian microRNAs: experimental evaluation of novel and previously annotated genes. Genes Dev 2010;24:992-1009. [Crossref] [PubMed]
  43. Sin TK, Wang F, Meng F, et al. Implications of MicroRNAs in the Treatment of Gefitinib- Resistant Non-Small Cell Lung Cancer. Int J Mol Sci 2016;17:237. [Crossref] [PubMed]
  44. Ohtsuka M, Ling H, Doki Y, et al. MicroRNA Processing and Human Cancer. J Clin Med 2015;4:1651-67. [Crossref] [PubMed]
  45. Hannafon BN, Ding WQ. miRNAs as Biomarkers for Predicting the Progression of Ductal Carcinoma in Situ. Am J Pathol 2018;188:542-9. [Crossref] [PubMed]
  46. Frampton AE, Krell J, Jamieson NB, et al. microRNAs with prognostic significance in pancreatic ductal adenocarcinoma: A meta-analysis. Eur J Cancer 2015;51:1389-404. [Crossref] [PubMed]
  47. Hernandez YG, Lucas AL. MicroRNA in pancreatic ductal adenocarcinoma and its precursor lesions. World J Gastrointest Oncol 2016;8:18-29. [Crossref] [PubMed]
  48. Sun L, Chua CY, Tian W, et al. MicroRNA Signaling Pathway Network in Pancreatic Ductal Adenocarcinoma. J Genet Genomics 2015;42:563-77. [Crossref] [PubMed]
  49. Li H, Xiang H, Ge W, et al. Expression and functional perspectives of miR-184 in pancreatic ductal adenocarcinoma. Int J Clin Exp Pathol 2015;8:12313-8. [PubMed]
  50. Le Large TY, Meijer LL, Mato Prado M, et al. Circulating microRNAs as diagnostic biomarkers for pancreatic cancer. Expert Rev Mol Diagn 2015;15:1525-9. [Crossref] [PubMed]
  51. Permuth-Wey J, Chen DT, Fulp WJ, et al. Plasma MicroRNAs as Novel Biomarkers for Patients with Intraductal Papillary Mucinous Neoplasms of the Pancreas. Cancer Prev Res (Phila) 2015;8:826-34. [Crossref] [PubMed]
  52. Cote GA, Gore AJ, McElyea SD, et al. A pilot study to develop a diagnostic test for pancreatic ductal adenocarcinoma based on differential expression of select miRNA in plasma and bile. Am J Gastroenterol 2014;109:1942-52. [Crossref] [PubMed]
  53. Liu R, Chen X, Du Y, et al. Serum microRNA expression profile as a biomarker in the diagnosis and prognosis of pancreatic cancer. Clin Chem 2012;58:610-8. [Crossref] [PubMed]
  54. Komatsu S, Ichikawa D, Takeshita H, et al. Circulating miR-18a: a sensitive cancer screening biomarker in human cancer. In Vivo 2014;28:293-7. [PubMed]
  55. Morimura R, Komatsu S, Ichikawa D, et al. Novel diagnostic value of circulating miR-18a in plasma of patients with pancreatic cancer. Br J Cancer 2011;105:1733-40. [Crossref] [PubMed]
  56. Liffers ST, Munding JB, Vogt M, et al. MicroRNA-148a is down-regulated in human pancreatic ductal adenocarcinomas and regulates cell survival by targeting CDC25B. Lab Invest 2011;91:1472-9. [Crossref] [PubMed]
  57. Munding JB, Adai AT, Maghnouj A, et al. Global microRNA expression profiling of microdissected tissues identifies miR-135b as a novel biomarker for pancreatic ductal adenocarcinoma. Int J Cancer 2012;131:E86-95. [Crossref] [PubMed]
  58. Zhang J, Zhao CY, Zhang SH, et al. Upregulation of miR-194 contributes to tumor growth and progression in pancreatic ductal adenocarcinoma. Oncol Rep 2014;31:1157-64. [Crossref] [PubMed]
  59. Zhao C, Zhang J, Zhang S, et al. Diagnostic and biological significance of microRNA-192 in pancreatic ductal adenocarcinoma. Oncol Rep 2013;30:276-84. [Crossref] [PubMed]
  60. Barceló M, Castells M, Bassas L, et al. Semen miRNAs Contained in Exosomes as Non-Invasive Biomarkers for Prostate Cancer Diagnosis. Sci Rep 2019;9:13772. [Crossref] [PubMed]
  61. Zhang X, Sai B, Wang F, et al. Hypoxic BMSC-derived exosomal miRNAs promote metastasis of lung cancer cells via STAT3-induced EMT. Mol Cancer 2019;18:40. [Crossref] [PubMed]
  62. Hannafon BN, Trigoso YD, Calloway CL, et al. Plasma exosome microRNAs are indicative of breast cancer. Breast Cancer Res 2016;18:90. [Crossref] [PubMed]
  63. Xu YF, Hannafon BN, Khatri U, et al. The origin of exosomal miR-1246 in human cancer cells. RNA Biol 2019;16:770-84. [Crossref] [PubMed]
  64. Xu YF, Hannafon BN, Zhao YD, et al. Plasma exosome miR-196a and miR-1246 are potential indicators of localized pancreatic cancer. Oncotarget 2017;8:77028-40. [PubMed]
  65. Zhang ZY, Li YC, Geng CY, et al. Serum exosomal microRNAs as novel biomarkers for multiple myeloma. Hematol Oncol 2019;37:409-17. [Crossref] [PubMed]
  66. Que R, Ding G, Chen J, et al. Analysis of serum exosomal microRNAs and clinicopathologic features of patients with pancreatic adenocarcinoma. World J Surg Oncol 2013;11:219. [Crossref] [PubMed]
  67. Arroyo JD, Chevillet JR, Kroh EM, et al. Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc Natl Acad Sci U S A 2011;108:5003-8. [Crossref] [PubMed]
  68. Suetsugu A, Honma K, Saji S, et al. Imaging exosome transfer from breast cancer cells to stroma at metastatic sites in orthotopic nude-mouse models. Adv Drug Deliv Rev 2013;65:383-90. [Crossref] [PubMed]
  69. Taylor DD, Gercel-Taylor C. MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol 2008;110:13-21. [Crossref] [PubMed]
  70. Madhavan B, Yue S, Galli U, et al. Combined evaluation of a panel of protein and miRNA serum-exosome biomarkers for pancreatic cancer diagnosis increases sensitivity and specificity. Int J Cancer 2015;136:2616-27. [Crossref] [PubMed]
  71. Lai X, Wang M, McElyea SD, et al. A microRNA signature in circulating exosomes is superior to exosomal glypican-1 levels for diagnosing pancreatic cancer. Cancer Lett 2017;393:86-93. [Crossref] [PubMed]
  72. Goto T, Fujiya M, Konishi H, et al. An elevated expression of serum exosomal microRNA-191, 21, -451a of pancreatic neoplasm is considered to be efficient diagnostic marker. BMC Cancer 2018;18:116. [Crossref] [PubMed]
  73. Takahasi K, Iinuma H, Wada K, et al. Usefulness of exosome-encapsulated microRNA-451a as a minimally invasive biomarker for prediction of recurrence and prognosis in pancreatic ductal adenocarcinoma. J Hepatobiliary Pancreat Sci 2018;25:155-61. [Crossref] [PubMed]
  74. Nakamura S, Sadakari Y, Ohtsuka T, et al. Pancreatic Juice Exosomal MicroRNAs as Biomarkers for Detection of Pancreatic Ductal Adenocarcinoma. Ann Surg Oncol 2019;26:2104-11. [Crossref] [PubMed]
  75. Machida T, Tomofuji T, Maruyama T, et al. miR1246 and miR4644 in salivary exosome as potential biomarkers for pancreatobiliary tract cancer. Oncol Rep 2016;36:2375-81. [Crossref] [PubMed]
  76. Kawamura S, Iinuma H, Wada K, et al. Exosome-encapsulated microRNA-4525, microRNA- 451a and microRNA-21 in portal vein blood is a high-sensitive liquid biomarker for the selection of high-risk pancreatic ductal adenocarcinoma patients. J Hepatobiliary Pancreat Sci 2019;26:63-72. [Crossref] [PubMed]
  77. Hannafon BN, Carpenter KJ, Berry WL, et al. Exosome-mediated microRNA signaling from breast cancer cells is altered by the anti-angiogenesis agent docosahexaenoic acid (DHA). Mol Cancer 2015;14:133. [Crossref] [PubMed]
  78. Tkach M, Thery C. Communication by Extracellular Vesicles: Where We Are and Where We Need to Go. Cell 2016;164:1226-32. [Crossref] [PubMed]
  79. Su MJ, Aldawsari H, Amiji M. Pancreatic Cancer Cell Exosome-Mediated Macrophage Reprogramming and the Role of MicroRNAs 155 and 125b2 Transfection using Nanoparticle Delivery Systems. Sci Rep 2016;6:30110. [Crossref] [PubMed]
  80. Thind A, Wilson C. Exosomal miRNAs as cancer biomarkers and therapeutic targets. J Extracell Vesicles 2016;5:31292. [Crossref] [PubMed]
  81. Pitt JM, Kroemer G, Zitvogel L. Extracellular vesicles: masters of intercellular communication and potential clinical interventions. J Clin Invest 2016;126:1139-43. [Crossref] [PubMed]
  82. Mirzaei H, Sahebkar A, Jaafari MR, et al. Diagnostic and Therapeutic Potential of Exosomes in Cancer: The Beginning of a New Tale? J Cell Physiol 2017;232:3251-60. [Crossref] [PubMed]
  83. Pigati L, Yaddanapudi SC, Iyengar R, et al. Selective release of microRNA species from normal and malignant mammary epithelial cells. PLoS One 2010;5:e13515. [Crossref] [PubMed]
  84. Ali S, Suresh R, Banerjee S, et al. Contribution of microRNAs in understanding the pancreatic tumor microenvironment involving cancer associated stellate and fibroblast cells. Am J Cancer Res 2015;5:1251-64. [PubMed]
  85. Chen D, Wu X, Xia M, et al. Upregulated exosomic miR23b3p plays regulatory roles in the progression of pancreatic cancer. Oncol Rep 2017;38:2182-8. [Crossref] [PubMed]
  86. Yu Z, Zhao S, Wang L, et al. miRNA-339-5p Plays an Important Role in Invasion and Migration of Pancreatic Cancer Cells. Med Sci Monit 2019;25:7509-17. [Crossref] [PubMed]
  87. Li Z, Tao Y, Wang X, et al. Tumor-Secreted Exosomal miR-222 Promotes Tumor Progression via Regulating P27 Expression and Re-Localization in Pancreatic Cancer. Cell Physiol Biochem 2018;51:610-29. [Crossref] [PubMed]
  88. Yin Z, Ma T, Huang B, et al. Macrophage-derived exosomal microRNA-501-3p promotes progression of pancreatic ductal adenocarcinoma through the TGFBR3-mediated TGF-beta signaling pathway. J Exp Clin Cancer Res 2019;38:310. [Crossref] [PubMed]
  89. Wu DM, Wen X, Han XR, et al. Bone Marrow Mesenchymal Stem Cell-Derived Exosomal MicroRNA-126-3p Inhibits Pancreatic Cancer Development by Targeting ADAM9. Mol Ther Nucleic Acids 2019;16:229-45. [Crossref] [PubMed]
  90. Shang S, Wang J, Chen S, et al. Exosomal miRNA-1231 derived from bone marrow mesenchymal stem cells inhibits the activity of pancreatic cancer. Cancer Med 2019;8:7728-40. [Crossref] [PubMed]
  91. Ding Y, Cao F, Sun H, et al. Exosomes derived from human umbilical cord mesenchymal stromal cells deliver exogenous miR-145-5p to inhibit pancreatic ductal adenocarcinoma progression. Cancer Lett 2019;442:351-61. [Crossref] [PubMed]
  92. Ding G, Zhou L, Qian Y, et al. Pancreatic cancer-derived exosomes transfer miRNAs to dendritic cells and inhibit RFXAP expression via miR-212-3p. Oncotarget 2015;6:29877-88. [Crossref] [PubMed]
  93. Batista IA, Melo SA. Exosomes and the Future of Immunotherapy in Pancreatic Cancer. Int J Mol Sci 2019. [Crossref] [PubMed]
  94. Richards KE, Zeleniak AE, Fishel ML, et al. Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells. Oncogene 2017;36:1770-8. [Crossref] [PubMed]
  95. Fang Y, Zhou W, Rong Y, et al. Exosomal miRNA-106b from cancer-associated fibroblast promotes gemcitabine resistance in pancreatic cancer. Exp Cell Res 2019;383:111543. [Crossref] [PubMed]
  96. Yang Z, Zhao N, Cui J, et al. Exosomes derived from cancer stem cells of gemcitabine-resistant pancreatic cancer cells enhance drug resistance by delivering miR-210. Cell Oncol (Dordr) 2020;43:123-36. [Crossref] [PubMed]
doi: 10.21037/sci.2020.02.01
Cite this article as: Xu Y, Xu X, Williams A, Ding W. The role of exosomal microRNAs in pancreatic cancer. Stem Cell Investig 2020;7:3.

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