Sharon Pan

Introduction. Pancreatic adenocarcinoma (PDAC) is globally the 11^th most common cancer, but is among the most lethal.^1,2 Arising from pancreas exocrine tissue responsible for production and secretion of digestive enzymes, PDAC has a 6-month median survival and 8% 5-year survival.^3,4 Barriers to early detection due to non-specific presenting clinical features and therapeutic challenges, including the tumor chemo-resistance and aggressive metastasis, make this disease difficult to treat.^1,5 Growing interest in the role of extracellular vesicles, called exosomes, in cancer pathobiology has recently been applied to studying PDAC.⁶ Studies have shown that exosomes secreted by tumor cells such as cancer-associated macrophages, cancer-associated fibroblasts (CAF), and cancer cells, seem to be means of intercellular communication that facilitate the tumor pathogenesis. Methods. dsDNA barcode fragments were transfected into macrophages that were injected into mice with PDAC tumors.⁷ Barcode fragment signaling strength was measured in normal pancreas tissue, tumor site, liver metastasis, normal liver tissue, spleen and lung.⁷ Mouse models were implanted with defective exosome machinery and treated with first-line chemotherapeutic gemcitabine, and compared with mice with intact exosomes receiving same treatment.⁷ PDAC cell lines were treated with and without exosomes isolated from CAF media to compare cell proliferation.⁶ Transwell assay was performed on coculture of PDAC with exosomes isolated from PANC-1 and MIA PaCa-2 PDAC cell lines, then compared to untreated normal pancreatic tissue and untreated PDAC to assess pancreatic stellate cell (PSC) recruitment.⁸ PDAC cell lines were injected into mice then subsequently treated with exosomes isolated from M2 macrophages, and tumor size was compared to mice with injected PDAC and non-exosome treatment.⁹ Results. Injected dsDNA barcode fragment signaling was strongest at tumor site and liver metastasis, suggesting selective transfer of exosomes to cancer-associated tissue sites.⁷ Mice with intact exosomes exhibited chemo-resistance while mice with defective exosomes demonstrated chemo-sensitivity.⁷ PDAC cell lines with exosomes in CAF media showed increased proliferation while cell lines without exosomes showed decreased PDAC survival.⁶ Coculture of PDAC with exosomes demonstrated increased PSC recruitment.⁸ PDAC injected mice with exosome treatment had greater tumor volume compared to PDAC injected mice with the non-exosomes treatment.⁹  Conclusions. Exosomes secreted by PDAC tumor environment cells such as macrophages, CAFs and the cancer cells communicate locally and distally in the body to support cancer aggression and development. Studies have shown delivery of exosome contents to recipient cells enhance tumor growth, chemoresistance and tumor survival. Further research is indicated to explore targeting exosomes for PDAC therapy.

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