Crosstalk between Pancreatic Cancer Cells and Cancer-Associated Fibroblasts in the Tumor Microenvironment Mediated by Exosomal MicroRNAs

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant digestive tumors, characterized by a low rate of early diagnosis, strong invasiveness, and early metastasis. The abundant stromal cells, dense extracellular matrix, and lack of blood supply in PDAC limit the penetration of chemotherapeutic drugs, resulting in poor efficacy of the current treatment regimens. Cancer-associated fibroblasts (CAFs) are the major stromal cells in the tumor microenvironment. Tumor cells can secrete exosomes to promote the generation of activated CAFs, meanwhile exosomes secreted by CAFs help promote tumor progression. The aberrant expression of miRNAs in exosomes is involved in the interaction between tumor cells and CAFs, which provides the possibility for the application of exosomal miRNAs in the diagnosis and treatment of PDAC. The current article reviews the mechanism of exosomal miRNAs in the crosstalk between PDAC cells and CAFs in the tumor microenvironment, in order to improve the understanding of TME regulation and provide evidence for designing diagnostic and therapeutic targets against exosome miRNA in human PDAC.

Stem Cell-Derived Extracellular Vesicles for Cancer Therapy and Tissue Engineering Applications

“…One study of patients with pancreatic cancer has found these EVs carry specific miRNAs that could serve as biomarkers for early detection of the disease. 83 Another study has shown that AD-MSC-secreted EVs could transfer functional mitochondria to recipient cells, which could potentially be used to rescue damaged cells or tissues. 84 Raza et al investigated the influence of AD-MSC-derived EV-regulated ovarian cancer cells by studying A2780 and SKOV-3 cells and found that AD-MSC-derived EVs can inhibit A2780 and SKOV-3 cell growth and proliferation that could be related to cancer progression.…”

“…EVs derived from AD-MSCs have also been shown to play a role in intercellular communication with potential as biomarkers for disease diagnosis and prognosis. One study of patients with pancreatic cancer has found these EVs carry specific miRNAs that could serve as biomarkers for early detection of the disease . Another study has shown that AD-MSC-secreted EVs could transfer functional mitochondria to recipient cells, which could potentially be used to rescue damaged cells or tissues …”

Cancer‐associated fibroblasts promote stemness maintenance and gemcitabine resistance via HIF‐1α/miR‐21 axis under hypoxic conditions in pancreatic cancer

“…In addition, microRNAs (miRNAs) are recognized as small endogenous noncoding RNAs that have something to do with the progression of disease 9 . Exosomal miRNAs mediates crosstalk between PC cells and CAFs in TME 10 . Especially, miR‐21, an oncogenic factor, is involved in the regulation of pancreatic ductal carcinoma cell stemness 11 .…”

“…9 Exosomal miRNAs mediates crosstalk between PC cells and CAFs in TME. 10 Especially, miR-21, an oncogenic factor, is involved in the regulation of pancreatic ductal carcinoma cell stemness. 11 It has been documented that miR-21 expression and activated CAFs are increased in patients with GEM-resistant pancreatic ductal carcinoma.…”

Expression of Selected miRNAs in Normal and Cancer-Associated Fibroblasts and in BxPc3 and MIA PaCa-2 Cell Lines of Pancreatic Ductal Adenocarcinoma

“…The stroma is biologically highly active and significantly influences tumor growth, metastatic spread, and resistance to therapy [ 4 ]. Therefore, it is likely that CAFs influence the biology of PDAC through several mechanisms [ 5 , 6 , 7 ]. Primarily, CAFs influence malignant cells across a plethora of tumor types [ 8 ], including PDAC, by their paracrine production.…”